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1.  Preoperative/Neoadjuvant Therapy in Pancreatic Cancer: A Systematic Review and Meta-analysis of Response and Resection Percentages 
PLoS Medicine  2010;7(4):e1000267.
Jörg Kleef and colleagues systematically reviewed studies on neoadjuvant therapy and tumor response, toxicity, resection, and survival percentages in pancreatic cancer and suggest that patients with locally nonresectable tumors should be included in neoadjuvant protocols.
Background
Pancreatic cancer has an extremely poor prognosis and prolonged survival is achieved only by resection with macroscopic tumor clearance. There is a strong rationale for a neoadjuvant approach, since a relevant percentage of pancreatic cancer patients present with non-metastatic but locally advanced disease and microscopic incomplete resections are common. The objective of the present analysis was to systematically review studies concerning the effects of neoadjuvant therapy on tumor response, toxicity, resection, and survival percentages in pancreatic cancer.
Methods and Findings
Trials were identified by searching MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from 1966 to December 2009 as well as through reference lists of articles and proceedings of major meetings. Retrospective and prospective studies analyzing neoadjuvant radiochemotherapy, radiotherapy, or chemotherapy of pancreatic cancer patients, followed by re-staging, and surgical exploration/resection were included. Two reviewers independently extracted data and assessed study quality. Pooled relative risks and 95% confidence intervals were calculated using random-effects models. Primary outcome measures were proportions of tumor response categories and percentages of exploration and resection. A total of 111 studies (n = 4,394) including 56 phase I–II trials were analyzed. A median of 31 (interquartile range [IQR] 19–46) patients per study were included. Studies were subdivided into surveys considering initially resectable tumors (group 1) and initially non-resectable (borderline resectable/unresectable) tumors (group 2). Neoadjuvant chemotherapy was given in 96.4% of the studies with the main agents gemcitabine, 5-FU (and oral analogues), mitomycin C, and platinum compounds. Neoadjuvant radiotherapy was applied in 93.7% of the studies with doses ranging from 24 to 63 Gy. Averaged complete/partial response probabilities were 3.6% (95% CI 2%–5.5%)/30.6% (95% CI 20.7%–41.4%) and 4.8% (95% CI 3.5%–6.4%)/30.2% (95% CI 24.5%–36.3%) for groups 1 and 2, respectively; whereas progressive disease fraction was estimated to 20.9% (95% CI 16.9%–25.3%) and 20.8% (95% CI 14.5%–27.8%). In group 1, resectability was estimated to 73.6% (95% CI 65.9%–80.6%) compared to 33.2% (95% CI 25.8%–41.1%) in group 2. Higher resection-associated morbidity and mortality rates were observed in group 2 versus group 1 (26.7%, 95% CI 20.7%–33.3% versus 39.1%, 95% CI 29.5%–49.1%; and 3.9%, 95% CI 2.2%–6% versus 7.1%, 95% CI 5.1%–9.5%). Combination chemotherapies resulted in higher estimated response and resection probabilities for patients with initially non-resectable tumors (“non-resectable tumor patients”) compared to monotherapy. Estimated median survival following resection was 23.3 (range 12–54) mo for group 1 and 20.5 (range 9–62) mo for group 2 patients.
Conclusions
In patients with initially resectable tumors (“resectable tumor patients”), resection frequencies and survival after neoadjuvant therapy are similar to those of patients with primarily resected tumors and adjuvant therapy. Approximately one-third of initially staged non-resectable tumor patients would be expected to have resectable tumors following neoadjuvant therapy, with comparable survival as initially resectable tumor patients. Thus, patients with locally non-resectable tumors should be included in neoadjuvant protocols and subsequently re-evaluated for resection.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pancreatic cancer is the fourth leading cause of cancer-related deaths worldwide. It begins when a cell in the pancreas (an organ lying behind the stomach that produces digestive enzymes and hormones such as insulin that controls blood sugar levels) acquires genetic changes that allow it to grow uncontrollably and, sometimes, to spread around the body (metastasize). Because pancreatic cancer rarely causes any symptoms early in its development, it is locally advanced in more than a third of patients and has already metastasized in another half of patients by the time it is diagnosed. Consequently, on average, people die within 5–8 months of a diagnosis of pancreatic cancer. At present, the only chance for cure is surgical removal (resection) of the tumor, part of the pancreas, and other nearby digestive organs. This procedure—the Whipple procedure—is only possible in the fifth of patients whose tumor is found when it is small enough to be resectable, and even in these patients, the cure rate associated with surgery is less than 25%, although radiotherapy or chemotherapy after surgery (adjuvant therapy) can be beneficial.
Why Was This Study Done?
For patients whose tumor has metastasized, palliative chemotherapy to slow down tumor growth and to minimize pain is the only treatment option. But, for the many patients whose disease is locally advanced and unresectable at diagnosis, experts think that “neoadjuvant” therapy might be helpful. Neoadjuvant therapy—chemotherapy and/or radiotherapy given before surgery—aims to convert unresectable tumors into resectable tumors by shrinking the visible tumor and removing cancer cells that cannot be seen with the naked eye. Randomized phase III trials—studies in which groups of patients are randomly assigned to different interventions and specific outcomes measured—are the best way to determine whether an intervention has any clinical benefits, but no randomized phase III trials of neoadjuvant therapy for unresectable pancreatic cancer have been undertaken. Therefore, in this systematic review (a study that uses predefined criteria to identify all the research on a given topic) and meta-analysis (a statistical method for combining the results of several studies), the researchers analyze data from other types of studies to investigate whether neoadjuvant therapy for pancreatic cancer provides any clinical benefits.
What Did the Researchers Do and Find?
In their systematic review, the researchers identified 111 studies involving 4,394 patients in which the effects of neoadjuvant chemotherapy and/or radiotherapy on tumor response, tumor resectability, and patient survival had been investigated. They subdivided the studies into two groups: group 1 studies included patients whose tumors were considered resectable on preoperative examination, and group 2 studies included patients whose tumors were borderline resectable or unresectable. In their meta-analysis, the researchers found that similar percentages of the tumors in both groups responded to neoadjuvant therapy by shrinking or regressing and that about a fifth of the tumors in each group grew larger or metastasized during neoadjuvant therapy. In the group 1 studies, three-quarters of the tumors were resectable after neoadjuvant therapy (a decrease in the proportion of tumors that could be treated surgically) whereas in the group 2 studies, a third of the tumors were resectable after neoadjuvant therapy (an increase in the proportion of tumors that could be treated surgically). After resection, the average survival time for group 1 patients was 23.3 months, a similar survival time to that seen in patients treated with surgery and adjuvant therapy. The average survival time for group 2 patients after resection was 20.5 months.
What Do These Findings Mean?
The finding that the average survival time after neoadjuvant therapy and surgery in patients whose tumor was judged resectable before neoadjuvant therapy was similar to that of patients treated with chemotherapy and/or radiotherapy after surgery suggests that for patients with resectable tumors, neoadjuvant therapy will not provide any clinical benefit. By contrast, the finding that a third of patients initially judged unresectable were able to undergo resection after neoadjuvant therapy and then had a similar survival rate to patients judged resectable before neoadjuvant treatment strongly suggests that patients presenting with locally advanced/unresectable tumors should be offered neoadjuvant therapy and then re-evaluated for resection. Randomized trials are now needed to confirm this finding and to determine the optimum neoadjuvant therapy for this group of patients.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000267.
The US National Cancer Institute provides information for patients and health professionals about all aspects of pancreatic cancer (in English and Spanish), including a booklet for patients
The American Cancer Society also provides detailed information about pancreatic cancer
The UK National Health Service and Cancer Research UK include information for patients on pancreatic cancer on their Web sites
MedlinePlus provides links to further resources on pancreatic cancer (in English and Spanish)
Pancreatica.org, PancreaticDuct.org, and the Pancreatic Cancer Action Network give more information to pancreatic cancer patients, their families, and caregivers
doi:10.1371/journal.pmed.1000267
PMCID: PMC2857873  PMID: 20422030
2.  Dynamic Contrast-Enhanced MR Imaging in a Phase Ⅱ Study on Neoadjuvant Chemotherapy Combining Rh-Endostatin with Docetaxel and Epirubicin for Locally Advanced Breast Cancer 
Background: Anti-angiogenesis is a promising therapeutic strategy for locally advanced breast cancer. We performed this phase II trial to evaluate the anti-angiogenesis and anti-tumor effect of rh-endostatin combined with docetaxel and epirubicin in patients with locally advanced breast cancer by dynamic contrast-enhanced magnetic resonance imaging in 70 previously untreated locally advanced breast cancer patients.
Methods: The study population was randomly assigned to neoadjuvant chemotherapy with docetaxel and epirubicin (neoadjuvant chemotherapy group) or neoadjuvant chemotherapy combining rh-endostatin with docetaxel and epirubicin (neoadjuvant chemotherapy+rh-endostatin group). The anti-angiogenic and anti-tumor effects of both regimens were evaluated by serial dynamic contrast-enhanced magnetic resonance imaging and microvessel density measurements after final surgery.
Results: The results suggested a higher clinical objective response (90.9% vs. 67.7%, P = 0.021) and greater reductions in tumor size (67.2% vs. 55.9%, P = 0.000), Ki-67 proliferation index (32.79% vs. 12.47%, P = 0.000), tumor signal enhanced ratio (64% vs. 48%, P = 0.018), and Ktrans (67% vs. 39%, P = 0.026) in neoadjuvant chemotherapy+rh-endostatin group than those in neoadjuvant chemotherapy group. In addition, the microvessel density value in the neoadjuvant chemotherapy+rh-endostatin group was significantly lower than in the neoadjuvant chemotherapy group (18.67 ± 6.53 vs. 36.05 ± 9.64, P = 0.000). Moreover, the microvessel density value was significantly correlated with Ktrans after neoadjuvant chemotherapy+rh-endostatin treatment (r=0.88, P = 0.00).
Conclusions: The neoadjuvant chemotherapy+rh-endostatin treatment significantly repressed angiogenesis in locally advanced breast cancer and synergistically enhanced the anti-tumor effect of neoadjuvant chemotherapy. Serial dynamic contrast-enhanced magnetic resonance imaging data including reductions in tumor size and Ktrans, could provide non-invasive evaluation for chemotherapeutic efficacy and, consequently, optimization of individual chemotherapy for locally advanced breast cancer patients.
doi:10.7150/ijms.5123
PMCID: PMC3547207  PMID: 23329881
breast cancer; neoadjuvant chemotherapy; rh-endostatin; microvessel density; dynamic contrast-enhanced MR imaging
3.  Exquisite Sensitivity of TP53 Mutant and Basal Breast Cancers to a Dose-Dense Epirubicin−Cyclophosphamide Regimen 
PLoS Medicine  2007;4(3):e90.
Background
In breast cancers, only a minority of patients fully benefit from the different chemotherapy regimens currently in use. Identification of markers that could predict the response to a particular regimen would thus be critically important for patient care. In cell lines or animal models, tumor protein p53 (TP53) plays a critical role in modulating the response to genotoxic drugs. TP53 is activated in response to DNA damage and triggers either apoptosis or cell-cycle arrest, which have opposite effects on cell fate. Yet, studies linking TP53 status and chemotherapy response have so far failed to unambiguously establish this paradigm in patients. Breast cancers with a TP53 mutation were repeatedly shown to have a poor outcome, but whether this reflects poor response to treatment or greater intrinsic aggressiveness of the tumor is unknown.
Methods and Findings
In this study we analyzed 80 noninflammatory breast cancers treated by frontline (neoadjuvant) chemotherapy. Tumor diagnoses were performed on pretreatment biopsies, and the patients then received six cycles of a dose-dense regimen of 75 mg/m2 epirubicin and 1,200 mg/m2 cyclophosphamide, given every 14 days. After completion of chemotherapy, all patients underwent mastectomies, thus allowing for a reliable assessment of chemotherapy response. The pretreatment biopsy samples were used to determine the TP53 status through a highly efficient yeast functional assay and to perform RNA profiling. All 15 complete responses occurred among the 28 TP53-mutant tumors. Furthermore, among the TP53-mutant tumors, nine out of ten of the highly aggressive basal subtypes (defined by basal cytokeratin [KRT] immunohistochemical staining) experienced complete pathological responses, and only TP53 status and basal subtype were independent predictors of a complete response. Expression analysis identified many mutant TP53-associated genes, including CDC20, TTK, CDKN2A, and the stem cell gene PROM1, but failed to identify a transcriptional profile associated with complete responses among TP53 mutant tumors. In patients with unresponsive tumors, mutant TP53 status predicted significantly shorter overall survival. The 15 patients with responsive TP53-mutant tumors, however, had a favorable outcome, suggesting that this chemotherapy regimen can overcome the poor prognosis generally associated with mutant TP53 status.
Conclusions
This study demonstrates that, in noninflammatory breast cancers, TP53 status is a key predictive factor for response to this dose-dense epirubicin–cyclophosphamide regimen and further suggests that the basal subtype is exquisitely sensitive to this association. Given the well-established predictive value of complete responses for long-term survival and the poor prognosis of basal and TP53-mutant tumors treated with other regimens, this chemotherapy could be particularly suited for breast cancer patients with a mutant TP53, particularly those with basal features.
Hugues de The and colleagues report thatTP53 status is a predictive factor for responsiveness in breast cancers to a dose-dense epirubicin-cyclophosphamide chemotherapy regimen, and suggests that this regimen might be well suited for patientsTP53 mutant tumors.
Editors' Summary
Background.
One woman in eight will develop breast cancer during her life. As with other cancers, breast cancer arises when cells accumulate genetic changes (mutations) that allow them to grow uncontrollably and to move around the body. These altered cells are called malignant cells. The normal human breast contains several types of cell, any of which can become malignant. In addition, there is more than one route to malignancy—different sets of genes can be mutated. As a result, breast cancer is a heterogeneous disease that cannot be cured with a single type of treatment. Ideally, oncologists would like to know before they start treating a patient which therapeutic approach is going to be successful for that individual. Recently, researchers have begun to identify molecular changes that might eventually allow oncologists to make such rational treatment decisions. For example, laboratory studies in cell lines or animals indicate that the status of a gene called TP53 determines the chemotherapy agents (drugs that preferentially kill rapidly dividing cancer cells) to which cells respond. p53, the protein encoded by TP53, is a tumor suppressor. That is, in normal cells it prevents unregulated growth by controlling the expression of proteins involved in cell division and cell death. Consequently, p53 is often inactivated during cancer development.
Why Was This Study Done?
Although laboratory studies have linked TP53 status to chemotherapy responses, little is known about this relationship in human breast cancers. The clinical studies that have investigated whether TP53 status affects chemotherapy responses have generally found that patients whose tumors contain mutant TP53 have a poorer response to therapy and/or a shorter survival time than those whose tumors contain normal TP53. In this study, the researchers have asked whether TP53 status affects tumor responses to a dose-intense chemotherapy regimen (frequent, high doses of drugs) given to women with advanced noninflammatory breast cancer before surgery. This type of treatment is called neoadjuvant chemotherapy and is used to shrink tumors before surgery.
What Did the Researchers Do and Find?
The researchers collected breast tumor samples from 80 women before starting six fortnightly cycles of chemotherapy with epirubicin and cyclophosphamide. After this, each woman had her affected breast removed and examined to see whether the chemotherapy had killed the tumor cells. The researchers determined which original tumor samples contained mutated TP53 and used a technique called microarray expression profiling to document gene expression patterns in them. Overall, 28 tumors contained mutated TP53. Strikingly, all 15 tumors that responded completely to neoadjuvant chemotherapy (no tumor cells detectable in the breast tissue after chemotherapy) contained mutated TP53. Nine of these responsive tumors were basal-cell–like breast tumors, a particularly aggressive type of breast cancer; only one basal-cell–like, TP53-mutated tumor did not respond to chemotherapy. Patients whose tumors were unresponsive to the neoadjuvant chemotherapy but contained mutated TP53 tended to die sooner than those whose tumors contained normal TP53 or those with chemotherapy-responsive TP53-mutated tumors. Finally, expression profiling identified changes in the expression of many p53-regulated genes, but did not identify an expression profile in the TP53-mutated tumors unique to those that responded to chemotherapy.
What Do These Findings Mean?
These findings indicate that noninflammatory breast tumors containing mutant TP53—in particular, basal-cell–like tumors—are very sensitive to dose-dense epirubicin and cyclophosphamide chemotherapy. Intensive regimens of this type have rarely been used in previous studies, which might explain the apparent contradiction between these results and the generally poor response to chemotherapy of TP53-mutated breast tumors. More tumors now need to be examined to confirm the association between complete response, TP53 status and basal-cell–like tumors. In addition, although complete tumor responses generally predict good overall survival, longer survival studies than those reported here are needed to show that the tumor response to this particular neoadjuvant chemotherapy regimen translates into improved overall survival. If the present results can be confirmed and extended, dose-dense neoadjuvant chemotherapy with epirubicin and cyclophosphamide could considerably improve the outlook for patients with aggressive TP53-mutant, basal-cell–like breast tumors.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040090.
The US National Cancer Institute provides patient and physician information on breast cancer and general information on understanding cancer
Cancer Research UK offers patient information on cancer and breast cancer
The MedlinePlus encyclopedia has pages on breast cancer
Emory University's CancerQuest discusses the biology of cancer, including the role of tumor suppressor proteins
Wikipedia has pages on p53 (note that Wikipedia is a free online encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0040090
PMCID: PMC1831731  PMID: 17388661
4.  Pathologic Complete Response Predicts Recurrence-Free Survival More Effectively by Cancer Subset: Results From the I-SPY 1 TRIAL—CALGB 150007/150012, ACRIN 6657 
Journal of Clinical Oncology  2012;30(26):3242-3249.
Purpose
Neoadjuvant chemotherapy for breast cancer provides critical information about tumor response; how best to leverage this for predicting recurrence-free survival (RFS) is not established. The I-SPY 1 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis) was a multicenter breast cancer study integrating clinical, imaging, and genomic data to evaluate pathologic response, RFS, and their relationship and predictability based on tumor biomarkers.
Patients and Methods
Eligible patients had tumors ≥ 3 cm and received neoadjuvant chemotherapy. We determined associations between pathologic complete response (pCR; defined as the absence of invasive cancer in breast and nodes) and RFS, overall and within receptor subsets.
Results
In 221 evaluable patients (median tumor size, 6.0 cm; median age, 49 years; 91% classified as poor risk on the basis of the 70-gene prognosis profile), 41% were hormone receptor (HR) negative, and 31% were human epidermal growth factor receptor 2 (HER2) positive. For 190 patients treated without neoadjuvant trastuzumab, pCR was highest for HR-negative/HER2-positive patients (45%) and lowest for HR-positive/HER2-negative patients (9%). Achieving pCR predicted favorable RFS. For 172 patients treated without trastuzumab, the hazard ratio for RFS of pCR versus no pCR was 0.29 (95% CI, 0.07 to 0.82). pCR was more predictive of RFS by multivariate analysis when subtype was taken into account, and point estimates of hazard ratios within the HR-positive/HER2-negative (hazard ratio, 0.00; 95% CI, 0.00 to 0.93), HR-negative/HER2-negative (hazard ratio, 0.25; 95% CI, 0.04 to 0.97), and HER2-positive (hazard ratio, 0.14; 95% CI, 0.01 to 1.0) subtypes are lower. Ki67 further improved the prediction of pCR within subsets.
Conclusion
In this biologically high-risk group, pCR differs by receptor subset. pCR is more highly predictive of RFS within every established receptor subset than overall, demonstrating that the extent of outcome advantage conferred by pCR is specific to tumor biology.
doi:10.1200/JCO.2011.39.2779
PMCID: PMC3434983  PMID: 22649152
5.  Effects of a physical activity behavior change intervention on inflammation and related health outcomes in breast cancer survivors: pilot randomized trial 
Integrative cancer therapies  2012;12(4):323-335.
Background
Physical activity may provide benefits for breast cancer survivors in part by reducing systemic inflammation. Physical activity behavior change studies are a type of implementation research in which exercise efficacy information is translated into a “real world” setting, allowing determination of whether physical activity changes are sufficient to improve health outcomes. We hypothesized that breast cancer survivors (BCS) who undertook a physical activity behavior change intervention would have less systemic inflammation and improved cardiorespiratory fitness, muscle strength, body composition, fatigue, and sleep as compared with BCS receiving usual care. The goal of this pilot study was to determine the magnitude and direction of intervention effect sizes for inflammatory related serum markers and relevant health outcomes.
Methods
This randomized controlled trial enrolled 28 Stage I, II, or IIIA BCS who were post-primary treatment and were not regular exercisers. These women were assigned to either a 3-month physical activity behavior change intervention group (ING) or usual care group (UCG). Intervention included supervised aerobic (150 weekly minutes, moderate-intensity) and resistance (two sessions per week) exercise that gradually tapered to home-based exercise. At baseline and after 3 months, health outcomes and serum concentrations of interleukin (IL)-1 beta, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, leptin, and adiponectin were measured.
Results
Cardiorespiratory fitness significantly improved in the ING versus UCG (between group difference=3.8 ml/kg/min; d=1.1; P=0.015). Self-reported sleep latency was significantly reduced in the ING versus UCG (between group difference=−0.5; d=−1.2; P=0.02) as was serum leptin (between group difference=−9.0 ng/ml; d=−1.0; P=0.031). Small to medium non-significant negative effect sizes were noted for IL-10 and TNF-alpha and ratios of IL-6:IL-10, IL-8:IL10, and TNF-alpha:IL-10, with non-significant positive effect sizes noted for IL-6 and high molecular weight adiponectin.
Conclusions
Physical activity behavior change interventions in BCS can achieve large effect size changes for several health outcomes. Although effect sizes for inflammatory markers were often small and not significant, changes were in the hypothesized direction for all except IL-6 and IL-10. These preliminary data support larger trials that would more fully examine potential inflammatory changes that accompany physical activity behavior change interventions.
doi:10.1177/1534735412449687
PMCID: PMC3909487  PMID: 22831916
exercise; intervention; oncology; cytokine; inflammation; survivorship
6.  A Community-Based Exercise and Support Group Program in African-American Breast Cancer Survivors (ABCs) 
African-American (AA) women have higher rates of breast cancer (BCa) mortality than Caucasian women, and a recent study using data from the Surveillance, Epidemiology and End Results (SEER) registry suggests that this disparity may be due, in part, to the poorer health status of AAs at diagnosis and not treatment related issues. Randomized controlled trials involving supervised aerobic and resistance exercise have shown improved body composition and improvement in cancer-related biomarkers in BCa patients and may lead to improved recurrence and survival rates; however, most trials have focused on Caucasians and many have been conducted in academic- and clinic-based settings. We evaluated the feasibility of conducting a 20-week, supervised, resistance training, group exercise intervention coupled with a support group and home walking program utilizing facilities and personnel at a community cancer support center (The Gathering Place, Beachwood, Ohio) in AA Stage I–III BCa survivors who were within 12 months of completing treatment (surgery, chemotherapy, and/or breast irradiation); and, evaluated the potential effects of this intervention on physical measures and cancer-related biomarkers. 27 patients provided informed consent and 19 participated in the program. On average, attendance rates were 70.0% ± 19.1% for the exercise sessions and 63.1% ± 13.8% for the support group. We observed a significant decrease in circulating C-peptide levels (B: 893.9 ± 399.1 pg/mL; EOI: 723.9 ± 319.0 pg/mL; p=0.01). Although we did not observe a significant decrease in weight in the entire sample, there was a significant decrease in waist circumference and percent total body fat among those who attended 70% or more of the exercise sessions. In summary, we demonstrated that conducting lifestyle interventions in AA BCa survivors in a community setting is feasible. Future interventions should invoke strategies to enhance adherence and include a structured dietary intervention to enable greater weight loss.
PMCID: PMC3975605  PMID: 24707505
Breast Cancer; Exercise; African-American; Community-Based; Biomarkers
7.  Screening Mammography for Women Aged 40 to 49 Years at Average Risk for Breast Cancer 
Executive Summary
Objective
The aim of this review was to determine the effectiveness of screening mammography in women aged 40 to 49 years at average risk for breast cancer.
Clinical Need
The effectiveness of screening mammography in women aged over 50 years has been established, yet the issue of screening in women aged 40 to 49 years is still unsettled. The Canadian Task Force of Preventive Services, which sets guidelines for screening mammography for all provinces, supports neither the inclusion nor the exclusion of this screening procedure for 40- to 49-year-old women from the periodic health examination. In addition to this, 2 separate reviews, one conducted in Quebec in 2005 and the other in Alberta in 2000, each concluded that there is an absence of convincing evidence on the effectiveness of screening mammography for women in this age group who are at average risk for breast cancer.
In the United States, there is disagreement among organizations on whether population-based mammography should begin at the age of 40 or 50 years. The National Institutes of Health, the American Association for Cancer Research, and the American Academy of Family Physicians recommend against screening women in their 40s, whereas the United States Preventive Services Task Force, the National Cancer Institute, the American Cancer Society, the American College of Radiology, and the American College of Obstetricians and Gynecologists recommend screening mammograms for women aged 40 to 49 years. Furthermore, in comparing screening guidelines between Canada and the United States, it is also important to recognize that “standard care” within a socialized medical system such as Canada’s differs from that of the United States. The National Breast Screening Study (NBSS-1), a randomized screening trial conducted in multiple centres across Canada, has shown there is no benefit in mortality from breast cancer from annual mammograms in women randomized between the ages of 40 and 49, relative to standard care (i.e. physical exam and teaching of breast-self examination on entry to the study, with usual community care thereafter).
At present, organized screening programs in Canada systematically screen women starting at 50 years of age, although with a physician’s referral, a screening mammogram is an insured service in Ontario for women under 50 years of age.
International estimates of the epidemiology of breast cancer show that the incidence of breast cancer is increasing for all ages combined, whereas mortality is decreasing, though at a slower rate. These decreasing mortality rates may be attributed to screening and advances in breast cancer therapy over time. Decreases in mortality attributable to screening may be a result of the earlier detection and treatment of invasive cancers, in addition to the increased detection of ductal carcinoma in situ (DCIS), of which certain subpathologies are less lethal. Evidence from the SEER cancer registry in the United States indicates that the age-adjusted incidence of DCIS has increased almost 10-fold over a 20-year period (from 2.7 to 25 per 100,000).
The incidence of breast cancer is lower in women aged 40 to 49 years than in women aged 50 to 69 years (about 140 per 100,000 versus 500 per 100,000 women, respectively), as is the sensitivity (about 75% versus 85% for women aged under and over 50, respectively) and specificity of mammography (about 80% versus 90% for women aged under and over 50, respectively). The increased density of breast tissue in younger women is mainly responsible for the lower accuracy of this procedure in this age group. In addition, as the proportion of breast cancers that occur before the age of 50 are more likely to be associated with genetic predisposition as compared with those diagnosed in women after the age of 50, mammography may not be an optimal screening method for younger women.
Treatment options vary with the stage of disease (based on tumor size, involvement of surrounding tissue, and number of affected axillary lymph nodes) and its pathology, and may include a combination of surgery, chemotherapy, and/or radiotherapy.
Surgery is the first-line intervention for biopsy confirmed tumours. The subsequent use of radiation, chemotherapy, or hormonal treatments is dependent on the histopathologic characteristics of the tumor and the type of surgery. There is controversy regarding the optimal treatment of DCIS, which is noninvasive.
With such controversy as to the effectiveness of mammography and the potential risk associated with women being overtreated or actual cancers being missed, and the increased risk of breast cancer associated with exposure to annual mammograms over a 10-year period, the Ontario Health Technology Advisory Committee requested this review of screening mammography in women aged 40 to 49 years at average risk for breast cancer. This review is the first of 2 parts and concentrates on the effectiveness of screening mammography (i.e., film mammography, FM) for women at average risk aged 40 to 49 years. The second part will be an evaluation of screening by either magnetic resonance imaging or digital mammography, with the objective of determining the optimal screening modality in these younger women.
Review Strategy
The following questions were asked:
Does screening mammography for women aged 40 to 49 years who are at average risk for breast cancer reduce breast cancer mortality?
What is the sensitivity and specificity of mammography for this age group?
What are the risks associated with annual screening from ages 40 to 49?
What are the risks associated with false positive and false negative mammography results?
What are the economic considerations if evidence for effectiveness is established?
The Medical Advisory Secretariat followed its standard procedures and searched these electronic databases: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and the International Network of Agencies for Health Technology Assessment.
Keywords used in the search were breast cancer, breast neoplasms, mass screening, and mammography.
In total, the search yielded 6,359 articles specific to breast cancer screening and mammography. This did not include reports on diagnostic mammograms. The search was further restricted to English-language randomized controlled trials (RCTs), systematic reviews, and meta-analyses published between 1995 and 2005. Excluded were case reports, comments, editorials, and letters, which narrowed the results to 516 articles and previous health technology policy assessments.
These were examined against the criteria outlined below. This resulted in the inclusion of 5 health technology assessments, the Canadian Preventive Services Task Force report, the United States Preventive Services Task Force report, 1 Cochrane review, and 8 RCTs.
Inclusion Criteria
English-language articles, and English and French-language health technology policy assessments, conducted by other organizations, from 1995 to 2005
Articles specific to RCTs of screening mammography of women at average risk for breast cancer that included results for women randomized to studies between the ages of 40 and 49 years
Studies in which women were randomized to screening with or without mammography, although women may have had clinical breast examinations and/or may have been conducting breast self-examination.
UK Age Trial results published in December 2006.
Exclusion Criteria
Observational studies, including those nested within RCTs
RCTs that do not include results on women between the ages of 40 and 49 at randomization
Studies in which mammography was compared with other radiologic screening modalities, for example, digital mammography, magnetic resonance imaging or ultrasound.
Studies in which women randomized had a personal history of breast cancer.
Intervention
Film mammography
Comparators
Within RCTs, the comparison group would have been women randomized to not undergo screening mammography, although they may have had clinical breast examinations and/or have been conducting breast self-examination.
Outcomes of Interest
Breast cancer mortality
Summary of Findings
There is Level 1 Canadian evidence that screening women between the ages of 40 and 49 years who are at average risk for breast cancer is not effective, and that the absence of a benefit is sustained over a maximum follow-up period of 16 years.
All remaining studies that reported on women aged under 50 years were based on subset analyses. They provide additional evidence that, when all these RCTs are taken into account, there is no significant reduction in breast cancer mortality associated with screening mammography in women aged 40 to 49 years.
Conclusions
There is Level 1 evidence that screening mammography in women aged 40 to 49 years at average risk for breast cancer is not effective in reducing mortality.
Moreover, risks associated with exposure to mammographic radiation, the increased risk of missed cancers due to lower mammographic sensitivity, and the psychological impact of false positives, are not inconsequential.
The UK Age Trial results published in December 2006 did not change these conclusions.
PMCID: PMC3377515  PMID: 23074501
8.  Neoadjuvant Chemotherapy Is Associated with Improved Survival Compared with Adjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer Only after Complete Pathologic Response 
Annals of surgical oncology  2011;19(1):253-258.
Introduction
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is known to be chemosensitive. In patients with TNBC, we sought to compare survival outcomes between patients receiving neoadjuvant chemotherapy, with and without complete pathologic response (pCR), and those receiving adjuvant chemotherapy.
Methods
We performed a retrospective chart review and identified 385 patients with stage I–III TNBC who were treated with neoadjuvant or adjuvant chemotherapy between 2000 and 2008. Patients were divided according to receipt of neoadjuvant chemotherapy with pCR, neoadjuvant chemotherapy without pCR, and adjuvant chemotherapy. Data were compared using Fisher’s exact test and analysis of variance (ANOVA). Kaplan–Meier curves were generated.
Results
Of 385 patients, 151 (39%) received neoadjuvant chemotherapy and 234 (61%) received adjuvant chemotherapy. Twenty-six (17%) of those patients receiving neoadjuvant chemotherapy had pCR. After controlling for covariates associated with survival in unadjusted tests, patients undergoing neoadjuvant chemotherapy with residual tumor had significantly worse survival compared with patients receiving adjuvant therapy [hazard ratio (HR) = 0.51, P = 0.007] and a trend towards worse survival compared with patients receiving neoadjuvant therapy with pCR (HR = 0.19, P = 0.10).
Conclusions
Although previous clinical trials have not demonstrated a survival difference between patients receiving neoadjuvant versus adjuvant chemotherapy for breast cancer, our study suggests an overall survival benefit in patients with pCR following neoadjuvant chemotherapy compared with patients receiving adjuvant therapy. It is clear that a prospective study needs to be carried out to better elucidate the timing of chemotherapy in patients with TNBC.
doi:10.1245/s10434-011-1877-y
PMCID: PMC3892697  PMID: 21725686
9.  Cancer Screening with Digital Mammography for Women at Average Risk for Breast Cancer, Magnetic Resonance Imaging (MRI) for Women at High Risk 
Executive Summary
Objective
The purpose of this review is to determine the effectiveness of 2 separate modalities, digital mammography (DM) and magnetic resonance imaging (MRI), relative to film mammography (FM), in the screening of women asymptomatic for breast cancer. A third analysis assesses the effectiveness and safety of the combination of MRI plus mammography (MRI plus FM) in screening of women at high risk. An economic analysis was also conducted.
Research Questions
How does the sensitivity and specificity of DM compare to FM?
How does the sensitivity and specificity of MRI compare to FM?
How do the recall rates compare among these screening modalities, and what effect might this have on radiation exposure? What are the risks associated with radiation exposure?
How does the sensitivity and specificity of the combination of MRI plus FM compare to either MRI or FM alone?
What are the economic considerations?
Clinical Need
The effectiveness of FM with respect to breast cancer mortality in the screening of asymptomatic average- risk women over the age of 50 has been established. However, based on a Medical Advisory Secretariat review completed in March 2006, screening is not recommended for women between the ages of 40 and 49 years. Guidelines published by the Canadian Task Force on Preventive Care recommend mammography screening every 1 to 2 years for women aged 50 years and over, hence, the inclusion of such women in organized breast cancer screening programs. In addition to the uncertainty of the effectiveness of mammography screening from the age of 40 years, there is concern over the risks associated with mammographic screening for the 10 years between the ages of 40 and 49 years.
The lack of effectiveness of mammography screening starting at the age of 40 years (with respect to breast cancer mortality) is based on the assumption that the ability to detect cancer decreases with increased breast tissue density. As breast density is highest in the premenopausal years (approximately 23% of postmenopausal and 53% of premenopausal women having at least 50% of the breast occupied by high density), mammography screening is not promoted in Canada nor in many other countries for women under the age of 50 at average risk for breast cancer. It is important to note, however, that screening of premenopausal women (i.e., younger than 50 years of age) at high risk for breast cancer by virtue of a family history of cancer or a known genetic predisposition (e.g., having tested positive for the breast cancer genes BRCA1 and/or BRCA2) is appropriate. Thus, this review will assess the effectiveness of breast cancer screening with modalities other than film mammography, specifically DM and MRI, for both pre/perimenopausal and postmenopausal age groups.
International estimates of the epidemiology of breast cancer show that the incidence of breast cancer is increasing for all ages combined whereas mortality is decreasing, though at a slower rate. The observed decreases in mortality rates may be attributable to screening, in addition to advances in breast cancer therapy over time. Decreases in mortality attributable to screening may be a result of the earlier detection and treatment of invasive cancers, in addition to the increased detection of ductal carcinoma in situ (DCIS), of which certain subpathologies are less lethal. Evidence from the Surveillance, Epidemiology and End Results (better known as SEER) cancer registry in the United States, indicates that the age-adjusted incidence of DCIS has increased almost 10-fold over a 20 year period, from 2.7 to 25 per 100,000.
There is a 4-fold lower incidence of breast cancer in the 40 to 49 year age group than in the 50 to 69 year age group (approximately 140 per 100,000 versus 500 per 100,000 women, respectively). The sensitivity of FM is also lower among younger women (approximately 75%) than for women aged over 50 years (approximately 85%). Specificity is approximately 80% for younger women versus 90% for women over 50 years. The increased density of breast tissue in younger women is likely responsible for the decreased accuracy of FM.
Treatment options for breast cancer vary with the stage of disease (based on tumor size, involvement of surrounding tissue, and number of affected axillary lymph nodes) and its pathology, and may include a combination of surgery, chemotherapy and/or radiotherapy. Surgery is the first-line intervention for biopsy-confirmed tumors. The subsequent use of radiation, chemotherapy or hormonal treatments is dependent on the histopathologic characteristics of the tumor and the type of surgery. There is controversy regarding the optimal treatment of DCIS, which is considered a noninvasive tumour.
Women at high risk for breast cancer are defined as genetic carriers of the more commonly known breast cancer genes (BRCA1, BRCA2 TP53), first degree relatives of carriers, women with varying degrees of high risk family histories, and/or women with greater than 20% lifetime risk for breast cancer based on existing risk models. Genetic carriers for this disease, primarily women with BRCA1 or BRCA2 mutations, have a lifetime probability of approximately 85% of developing breast cancer. Preventive options for these women include surgical interventions such as prophylactic mastectomy and/or oophorectomy, i.e., removal of the breasts and/or ovaries. Therefore, it is important to evaluate the benefits and risks of different screening modalities, to identify additional options for these women.
This Medical Advisory Secretariat review is the second of 2 parts on breast cancer screening, and concentrates on the evaluation of both DM and MRI relative to FM, the standard of care. Part I of this review (March 2006) addressed the effectiveness of screening mammography in 40 to 49 year old average-risk women. The overall objective of the present review is to determine the optimal screening modality based on the evidence.
Evidence Review Strategy
The Medical Advisory Secretariat followed its standard procedures and searched the following electronic databases: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and The International Network of Agencies for Health Technology Assessment database. The subject headings and keywords searched included breast cancer, breast neoplasms, mass screening, digital mammography, magnetic resonance imaging. The detailed search strategies can be viewed in Appendix 1.
Included in this review are articles specific to screening and do not include evidence on diagnostic mammography. The search was further restricted to English-language articles published between January 1996 and April 2006. Excluded were case reports, comments, editorials, nonsystematic reviews, and letters.
Digital Mammography: In total, 224 articles specific to DM screening were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 5 health technology assessments (HTAs) (plus 1 update) and 4 articles specific to screening with DM.
Magnetic Resonance Imaging: In total, 193 articles specific to MRI were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 2 HTAs and 7 articles specific to screening with MRI.
The evaluation of the addition of FM to MRI in the screening of women at high risk for breast cancer was also conducted within the context of standard search procedures of the Medical Advisory Secretariat. as outlined above. The subject headings and keywords searched included the concepts of breast cancer, magnetic resonance imaging, mass screening, and high risk/predisposition to breast cancer. The search was further restricted to English-language articles published between September 2007 and January 15, 2010. Case reports, comments, editorials, nonsystematic reviews, and letters were not excluded.
MRI plus mammography: In total, 243 articles specific to MRI plus FM screening were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 2 previous HTAs, and 1 systematic review of 11 paired design studies.
Inclusion Criteria
English-language articles, and English or French-language HTAs published from January 1996 to April 2006, inclusive.
Articles specific to screening of women with no personal history of breast cancer.
Studies in which DM or MRI were compared with FM, and where the specific outcomes of interest were reported.
Randomized controlled trials (RCTs) or paired studies only for assessment of DM.
Prospective, paired studies only for assessment of MRI.
Exclusion Criteria
Studies in which outcomes were not specific to those of interest in this report.
Studies in which women had been previously diagnosed with breast cancer.
Studies in which the intervention (DM or MRI) was not compared with FM.
Studies assessing DM with a sample size of less than 500.
Intervention
Digital mammography.
Magnetic resonance imaging.
Comparator
Screening with film mammography.
Outcomes of Interest
Breast cancer mortality (although no studies were found with such long follow-up).
Sensitivity.
Specificity.
Recall rates.
Summary of Findings
Digital Mammography
There is moderate quality evidence that DM is significantly more sensitive than FM in the screening of asymptomatic women aged less than 50 years, those who are premenopausal or perimenopausal, and those with heterogeneously or extremely dense breast tissue (regardless of age).
It is not known what effect these differences in sensitivity will have on the more important effectiveness outcome measure of breast cancer mortality, as there was no evidence of such an assessment.
Other factors have been set out to promote DM, for example, issues of recall rates and reading and examination times. Our analysis did not show that recall rates were necessarily improved in DM, though examination times were lower than for FM. Other factors including storage and retrieval of screens were not the subject of this analysis.
Magnetic Resonance Imaging
There is moderate quality evidence that the sensitivity of MRI is significantly higher than that of FM in the screening of women at high risk for breast cancer based on genetic or familial factors, regardless of age.
Radiation Risk Review
Cancer Care Ontario conducted a review of the evidence on radiation risk in screening with mammography women at high risk for breast cancer. From this review of recent literature and risk assessment that considered the potential impact of screening mammography in cohorts of women who start screening at an earlier age or who are at increased risk of developing breast cancer due to genetic susceptibility, the following conclusions can be drawn:
For women over 50 years of age, the benefits of mammography greatly outweigh the risk of radiation-induced breast cancer irrespective of the level of a woman’s inherent breast cancer risk.
Annual mammography for women aged 30 – 39 years who carry a breast cancer susceptibility gene or who have a strong family breast cancer history (defined as a first degree relative diagnosed in their thirties) has a favourable benefit:risk ratio. Mammography is estimated to detect 16 to 18 breast cancer cases for every one induced by radiation (Table 1). Initiation of screening at age 35 for this same group would increase the benefit:risk ratio to an even more favourable level of 34-50 cases detected for each one potentially induced.
Mammography for women under 30 years of age has an unfavourable benefit:risk ratio due to the challenges of detecting cancer in younger breasts, the aggressiveness of cancers at this age, the potential for radiation susceptibility at younger ages and a greater cumulative radiation exposure.
Mammography when used in combination with MRI for women who carry a strong breast cancer susceptibility (e.g., BRCA1/2 carriers), which if begun at age 35 and continued for 35 years, may confer greatly improved benefit:risk ratios which were estimated to be about 220 to one.
While there is considerable uncertainty in the risk of radiation-induced breast cancer, the risk expressed in published studies is almost certainly conservative as the radiation dose absorbed by women receiving mammography recently has been substantially reduced by newer technology.
A CCO update of the mammography radiation risk literature for 2008 and 2009 gave rise to one article by Barrington de Gonzales et al. published in 2009 (Barrington de Gonzales et al., 2009, JNCI, vol. 101: 205-209). This article focuses on estimating the risk of radiation-induced breast cancer for mammographic screening of young women at high risk for breast cancer (with BRCA gene mutations). Based on an assumption of a 15% to 25% or less reduction in mortality from mammography in these high risk women, the authors conclude that such a reduction is not substantially greater than the risk of radiation-induced breast cancer mortality when screening before the age of 34 years. That is, there would be no net benefit from annual mammographic screening of BRCA mutation carriers at ages 25-29 years; the net benefit would be zero or small if screening occurs in 30-34 year olds, and there would be some net benefit at age 35 years or older.
The Addition of Mammography to Magnetic Resonance Imaging
The effects of the addition of FM to MRI screening of high risk women was also assessed, with inclusion and exclusion criteria as follows:
Inclusion Criteria
English-language articles and English or French-language HTAs published from September 2007 to January 15, 2010.
Articles specific to screening of women at high risk for breast cancer, regardless of the definition of high risk.
Studies in which accuracy data for the combination of MRI plus FM are available to be compared to that of MRI and FM alone.
RCTs or prospective, paired studies only.
Studies in which women were previously diagnosed with breast cancer were also included.
Exclusion Criteria
Studies in which outcomes were not specific to those of interest in this report.
Studies in which there was insufficient data on the accuracy of MRI plus FM.
Intervention
Both MRI and FM.
Comparators
Screening with MRI alone and FM alone.
Outcomes of Interest
Sensitivity.
Specificity.
Summary of Findings
Magnetic Resonance Imaging Plus Mammography
Moderate GRADE Level Evidence that the sensitivity of MRI plus mammography is significantly higher than that of MRI or FM alone, although the specificity remains either unchanged or decreases in the screening of women at high risk for breast cancer based on genetic/familial factors, regardless of age.
These studies include women at high risk defined as BRCA1/2 or TP53 carriers, first degree relatives of carriers, women with varying degrees of high risk family histories, and/or >20% lifetime risk based on existing risk models. This definition of high risk accounts for approximately 2% of the female adult population in Ontario.
PMCID: PMC3377503  PMID: 23074406
10.  Clinical Efficacy of Including Capecitabine in Neoadjuvant Chemotherapy for Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2013;8(1):e53403.
Background
Capecitabine has proven effective as a chemotherapy for metastatic breast cancer. Though several Phase II/III studies of capecitabine as neoadjuvant chemotherapy have been conducted, the results still remain inconsistent. Therefore, we performed a meta-analysis to obtain more precise understanding of the role of capecitabine in neoadjuvant chemotherapy for breast cancer patients.
Methods
The electronic database PubMed and online abstracts from ASCO and SABCS were searched to identify randomized clinical trials comparing neoadjuvant chemotherapy with or without capecitabine in early/operable breast cancer patients without distant metastasis. Risk ratios were used to estimate the association between capecitabine in neoadjuvant chemotherapy and various efficacy outcomes. Fixed- or random-effect models were adopted to pool data in RevMan 5.1.
Results
Five studies were included in the meta-analysis. Neoadjuvant use of capecitabine with anthracycline and/or taxane based therapy was not associated with significant improvement in clinical outcomes including: pathologic complete response in breast (pCR; RR = 1.10, 95% CI 0.87–1.40, p = 0.43), pCR in breast tumor and nodes (tnpCR RR = 0.99, 95% CI 0.83–1.18, p = 0.90), overall response rate (ORR; RR = 1.00, 95% CI 0.94–1.07, p = 0.93), or breast-conserving surgery (BCS; RR = 0.98, 95% CI 0.93–1.04, p = 0.49).
Conclusions
Neoadjuvant treatment of breast cancer involving capecitabine did not significantly improve pCR, tnpCR, BCS or ORR. Thus adding capecitabine to neoadjuvant chemotherapy regimes is unlikely to improve outcomes in breast cancer patients without distant metastasis. Further research is required to establish the condition that capecitabine may be useful in breast cancer neoadjuvant chemotherapy.
doi:10.1371/journal.pone.0053403
PMCID: PMC3536736  PMID: 23301067
11.  Effects of Home-Based Diet and Exercise on Functional Outcomes Among Older, Overweight Long-Term Cancer Survivors: The RENEW: Randomized Clinical Trial 
Context
Five-year survival rates for early-stage colorectal, breast and prostate cancer currently exceed 90% and are increasing. Cancer survivors are at greater risk for second malignancies, other co-morbidities, and accelerated functional decline. Lifestyle interventions may provide benefit, but it is unknown whether long-term cancer survivors can modify their lifestyle behaviors sufficiently to improve functional status.
Objective
To determine whether a telephone counseling and mailed material-based diet-exercise intervention is effective in reorienting functional decline in older, overweight cancer survivors.
Design
Randomized controlled trial in which survivors were randomly assigned to intervention (Intervention, n=319) or delayed-intervention control arms (Control, n=322).
Setting
Home-based from Canada, United Kingdom and 21 United States
Participants
641 overweight (body mass index [BMI] ≥ 25), long-term (≥ 5 years) survivors (ages 65–91) of colorectal, breast and prostate cancer recruited July 2005-May 2007.
Intervention
12-month home-based tailored program of telephone counseling and mailed materials promoting exercise, improved diet quality, and modest weight loss. Control group wait-listed for 12 months.
Main Outcome Measures
Change in self-reported physical function (SF-36 physical function subscale: 0–100, high score indicates better function) from baseline to 12 months was the primary endpoint. Secondary outcomes included changes in basic and advanced lower extremity function (0–100), physical activity, BMI, and overall health quality-of-life.
Results
From an average baseline score of 75.7 to 12-month follow-up, SF-36 function scores declined less rapidly in Intervention [−2.15(95% CI-0.36,−3.93)] versus Control [−4.84(−3.04,−6.63)] arms (p=0.03). Likewise, changes in basic lower extremity function were +0.34(−0.84,1.52) versus −1.89(−0.70,−3.09) from an average baseline score of 78.2, p=0.005. Physical activity, dietary behaviors and overall quality of life increased significantly in Intervention versus Control arms, and weight loss also was greater, −2.06(−1.69, −2.43) versus −0.92 (−0.51,−1.33) kg, respectively (p<0.0001).
Conclusion
Among older long-term colorectal, breast, and prostate cancer survivors, a diet and exercise intervention reduced the rate of self-reported functional decline compared to no intervention.
doi:10.1001/jama.2009.643
PMCID: PMC2752421  PMID: 19436015
12.  Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS) 
BMC Surgery  2008;8:21.
Background
A surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial.
Methods/design
The CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm.
The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up.
Discussion
This study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen.
Trial registration
ISRCTN80832026
doi:10.1186/1471-2482-8-21
PMCID: PMC2605735  PMID: 19036143
13.  Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma 
British Journal of Cancer  2000;83(12):1594-1598.
The objective of the study was to evaluate the effect of neoadjuvant chemotherapy on the survival of patients with oropharyngeal cancer. Patients with a squamous cell carcinoma of the oropharynx for whom curative radiotherapy or surgery was considered feasible were entered in a multicentric randomized trial comparing neoadjuvant chemotherapy followed by loco-regional treatment to the same loco-regional treatment without chemotherapy. The loco-regional treatment consisted either of surgery plus radiotherapy or of radiotherapy alone. Three cycles of chemotherapy consisting of Cisplatin (100 mg/m2) on day 1 followed by a 24-hour i.v. infusion of fluorouracil (1000 mg/m2/day) for 5 days were delivered every 21 days. 2–3 weeks after the end of chemotherapy, local treatment was performed. The trial was conducted by the Groupe d'Etude des Tumeurs de la Tête Et du Cou (GETTEC). A total of 318 patients were enrolled in the study between 1986 and 1992. Overall survival was significantly better (P = 0.03) in the neoadjuvant chemotherapy group than in the control group, with a median survival of 5.1 years versus 3.3 years in the no chemotherapy group. The effect of neoadjuvant chemotherapy on event-free survival was smaller and of borderline significance (P = 0.11). Stratification of the results on the type of local treatment, surgery plus radiotherapy or radiotherapy alone, did not reveal any heterogeneity in the effect of chemotherapy. © 2000 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2000.1512
PMCID: PMC2363468  PMID: 11189100
oropharyngeal cancer; chemotherapy; randomized trial; cisplatin; fluorouracil
14.  Neoadjuvant or adjuvant therapy for resectable esophageal cancer: a systematic review and meta-analysis 
BMC Medicine  2004;2:35.
Background
Carcinoma of the esophagus is an aggressive malignancy with an increasing incidence. Its virulence, in terms of symptoms and mortality, justifies a continued search for optimal therapy. The large and growing number of patients affected, the high mortality rates, the worldwide geographic variation in practice, and the large body of good quality research warrants a systematic review with meta-analysis.
Methods
A systematic review and meta-analysis investigating the impact of neoadjuvant or adjuvant therapy on resectable thoracic esophageal cancer to inform evidence-based practice was produced.
MEDLINE, CANCERLIT, Cochrane Library, EMBASE, and abstracts from the American Society of Clinical Oncology and the American Society for Therapeutic Radiology and Oncology were searched for trial reports.
Included were randomized trials or meta-analyses of neoadjuvant or adjuvant treatments compared with surgery alone or other treatments in patients with resectable thoracic esophageal cancer. Outcomes of interest were survival, adverse effects, and quality of life. Either one- or three-year mortality data were pooled and reported as relative risk ratios.
Results
Thirty-four randomized controlled trials and six meta-analyses were obtained and grouped into 13 basic treatment approaches.
Single randomized controlled trials detected no differences in mortality between treatments for the following comparisons:
- Preoperative radiotherapy versus postoperative radiotherapy.
- Preoperative and postoperative radiotherapy versus postoperative radiotherapy. Preoperative and postoperative radiotherapy was associated with a significantly higher mortality rate.
- Postoperative chemotherapy versus postoperative radiotherapy.
- Postoperative radiotherapy versus postoperative radiotherapy plus protein-bound polysaccharide versus chemoradiation versus chemoradiation plus protein-bound polysaccharide.
Pooling one-year mortality detected no statistically significant differences in mortality between treatments for the following comparisons:
- Preoperative radiotherapy compared with surgery alone (five randomized trials).
- Postoperative radiotherapy compared with surgery alone (five randomized trials).
- Preoperative chemotherapy versus surgery alone (six randomized trials).
- Preoperative and postoperative chemotherapy versus surgery alone (two randomized trials).
- Preoperative chemoradiation therapy versus surgery alone (six randomized trials).
Single randomized controlled trials detected differences in mortality between treatments for the following comparison:
- Preoperative hyperthermia and chemoradiotherapy versus preoperative chemoradiotherapy in favour of hyperthermia.
Pooling three-year mortality detected no statistically significant difference in mortality between treatments for the following comparison:
- Postoperative chemotherapy compared with surgery alone (two randomized trials).
Pooling three-year mortality detected statistically significant differences between treatments for the following comparisons:
- Preoperative chemoradiation therapy versus surgery alone (six randomized trials) in favour of preoperative chemoradiation with surgery.
- Preoperative chemotherapy compared with preoperative radiotherapy (one randomized trial) in favour of preoperative radiotherapy.
Conclusion
For adult patients with resectable thoracic esophageal cancer for whom surgery is considered appropriate, surgery alone (i.e., without neoadjuvant or adjuvant therapy) is recommended as the standard practice.
doi:10.1186/1741-7015-2-35
PMCID: PMC529457  PMID: 15447788
15.  Computer-Aided Evaluation of Breast MRI for the Residual Tumor Extent and Response Monitoring in Breast Cancer Patients Receiving Neoadjuvant Chemotherapy 
Korean Journal of Radiology  2011;12(1):34-43.
Objective
To evaluate the accuracy of a computer-aided evaluation program (CAE) of breast MRI for the assessment of residual tumor extent and response monitoring in breast cancer patients receiving neoadjuvant chemotherapy.
Materials and Methods
Fifty-seven patients with breast cancers who underwent neoadjuvant chemotherapy before surgery and dynamic contrast enhanced MRI before and after chemotherapy were included as part of this study. For the assessment of residual tumor extent after completion of chemotherapy, the mean tumor diameters measured by radiologists and CAE were compared to those on histopathology using a paired student t-test. Moreover, the agreement between unidimensional (1D) measurement by radiologist and histopathological size or 1D measurement by CAE and histopathological size was assessed using the Bland-Altman method. For chemotherapy monitoring, we evaluated tumor response through the change in the 1D diameter by a radiologist and CAE and three-dimensional (3D) volumetric change by CAE based on Response Evaluation Criteria in Solid Tumors (RECIST). Agreement between the 1D response by the radiologist versus the 1D response by CAE as well as by the 3D response by CAE were evaluated using weighted kappa (k) statistics.
Results
For the assessment of residual tumor extent after chemotherapy, the mean tumor diameter measured by radiologists (2.0 ± 1.7 cm) was significantly smaller than the mean histological diameter (2.6 ± 2.3 cm) (p = 0.01), whereas, no significant difference was found between the CAE measurements (mean = 2.2 ± 2.0 cm) and histological diameter (p = 0.19). The mean difference between the 1D measurement by the radiologist and histopathology was 0.6 cm (95% confidence interval: -3.0, 4.3), whereas the difference between CAE and histopathology was 0.4 cm (95% confidence interval: -3.9, 4.7). For the monitoring of response to chemotherapy, the 1D measurement by the radiologist and CAE showed a fair agreement (k = 0.358), while the 1D measurement by the radiologist and 3D measurement by CAE showed poor agreement (k = 0.106).
Conclusion
CAE for breast MRI is sufficiently accurate for the assessment of residual tumor extent in breast cancer patients receiving neoadjuvant chemotherapy. However, for the assessment of response to chemotherapy, the assessment by the radiologist and CAE showed a fair to poor agreement.
doi:10.3348/kjr.2011.12.1.34
PMCID: PMC3017882  PMID: 21228938
Breast neoplasm; Chemotherapy; MR imaging; Computer-aided
16.  High Expression of Class III β-Tubulin Predicts Good Response to Neoadjuvant Taxane and Doxorubicin/Cyclophosphamide-Based Chemotherapy in Estrogen Receptor–Negative Breast Cancer 
Clinical breast cancer  2012;13(2):103-108.
Class III β-tubulin (βIII-tubulin) has been associated with tumor response to taxane-based therapies in breast cancer. However its role in the neoadjuvant setting has not been explored. We evaluated βIII-tubulin expression by immunohistochemistry in 44 patients, and found high expression associated with good pathologic response in estrogen receptor–negative (ER−) breast cancers. Our results give strong reason to consider βIII-tubulin as a predictive biomarker for neoadjuvant chemotherapy response.
Background
Expression of class III β–tubulin (βIII-tubulin) correlates with tumor progression and resistance to taxane-based therapies for several human malignancies including breast cancer. However its predictive value in a neoadjuvant setting in breast cancer remains unexplored. The objective of this explorative study was to determine whether βIII-tubulin expression in breast cancer correlated with pathologic characteristics and whether its expression was predictive of response to neoadjuvant chemotherapy.
Patients and Methods
We determined βIII-tubulin expression in 85 breast cancers, including 41 localized breast cancers treated with primary surgery and 44 treated with neoadjuvant chemotherapy before surgery. βIII-tubulin expression was evaluated by immunohistochemical methods and was correlated with pathologic characteristics and response to neoadjuvant chemotherapy using residual cancer burden (RCB) score.
Results
High βIII-tubulin expression was significantly associated with poorly differentiated high-grade breast cancers (P = .003) but not with tumor size, estrogen receptor (ER) status, or human epidermal growth factor receptor 2 (HER2)/neu overexpression. In ER− tumors treated with neoadjuvant chemotherapy, high βIII-tubulin expression was associated with a significantly greater likelihood of achieving a good pathologic response to chemotherapy as reflected by lower RCB scores (P = .021).
Conclusion
This study reveals differential βIII-tubulin expression in breast cancers of different histologic grades, hormone receptors, and HER2/neu status. It also suggests a potential role for βIII-tubulin as a predictive biomarker for response in neoadjuvant chemotherapy for ER− breast cancer, which has not been previously reported. These data provide a strong rationale for considering βIII-tubulin status and further validation of this marker in a large study.
doi:10.1016/j.clbc.2012.11.003
PMCID: PMC4039021  PMID: 23218766
Breast cancer; Chemotherapy; Class III β-tubulin; Neoadjuvant; Predictive biomarker
17.  Randomized controlled trial to evaluate the effects of combined progressive exercise on metabolic syndrome in breast cancer survivors: rationale, design, and methods 
BMC Cancer  2014;14:238.
Background
Metabolic syndrome (MetS) is increasingly present in breast cancer survivors, possibly worsened by cancer-related treatments, such as chemotherapy. MetS greatly increases risk of cardiovascular disease and diabetes, co-morbidities that could impair the survivorship experience, and possibly lead to cancer recurrence. Exercise has been shown to positively influence quality of life (QOL), physical function, muscular strength and endurance, reduce fatigue, and improve emotional well-being; however, the impact on MetS components (visceral adiposity, hyperglycemia, low serum high-density lipoprotein cholesterol, hypertriglyceridemia, and hypertension) remains largely unknown. In this trial, we aim to assess the effects of combined (aerobic and resistance) exercise on components of MetS, as well as on physical fitness and QOL, in breast cancer survivors soon after completing cancer-related treatments.
Methods/Design
This study is a prospective randomized controlled trial (RCT) investigating the effects of a 16-week supervised progressive aerobic and resistance exercise training intervention on MetS in 100 breast cancer survivors. Main inclusion criteria are histologically-confirmed breast cancer stage I-III, completion of chemotherapy and/or radiation within 6 months prior to initiation of the study, sedentary, and free from musculoskeletal disorders. The primary endpoint is MetS; secondary endpoints include: muscle strength, shoulder function, cardiorespiratory fitness, body composition, bone mineral density, and QOL. Participants randomized to the Exercise group participate in 3 supervised weekly exercise sessions for 16 weeks. Participants randomized to the Control group are offered the same intervention after the 16-week period of observation.
Discussion
This is the one of few RCTs examining the effects of exercise on MetS in breast cancer survivors. Results will contribute a better understanding of metabolic disease-related effects of resistance and aerobic exercise training and inform intervention programs that will optimally improve physiological and psychosocial health during cancer survivorship, and that are ultimately aimed at improving prognosis.
Trial registration
NCT01140282; Registration: June 10, 2010
doi:10.1186/1471-2407-14-238
PMCID: PMC3985576  PMID: 24708832
Exercise; Breast cancer; Metabolic syndrome
18.  Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment 
BMC Cancer  2011;11:486.
Background
The pathological complete response (pCR) after neoadjuvant chemotherapy is a surrogate marker for a favorable prognosis in breast cancer patients. Factors capable of predicting a pCR, such as the proliferation marker Ki67, may therefore help improve our understanding of the drug response and its effect on the prognosis. This study investigated the predictive and prognostic value of Ki67 in patients with invasive breast cancer receiving neoadjuvant treatment for breast cancer.
Methods
Ki67 was stained routinely from core biopsies in 552 patients directly after the fixation and embedding process. HER2/neu, estrogen and progesterone receptors, and grading were also assessed before treatment. These data were used to construct univariate and multivariate models for predicting pCR and prognosis. The tumors were also classified by molecular phenotype to identify subgroups in which predicting pCR and prognosis with Ki67 might be feasible.
Results
Using a cut-off value of > 13% positively stained cancer cells, Ki67 was found to be an independent predictor for pCR (OR 3.5; 95% CI, 1.4, 10.1) and for overall survival (HR 8.1; 95% CI, 3.3 to 20.4) and distant disease-free survival (HR 3.2; 95% CI, 1.8 to 5.9). The mean Ki67 value was 50.6 ± 23.4% in patients with pCR. Patients without a pCR had an average of 26.7 ± 22.9% positively stained cancer cells.
Conclusions
Ki67 has predictive and prognostic value and is a feasible marker for clinical practice. It independently improved the prediction of treatment response and prognosis in a group of breast cancer patients receiving neoadjuvant treatment. As mean Ki67 values in patients with a pCR were very high, cut-off values in a high range above which the prognosis may be better than in patients with lower Ki67 values may be hypothesized. Larger studies will be needed in order to investigate these findings further.
doi:10.1186/1471-2407-11-486
PMCID: PMC3262864  PMID: 22081974
19.  Accuracy of Clinical Evaluation of Locally Advanced Breast Cancer in Patients Receiving Neoadjuvant Chemotherapy 
Cancer  2009;115(6):1194-1202.
Physical examination (PE), mammography (MG), breast MRI, FDG-PET and pathologic evaluation are used to assess primary breast cancer. Their accuracy has not been well studied in patients receiving neoadjuvant chemotherapy. Accuracies of each modality in tumor and nodal assessment in patients with T3/4 tumors receiving neoadjuvant chemotherapy were compared.
METHODS
45 patients of a prospective clinical trial studying T3-T4M0 tumors were included. Patients received neoadjuvant chemotherapy: docetaxel/carboplatin with or without trastuzumab before and/or after surgery (depending on HER-2/neu status and randomization). Tumor measurements by PE, MG, and MRI and nodal status by PE and PET were obtained before and after neoadjuvant chemotherapy. Concordance among different clinical measurements was assessed and compared with the tumor and nodal staging by pathology. Spearman corr (r) and root mean square error (RMSE) were used to measure the accuracy of measurements among all modalities and between modalities and pathological tumor size.
RESULTS
Comparing to the tumor size measured by PE, MRI was more accurate than MG at baseline (r 0.559, RMSE 35.4% vs. r 0.046, RMSE 66.1%). After neoadjuvant chemotherapy, PE correlated better with pathology than MG or MRI (r 0.655, RMSE 88.6% vs. r 0.146, RMSE 147.1% and r 0.364, RMSE 92.6%). Axillary nodal assessment after neoadjuvant chemotherapy showed high specificity but low sensitivity by PET and PE.
CONCLUSION
Findings suggested that MRI was a more accurate imaging study at baseline for T3/T4 tumor and PE correlated best with pathology finding. PET and PE both correctly predicted positive axillary nodes but not negative nodes.
doi:10.1002/cncr.24154
PMCID: PMC2761029  PMID: 19156919
20.  Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer 
Context
Breast cancer estrogen-receptor status is useful in predicting benefit from endocrine therapy. It may also help predict which patients benefit from advances in adjuvant chemotherapy.
Objective
Compare differences in benefits from adjuvant chemotherapy achieved by patients with ER-negative versus ER-positive tumors.
Design
Trial data from the Cancer and Leukemia Group B and U.S. Breast Cancer Intergroup analyzed; patient outcomes by ER status compared using hazards over time and multivariate models.
Setting
Randomized trials comparing (1): three regimens of cyclophosphamide, doxorubicin, and fluorouracil; (2) three doses of doxorubicin concurrent with cyclophosphamide, with/without subsequent paclitaxel; (3) sequential doxorubicin, paclitaxel, and cyclophosphamide with concurrent doxorubicin and cyclophosphamide followed by paclitaxel, and also three-week versus two-week cycles.
Patients
Total of 6644 node-positive breast cancer patients receiving adjuvant treatment.
Main Outcome Measures
Disease-free and overall survival.
Results
For ER-negative tumors, chemotherapy improvements reduced the relative risk of recurrence by 21, 25 and 23 percent in the three studies, respectively, and 55 percent comparing the lowest dose in the first study with biweekly cycles in the third study. Corresponding relative risk reductions for ER-positive tumors treated with tamoxifen were 9, 12, and 8 percent in the three studies, and 26 percent overall. The overall mortality rate reductions associated with chemotherapy improvements were 55 and 23 percent among ER-negative and ER-positive patients, respectively. All individual ER-negative comparisons and no ER-positive comparisons were statistically significant. Absolute benefits due to chemotherapy were greater for patients with ER-negative compared with ER-positive tumors: 22.8 percent more ER-negative patients survived to 5 years disease-free if receiving chemotherapy versus 7.0 percent for ER-positive patients; corresponding improvements for overall survival were 16.7 versus 4.0 percent.
Conclusions
Among patients with node-positive, ER-negative breast cancer, biweekly doxorubicin/cyclophosphamide plus paclitaxel lowers the rate of recurrence and death by more than 50 percent in comparison with low dose CAF as used in the first study.
doi:10.1001/jama.295.14.1658
PMCID: PMC1459540  PMID: 16609087
21.  Adjuvant gemcitabine versus NEOadjuvant gemcitabine/oxaliplatin plus adjuvant gemcitabine in resectable pancreatic cancer: a randomized multicenter phase III study (NEOPAC study) 
BMC Cancer  2011;11:346.
Background
Despite major improvements in the perioperative outcome of pancreas surgery, the prognosis of pancreatic cancer after curative resection remains poor. Adjuvant chemotherapy increases disease-free and overall survival, but this treatment cannot be offered to a significant proportion of patients due to the surgical morbidity. In contrast, almost all patients can receive (neo)adjuvant chemotherapy before surgery. This treatment is safe and effective, and has resulted in a median survival of 26.5 months in a recent phase II trial. Moreover, neoadjuvant chemotherapy improves the nutritional status of patients with pancreatic cancer. This multicenter phase III trial (NEOPAC) has been designed to explore the efficacy of neoadjuvant chemotherapy.
Methods/Design
This is a prospective randomized phase III trial. Patients with resectable cytologically proven adenocarcinoma of the pancreatic head are eligible for this study. All patients must be at least 18 years old and must provide written informed consent. An infiltration of the superior mesenteric vein > 180° or major visceral arteries are considered exclusion criteria. Eligible patients will be randomized to surgery followed by adjuvant gemcitabine (1000 mg/m2) for 6 months or neoadjuvant chemotherapy (gemcitabine 1000 mg/m2, oxaliplatin 100 mg/m2) followed by surgery and the same adjuvant treatment. Neoadjuvant chemotherapy is given four times every two weeks. The staging as well as the restaging protocol after neoadjuvant chemotherapy include computed tomography of chest and abdomen and diagnostic laparoscopy. The primary study endpoint is progression-free survival. According to the sample size calculation, 155 patients need to be randomized to each treatment arm. Disease recurrence will be documented by scheduled computed tomography scans 9, 12, 15, 21 and thereafter every 6 months until disease progression. For quality control, circumferential resection margins are marked intraoperatively, and representative histological sections will be centrally reviewed by a dedicated pathologist.
Discussion
The NEOPAC study will determine the efficacy of neoadjuvant chemotherapy in pancreatic cancer for the first time and offers a unique potential for translational research. Furthermore, this trial will provide the unbiased overall survival of all patients undergoing surgery for resectable cancer of the pancreatic head.
Trial registration
clinicalTrials.gov NCT01314027
doi:10.1186/1471-2407-11-346
PMCID: PMC3176241  PMID: 21831266
22.  Design of the Physical exercise during Adjuvant Chemotherapy Effectiveness Study (PACES):A randomized controlled trial to evaluate effectiveness and cost-effectiveness of physical exercise in improving physical fitness and reducing fatigue 
BMC Cancer  2010;10:673.
Background
Cancer chemotherapy is frequently associated with a decline in general physical condition, exercise tolerance, and muscle strength and with an increase in fatigue. While accumulating evidence suggests that physical activity and exercise interventions during chemotherapy treatment may contribute to maintaining cardiorespiratory fitness and strength, the results of studies conducted to date have not been consistent. Additional research is needed to determine the optimal intensity of exercise training programs in general and in particular the relative effectiveness of supervised, outpatient (hospital- or physical therapy practice-based) versus home-based programs.
Methods
This multicenter, prospective, randomized trial will evaluate the effectiveness of a low to moderate intensity, home-based, self-management physical activity program, and a high intensity, structured, supervised exercise program, in maintaining or enhancing physical fitness (cardiorespiratory fitness and muscle strength), in minimizing fatigue and in enhancing the health-related quality of life (HRQoL). Patients receiving adjuvant chemotherapy for breast or colon cancer (n = 360) are being recruited from twelve hospitals in the Netherlands, and randomly allocated to one of the two treatment groups or to a 'usual care' control group. Performance-based and self-reported outcomes are assessed at baseline, at the end of chemotherapy and at six month follow-up.
Discussion
This large, multicenter, randomized clinical trial will provide additional empirical evidence regarding the effectiveness of physical exercise during adjuvant chemotherapy in enhancing physical fitness, minimizing fatigue, and maintaining or enhancing patients' quality of life. If demonstrated to be effective, exercise intervention programs will be a welcome addition to the standard program of care offered to patients with cancer receiving chemotherapy.
Trial registration
This study is registered at the Netherlands Trial Register (NTR 2159)
doi:10.1186/1471-2407-10-673
PMCID: PMC3002358  PMID: 21138561
23.  Weight Change During Chemotherapy as a Potential Prognostic Factor for Stage Iii Epithelial Ovarian Carcinoma: A Gynecologic Oncology Group Study 
Gynecologic oncology  2007;107(2):260-265.
Objective
Platinum/paclitaxel-based chemotherapy is a current treatment for advanced epithelial ovarian cancer. We sought to explore the association between weight change during treatment and survival, as well as the association between pre-chemotherapy body mass index (BMI) and survival.
Methods
A retrospective data review was conducted of 792 advanced ovarian cancer patients who participated in a phase III randomized trial of cisplatin/paclitaxel versus carboplatin/paclitaxel. Pre-chemotherapy BMI was calculated following surgery. Weight change was defined as the ratio of body weight at completion of protocol therapy to pre-chemotherapy body weight. Progression-free survival (PFS) and overall survival (OS), classified by BMI or relative weight change, were estimated by Kaplan-Meier, and associations were assessed using a Cox model controlled for known prognostic variables (age, race, performance status, histology, tumor grade, tumor residual and treatment group).
Results
There was no association between pre-chemotherapy BMI and survival. There was a significant relationship between median OS and weight change as follows: >5% decrease=48.0 months; 0-5% decrease=49.3 months; 0-5% increase=61.1 months; and >5% increase=68.2 months. Adjusted for covariates, the relative risk of death increased by 7% for each 5% decrease in body weight (HR=0.93, 95% CI=0.88-0.99; p=0.013)
Conclusions
Change of body weight during primary chemotherapy was a strong prognostic factor for overall survival. Loss of body weight during primary therapy is an indicator for poor OS; weight gain is an indicator for improved survival. This study supports the development of strategies to minimize weight loss that can be assessed in a prospective, randomized study to improve patient outcomes.
doi:10.1016/j.ygyno.2007.06.010
PMCID: PMC2517223  PMID: 17675142
body weight; BMI; chemotherapy; ovarian cancer; survival
24.  Survival-Related Profile, Pathways, and Transcription Factors in Ovarian Cancer 
PLoS Medicine  2009;6(2):e1000024.
Background
Ovarian cancer has a poor prognosis due to advanced stage at presentation and either intrinsic or acquired resistance to classic cytotoxic drugs such as platinum and taxoids. Recent large clinical trials with different combinations and sequences of classic cytotoxic drugs indicate that further significant improvement in prognosis by this type of drugs is not to be expected. Currently a large number of drugs, targeting dysregulated molecular pathways in cancer cells have been developed and are introduced in the clinic. A major challenge is to identify those patients who will benefit from drugs targeting these specific dysregulated pathways.The aims of our study were (1) to develop a gene expression profile associated with overall survival in advanced stage serous ovarian cancer, (2) to assess the association of pathways and transcription factors with overall survival, and (3) to validate our identified profile and pathways/transcription factors in an independent set of ovarian cancers.
Methods and Findings
According to a randomized design, profiling of 157 advanced stage serous ovarian cancers was performed in duplicate using ∼35,000 70-mer oligonucleotide microarrays. A continuous predictor of overall survival was built taking into account well-known issues in microarray analysis, such as multiple testing and overfitting. A functional class scoring analysis was utilized to assess pathways/transcription factors for their association with overall survival. The prognostic value of genes that constitute our overall survival profile was validated on a fully independent, publicly available dataset of 118 well-defined primary serous ovarian cancers. Furthermore, functional class scoring analysis was also performed on this independent dataset to assess the similarities with results from our own dataset. An 86-gene overall survival profile discriminated between patients with unfavorable and favorable prognosis (median survival, 19 versus 41 mo, respectively; permutation p-value of log-rank statistic = 0.015) and maintained its independent prognostic value in multivariate analysis. Genes that composed the overall survival profile were also able to discriminate between the two risk groups in the independent dataset. In our dataset 17/167 pathways and 13/111 transcription factors were associated with overall survival, of which 16 and 12, respectively, were confirmed in the independent dataset.
Conclusions
Our study provides new clues to genes, pathways, and transcription factors that contribute to the clinical outcome of serous ovarian cancer and might be exploited in designing new treatment strategies.
Ate van der Zee and colleagues analyze the gene expression profiles of ovarian cancer samples from 157 patients, and identify an 86-gene expression profile that seems to predict overall survival.
Editors' Summary
Background.
Ovarian cancer kills more than 100,000 women every year and is one of the most frequent causes of cancer death in women in Western countries. Most ovarian cancers develop when an epithelial cell in one of the ovaries (two small organs in the pelvis that produce eggs) acquires genetic changes that allow it to grow uncontrollably and to spread around the body (metastasize). In its early stages, ovarian cancer is confined to the ovaries and can often be treated successfully by surgery alone. Unfortunately, early ovarian cancer rarely has symptoms so a third of women with ovarian cancer have advanced disease when they first visit their doctor with symptoms that include vague abdominal pains and mild digestive disturbances. That is, cancer cells have spread into their abdominal cavity and metastasized to other parts of the body (so-called stage III and IV disease). The outlook for women diagnosed with stage III and IV disease, which are treated with a combination of surgery and chemotherapy, is very poor. Only 30% of women with stage III, and 5% with stage IV, are still alive five years after their cancer is diagnosed.
Why Was This Study Done?
If the cellular pathways that determine the biological behavior of ovarian cancer could be identified, it might be possible to develop more effective treatments for women with stage III and IV disease. One way to identify these pathways is to use gene expression profiling (a technique that catalogs all the genes expressed by a cell) to compare gene expression patterns in the ovarian cancers of women who survive for different lengths of time. Genes with different expression levels in tumors with different outcomes could be targets for new treatments. For example, it might be worth developing inhibitors of proteins whose expression is greatest in tumors with short survival times. In this study, the researchers develop an expression profile that is associated with overall survival in advanced-stage serous ovarian cancer (more than half of ovarian cancers originate in serous cells, epithelial cells that secrete a watery fluid). The researchers also assess the association of various cellular pathways and transcription factors (proteins that control the expression of other proteins) with survival in this type of ovarian carcinoma.
What Did the Researchers Do and Find?
The researchers analyzed the gene expression profiles of tumor samples taken from 157 patients with advanced stage serous ovarian cancer and used the “supervised principal components” method to build a predictor of overall survival from these profiles and patient survival times. This 86-gene predictor discriminated between patients with favorable and unfavorable outcomes (average survival times of 41 and 19 months, respectively). It also discriminated between groups of patients with these two outcomes in an independent dataset collected from 118 additional serous ovarian cancers. Next, the researchers used “functional class scoring” analysis to assess the association between pathway and transcription factor expression in the tumor samples and overall survival. Seventeen of 167 KEGG pathways (“wiring” diagrams of molecular interactions, reactions and relations involved in cellular processes and human diseases listed in the Kyoto Encyclopedia of Genes and Genomes) were associated with survival, 16 of which were confirmed in the independent dataset. Finally, 13 of 111 analyzed transcription factors were associated with overall survival in the tumor samples, 12 of which were confirmed in the independent dataset.
What Do These Findings Mean?
These findings identify an 86-gene overall survival gene expression profile that seems to predict overall survival for women with advanced serous ovarian cancer. However, before this profile can be used clinically, further validation of the profile and more robust methods for determining gene expression profiles are needed. Importantly, these findings also provide new clues about the genes, pathways and transcription factors that contribute to the clinical outcome of serous ovarian cancer, clues that can now be exploited in the search for new treatment strategies. Finally, these findings suggest that it might eventually be possible to tailor therapies to the needs of individual patients by analyzing which pathways are activated in their tumors and thus improve survival times for women with advanced ovarian cancer.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000024.
This study is further discussed in a PLoS Medicine Perspective by Simon Gayther and Kate Lawrenson
See also a related PLoS Medicine Research Article by Huntsman and colleagues
The US National Cancer Institute provides a brief description of what cancer is and how it develops, and information on all aspects of ovarian cancer for patients and professionals (in English and Spanish)
The UK charity Cancerbackup provides general information about cancer, and more specific information about ovarian cancer
MedlinePlus also provides links to other information about ovarian cancer (in English and Spanish)
The KEGG Pathway database provides pathway maps of known molecular networks involved in a wide range of cellular processes
doi:10.1371/journal.pmed.1000024
PMCID: PMC2634794  PMID: 19192944
25.  HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer 
Introduction
Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial.
Methods
HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro.
Results
Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, P <0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, P <0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (P = 0.004), but not in HER2-positive/ESR1-negative tumors.
Conclusions
Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group.
Introduction The human epidermal growth factor receptor 2 (HER2) is the prototype of a predictive biomarker for targeted treatment [1-8]. International initiatives have established the combination of immunohistochemistry (IHC) and in situ hybridization as the current gold standard [9,10]. As an additional approach determination of HER2 mRNA expression is technically feasible in formalin-fixed paraffin-embedded (FFPE) tissue [11-13]. Crosstalk between the estrogen receptor (ER) and the HER2 pathway has been suggested based on cell culture and animal models [14]. Consequently, the 2011 St Gallen panel has pointed out that HER2-positive tumors should be divided into two groups based on expression of the ER [15].
A retrospective analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 study has suggested that mRNA levels of HER2 and ESR1 might be relevant for the degree of benefit from adjuvant trastuzumab. By subpopulation treatment effect pattern plot (STEPP) analysis in ER-positive tumors, benefit from trastuzumab was shown to be restricted to those with higher levels of HER2 mRNA (S Paik, personal communication, results summarized in [15]).
In our study we evaluated this hypothesis in the neoadjuvant setting in a cohort of 217 patients from the neoadjuvant GeparQuattro trial [5]. All patients had been HER2- positive by local pathology assessment and had received 24 to 36 weeks of neoadjuvant trastuzumab plus an anthracycline/taxane-based chemotherapy. For central evaluation we used three different methods, HER2 IHC, and HER2 silver in situ hybridization (SISH), as well as measurement of HER2 mRNA by quantitative real-time (qRT)-PCR [11].
The primary objective of this analysis was to investigate if pathological complete response (pCR) rate in HER2-positive breast cancer would depend on the level of HER2 mRNA expression, with a separate analysis for HR-positive and -negative tumors. Central evaluation of the HER2 status showed that 27% of the tumors with HER2 overexpression by local pathology were HER2-negative. This enabled us to compare response rates in patients with HER2-positive and -negative tumors as a secondary objective.
doi:10.1186/bcr3384
PMCID: PMC3672694  PMID: 23391338

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