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1.  Breast cancer (non-metastatic) 
BMJ Clinical Evidence  2011;2011:0102.
Introduction
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions after breast-conserving surgery for ductal carcinoma in situ? What are the effects of treatments for primary operable breast cancer? What are the effects of interventions in locally advanced breast cancer (stage 3B)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 83 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding chemotherapy (cyclophosphamide/methotrexate/fluorouracil and/or anthracycline and/or taxane-based regimens), or hormonal treatment to radiotherapy; adjuvant treatments (aromatase inhibitors, adjuvant anthracycline regimens, tamoxifen); axillary clearance; axillary dissection plus sentinel node dissection; axillary radiotherapy; axillary sampling; combined chemotherapy plus tamoxifen; chemotherapy plus monoclonal antibody (trastuzumab); extensive surgery; high-dose chemotherapy; hormonal treatment; less extensive mastectomy; less than whole-breast radiotherapy plus breast-conserving surgery; multimodal treatment; ovarian ablation; primary chemotherapy; prolonged adjuvant combination chemotherapy; radiotherapy (after breast-conserving surgery, after mastectomy, plus tamoxifen after breast-conserving surgery, to the internal mammary chain, and to the ipsilateral supraclavicular fossa, and total nodal radiotherapy); sentinel node biopsy; and standard chemotherapy regimens.
Key Points
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
In women with ductal carcinoma in situ (DCIS), radiotherapy reduces local recurrence and invasive carcinoma after breast-conserving surgery. The role of tamoxifen added to radiotherapy for DCIS remains unclear because of conflicting results.
In women with primary operable breast cancer, survival may be increased by full surgical excision, tamoxifen, chemotherapy, radiotherapy, ovarian ablation, or trastuzumab (in women who over-express HER2/neu oncogene). Incomplete excision may increase the risk of local recurrence, but less-extensive mastectomy that excises all local disease is as effective as radical mastectomy at prolonging survival, with better cosmetic results. Axillary clearance (removal of all axillary lymph nodes) achieves local disease control, but has not been shown to increase survival, and can cause arm lymphoedema. Sentinel lymph node biopsy or 4-node sampling may adequately stage the axilla with less morbidity compared with axillary clearance. Adjuvant tamoxifen reduces the risk of recurrence and death in women with oestrogen-positive tumours. Primary chemotherapy may facilitate successful breast-conserving surgery instead of mastectomy. Adjuvant combination chemotherapy improves survival compared with no chemotherapy, with greatest benefit likely with anthracycline-based regimens at standard doses for 4 to 6 months.Radiotherapy decreases recurrence and mortality after breast-conserving surgery. Post-mastectomy radiotherapy for women who are node-positive or at high risk of recurrence decreases recurrence and mortality. Adjuvant aromatase inhibitors improve disease-free survival compared with tamoxifen, but their effect on overall survival is unclear. Adjuvant taxane-based regimens may improve disease-free survival over standard anthracycline-based therapy.
In women with locally advanced breast cancer, radiotherapy may be as effective as surgery or tamoxifen at increasing survival and local disease control. Adding tamoxifen or ovarian ablation to radiotherapy increases survival compared with radiotherapy alone, but adding chemotherapy may not reduce recurrence or mortality compared with radiotherapy alone.We don't know if chemotherapy alone improves survival in women with locally advanced breast cancer as we found few trials.
PMCID: PMC3217212  PMID: 21718560
2.  Breast cancer (non-metastatic) 
BMJ Clinical Evidence  2007;2007:0102.
Introduction
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions after breast-conserving surgery for ductal carcinoma in situ? What are the effects of treatments for primary operable breast cancer? What are the effects of interventions in locally advanced breast cancer (stage IIIB)? We searched: Medline, Embase, The Cochrane Library and other important databases up to February 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 79 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding chemotherapy (cyclophosphamide/methotrexate/ fluorouracil and/or anthracycline and/or taxane-based regimens), or hormonal treatment to radiotherapy; adjuvant treatments (aromatase inhibitors, adjuvant anthracycline regimens, tamoxifen); axillary clearance; axillary dissection plus sentinel node dissection; axillary radiotherapy; axillary sampling; combined chemotherapy plus tamoxifen; chemotherapy plus monoclonal antibody (trastuzumab); extensive surgery; high-dose chemotherapy; hormonal treatment; less extensive mastectomy; less than whole breast radiotherapy plus breast conserving surgery; multimodal treatment; ovarian ablation; primary chemotherapy; prolonged adjuvant combination chemotherapy; radiotherapy (after breast-conserving surgery, after mastectomy, plus tamoxifen after breast-conserving surgery, to the internal mammary chain, and to the ipsilateral supraclavicular fossa, and total nodal radiotherapy); sentinel node biopsy; and standard chemotherapy regimens.
Key Points
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
In women with ductal carcinoma in situ, radiotherapy reduces local recurrence and invasive carcinoma after breast-conserving surgery, but may not improve survival.
In women with primary operable breast cancer, survival may be increased by full surgical excision, tamoxifen, chemotherapy, radiotherapy, ovarian ablation or trastuzumab (in women who overexpress HER2/neu oncogene). Incomplete excision may increase the risk of local recurrence, but less-extensive mastectomy that excises all local disease is as effective as radical mastectomy at prolonging survival, with better cosmetic results. Axillary clearance (removal of all axillary lymph nodes) achieves local disease control, but has not been shown to increase survival, and can cause arm lymphoedema. Sentinel lymph node biopsy or 4-node sampling may adequately stage the axilla with less morbidity compared with axillary clearance. Adjuvant tamoxifen reduces the risk of recurrence and death in women with oestrogen-positive tumours, but adverse effects begin to outweigh benefit after 5 years of treatment. Primary chemotherapy may facilitate successful breast-conserving surgery instead of mastectomy. Adjuvant combination chemotherapy improves survival compared with no chemotherapy, with greatest benefit likely with anthracycline-based regimens at standard doses for 4-6 months.Radiotherapy decreases recurrence and mortality after breast-conserving surgery. Post-mastectomy radiotherapy for women who are node-positive or at high risk of recurrence decreases recurrence and mortality, but may increase mortality in node-negative women. Adjuvant aromatase inhibitors improve disease-free survival compared with tamoxifen, but their effect on overall survival is unclear.Adjuvant taxoid regimens may improve disease-free survival over standard anthracycline-based therapy.
In women with locally advanced breast cancer, radiotherapy may be as effective as surgery or tamoxifen at increasing survival and local disease control. Adding tamoxifen or ovarian ablation to radiotherapy increases survival compared with radiotherapy alone, but adding chemotherapy may not reduce recurrence or mortality compared with radiotherapy alone.Chemotherapy alone, while widely used, does not improve survival in women with locally advanced breast cancer.
PMCID: PMC2943780  PMID: 19450345
3.  Completion of Adjuvant Radiation Therapy Among Women With Breast Cancer 
Cancer  2008;113(1):22-29.
BACKGROUND
Optimal treatment for breast cancer often involves lengthy multimodality care including 5 to 6 weeks of radiotherapy, but few studies have evaluated adherence to radiotherapy outside the context of a therapeutic clinical trial.
METHODS
Using a SEER-Medicare database, the authors identified women age 66 years or older with Stage I to III breast cancer diagnosed between 1992 and 2002. They evaluated rates of completion of radiotherapy, defined as a minimum of 25 sessions. Multivariate logistic regression analyses were performed to determine factors associated with completion of radiotherapy, and Cox multivariate models were used to determine the impact of radiotherapy completion on local recurrence.
RESULTS
Some 24,510 patients were included in the study. Eighty-seven percent of patients completed 25 or more radiotherapy sessions. In multivariate logistic regression models, mastectomy (HR 1.26, 95% CI 1.10-1.43), hospitalization during treatment (2.87, 2.49-3.31), earlier year of diagnosis, and black race (1.36, 1.14-1.63) were associated with increased risk of non-completion of radiotherapy. Among 21,269 patients treated with breast conservation, incomplete radiotherapy was associated with higher risk of local recurrence. A total of 98.7% of patients who did not complete radiation therapy were free of recurrence at 5 years vs. 97.5% of patients who completed radiation therapy (HR 1.46, CI 1.09-1.95).
CONCLUSION
This study demonstrates relatively high rates of completion of radiation therapy among a population of older woman with breast cancer. However, those who did not complete a full course of radiotherapy had small but statistically significant higher risk of breast cancer recurrence. Future efforts should focus on intervening with women at high risk of not receiving adjuvant radiotherapy and increasing rates of radiotherapy completion.
doi:10.1002/cncr.23513
PMCID: PMC4006973  PMID: 18442124
breast cancer; adjuvant radiotherapy completion; aging; recurrence
4.  Oncological safety of immediate rectus abdominis myocutaneous breast reconstruction in patients with locally advanced disease (stage IIb and III) 
South Asian Journal of Cancer  2013;2(4):239-242.
Background:
The management of locally advanced (Stage IIb and III) breast cancer is challenging. It often includes multimodal treatment with systemic therapy and/or radiation therapy and surgery. Immediate breast reconstruction has not traditionally been performed in these patients. We review the results of immediate rectus abdominis musculo-cutaneous (TRAM/VRAM) flap in 60 patients treated for Stage IIb and III breast cancer.
Materials and Methods:
Data were collected prospectively on 60 patients diagnosed with Stage IIb (32 patients) and Stage III (28 patients) breast cancer between May 2008 and May 2012. All patients had mastectomy and immediate rectus abdominis myocutaneous reconstruction (TRAM in 40 patients and VRAM in 20 patients). All patients received primary systemic therapy, and all patients received postoperative radiotherapy to the operative site.
Results:
Mean age was 40.13 (range 28-53) years, mean hospital stay was 8.86 days and mean follow-up for the group was 28 months. Neither of them developed local disease recurrence in the operative site till the last follow-up. Eight (13.3%) patients had some delay in chemo-radiation therapy due to flap-related complications. Flap-related complications were present in eight patients (partial flap failure in four and superficial skin necrosis in four). There was no adverse effect of chemo-radiation therapy on reconstructed breast.
Conclusion:
Immediate TRAM/VRAM breast reconstruction for locally advanced breast cancer is not associated with a significant delay in adjuvant therapy or an increased risk of local relapse. Radiation therapy can be delivered to the reconstructed breast when indicated without difficulty. Breast reconstruction facilitates surgical resection of locally advanced breast cancer with primary closure and should be considered if the patient desires immediate breast reconstruction.
doi:10.4103/2278-330X.119921
PMCID: PMC3889050  PMID: 24455647
Immediate breast reconstruction; rectus abdominis myocutaneous reconstruction; mastectomy
5.  Second Cancer Incidence Risk Estimates using BEIR VII Models for Standard and Complex External Beam Radiotherapy for Early Breast Cancer 
Medical physics  2012;39(10):5814-5824.
Purpose
To compare organ specific cancer incidence risks for standard and complex external beam radiotherapy including cone beam CT verification following breast conservation surgery for early breast cancer.
Method
Doses from breast radiotherapy and kilovoltage cone beam CT (CBCT) exposures were obtained from thermoluminescent dosimeter (TLD) measurements in an anthropomorphic phantom in which the positions of radiosensitive organs were delineated. Five treatment deliveries were investigated : (i) conventional tangential field whole breast radiotherapy (WBRT), (ii) non-coplanar conformal delivery applicable to accelerated partial beast irradiation (APBI), (iii) two-volume simultaneous integrated boost (SIB) treatment, (iv) forward planned three-volume SIB, (v) inverse-planned three volume SIB. Conformal and intensity modulated radiotherapy (IMRT) methods were used to plan the complex treatments. Techniques spanned the range from simple methods appropriate for patient cohorts with a low local cancer recurrence risk to complex plans relevant to cohorts with high recurrence risk. Delineated organs at risk included brain, salivary glands, thyroid, contra-lateral breast, left and right lung, oesophagus, stomach, liver, colon and bladder. Biological Effects of Ionising Radiation (BEIR) VII cancer incidence models were applied to the measured mean organ doses to determine Lifetime Attributable Risk (LAR) for ages at exposure from 35 to 80 years according to radiotherapy techniques, and included dose from the CBCT imaging.
Results
All LAR decreased with age at exposure and were lowest for brain, thyroid, liver and bladder (< 0.1%). There was little dependence of LAR on radiotherapy technique for these organs and for colon and stomach. LAR values for the lungs for the three SIB techniques were two to three times those from WBRT and APBI. Uncertainties in the LAR models outweigh any differences in lung LAR between the SIB methods. Constraints in the planning of the SIB methods ensured that contra-lateral breast doses and LAR were comparable to WBRT, despite their added complexity. The smaller irradiated volume of the ABPI plan contributed to a halving of LAR for contralateral breast compared with the other plan types. Daily image guided radiotherapy (IGRT) for a left breast protocol using kilovoltage CBCT contributed <10% to LAR for the majority of organs, and did not exceed 22% of total organ dose.
Conclusion
Phantom measurements and calculations of LAR from the BEIR VII models predict that complex breast radiotherapy techniques do not increase the theoretical risk of second cancer incidence for organs distant from the treated breast, or the contralateral breast where appropriate plan constraints are applied. Complex SIB treatments are predicted to increase the risk of second cancer incidence in the lungs compared to standard whole breast radiotherapy ; this is outweighed by the threefold reduction in 5 year local recurrence risk for patients of high risk of recurrence, and young age, from the use of radiotherapy. APBI may have a favourable impact on risk of second cancer in the contra-lateral breast and lung for older patients at low risk of recurrence. Intensive use of IGRT increased the estimated values of LAR but these are dominated by the effect of the dose from the radiotherapy, and any increase in LAR from IGRT is much lower than the models’ uncertainties.
doi:10.1118/1.4748332
PMCID: PMC3498624  PMID: 23039620
second cancer incidence; breast radiotherapy; image-guided radiotherapy; partial breast
6.  Radiotherapy in patients with distant metastatic breast cancer 
Background
The study evaluates frequency of and indications for disease-related radiotherapy in the palliative breast cancer (BC) situation and analyzes in which phase of the palliative disease course radiotherapy was applied.
Patients & methods
340 patients who developed distant metastatic disease (DMD) and died (i.e. patients with completed disease courses) were analyzed.
Results
165 patients (48.5%) received palliative radiotherapy (255 series, 337 planning target volumes) as a part of palliative care. The most common sites for radiotherapy were the bone (217 volumes, 64.4% of all radiated volumes) and the brain (57 volumes, 16.9%). 127 series (49.8%) were performed in the first third of the metastatic disease survival (MDS) period; 84 series (32.8%) were performed in the last third. The median survival after radiotherapy was 10 months. Patients who had received radiation were younger compared to those who had no radiation (61 vs. 68 years, p < 0.001) and had an improved MDS (26 vs. 14 months, p < 0.001). Compared to rapidly progressive disease courses with short survival times, in cases where effective systemic therapy achieved a longer MDS (≥24 months), radiotherapy was significantly more often a part of the multimodal palliative therapy (52.1% vs. 37.1%, p = 0.006).
Conclusions
In a cohort of BC patients with DMD, nearly one half of the patients received radiotherapy during the palliative disease course. In a palliative therapy approach, which increasingly allows for treatment according to the principles of a chronic disease, radiotherapy has a clearly established role in the therapy concept.
doi:10.1186/1748-717X-9-126
PMCID: PMC4058701  PMID: 24885766
Breast cancer; Distant metastases; Palliative radiotherapy
7.  Outcome and clinico-biological characteristics of advanced breast cancer patients with surgically resected brain metastases: a multidisciplinary approach 
ecancermedicalscience  2013;7:309.
Background:
Despite improvements in brain surgery and radiotherapy, patients with brain metastases (BM) from breast cancer still have a poor prognosis. The aim of the present study is to evaluate the outcome of a multimodal therapeutic strategy in an unselected cohort of patients.
Methods:
We retrospectively reviewed 24 breast cancer patients who developed BM and were treated with brain surgery, radiotherapy, and/or systemic therapy in the same institutions.
Results:
Primary treatment for BM was surgery in the whole cohort, radiotherapy in 11 patients, radiotherapy combined with systemic therapy in nine patients, and systemic therapy as single treatment in six patients (chemo/targeted therapy n= 4; hormonal therapy n=2). The median time from breast cancer diagnosis to brain surgery was 57.6 months (range 1.8–130.7 months). The overall survival from surgery for BM was 22 months and the overall survival from BM surgery by presence of other metastatic sites at surgery was 25 months for patients with BM only and 11 months for patients with other metastatic sites (p=0.046).
Conclusion:
Although this study is retrospective and limited by the small number of patients, the overall survival of 22 months from the time of brain surgery represents an excellent outcome. The multidisciplinary approach that combines the efforts of specialists from different disciplines leads to satisfactory results for patients in terms of survival in the current clinical practice and prospective subtype-oriented trials are urgently required in this category of patients.
doi:10.3332/ecancer.2013.309
PMCID: PMC3634722  PMID: 23634179
breast cancer; brain metastases; surgery; medical treatments; survival outcomes
8.  Simultaneous integrated boost for adjuvant treatment of breast cancer- intensity modulated vs. conventional radiotherapy: The IMRT-MC2 trial 
BMC Cancer  2011;11:249.
Background
Radiation therapy is an essential modality in the treatment of breast cancer. Addition of radiotherapy to surgery has significantly increased local control and survival rates of the disease. However, radiotherapy is also associated with side effects, such as tissue fibrosis or enhanced vascular morbidity. Modern radiotherapy strategies, such as intensity modulated radiotherapy (IMRT), can shorten the overall treatment time by integration of the additional tumor bed boost significantly. To what extent this might be possible without impairing treatment outcome and cosmetic results remains to be clarified.
Methods/Design
The IMRT-MC2 study is a prospective, two armed, multicenter, randomized phase-III-trial comparing intensity modulated radiotherapy with integrated boost to conventional radiotherapy with consecutive boost in patients with breast cancer after breast conserving surgery. 502 patients will be recruited and randomized into two arms: patients in arm A will receive IMRT in 28 fractions delivering 50.4 Gy to the breast and 64.4 Gy to the tumor bed by integrated boost, while patients in arm B will receive conventional radiotherapy of the breast in 28 fractions to a dose of 50.4 Gy and consecutive boost in 8 fractions to a total dose of 66.4 Gy.
Discussion
Primary objectives of the study are the evaluation of the cosmetic results 6 weeks and 2 years post treatment and the 2- and 5-year local recurrence rates for the two different radiotherapy strategies. Secondary objectives are long term overall survival, disease free survival and quality of life.
Trial Registration
ClinicalTrials.gov Protocol ID: NCT01322854.
doi:10.1186/1471-2407-11-249
PMCID: PMC3150341  PMID: 21676232
9.  DEAR1 Is a Dominant Regulator of Acinar Morphogenesis and an Independent Predictor of Local Recurrence-Free Survival in Early-Onset Breast Cancer 
PLoS Medicine  2009;6(5):e1000068.
Ann Killary and colleagues describe a new gene that is genetically altered in breast tumors, and that may provide a new breast cancer prognostic marker.
Background
Breast cancer in young women tends to have a natural history of aggressive disease for which rates of recurrence are higher than in breast cancers detected later in life. Little is known about the genetic pathways that underlie early-onset breast cancer. Here we report the discovery of DEAR1 (ductal epithelium–associated RING Chromosome 1), a novel gene encoding a member of the TRIM (tripartite motif) subfamily of RING finger proteins, and provide evidence for its role as a dominant regulator of acinar morphogenesis in the mammary gland and as an independent predictor of local recurrence-free survival in early-onset breast cancer.
Methods and Findings
Suppression subtractive hybridization identified DEAR1 as a novel gene mapping to a region of high-frequency loss of heterozygosity (LOH) in a number of histologically diverse human cancers within Chromosome 1p35.1. In the breast epithelium, DEAR1 expression is limited to the ductal and glandular epithelium and is down-regulated in transition to ductal carcinoma in situ (DCIS), an early histologic stage in breast tumorigenesis. DEAR1 missense mutations and homozygous deletion (HD) were discovered in breast cancer cell lines and tumor samples. Introduction of the DEAR1 wild type and not the missense mutant alleles to complement a mutation in a breast cancer cell line, derived from a 36-year-old female with invasive breast cancer, initiated acinar morphogenesis in three-dimensional (3D) basement membrane culture and restored tissue architecture reminiscent of normal acinar structures in the mammary gland in vivo. Stable knockdown of DEAR1 in immortalized human mammary epithelial cells (HMECs) recapitulated the growth in 3D culture of breast cancer cell lines containing mutated DEAR1, in that shDEAR1 clones demonstrated disruption of tissue architecture, loss of apical basal polarity, diffuse apoptosis, and failure of lumen formation. Furthermore, immunohistochemical staining of a tissue microarray from a cohort of 123 young female breast cancer patients with a 20-year follow-up indicated that in early-onset breast cancer, DEAR1 expression serves as an independent predictor of local recurrence-free survival and correlates significantly with strong family history of breast cancer and the triple-negative phenotype (ER−, PR−, HER-2−) of breast cancers with poor prognosis.
Conclusions
Our data provide compelling evidence for the genetic alteration and loss of expression of DEAR1 in breast cancer, for the functional role of DEAR1 in the dominant regulation of acinar morphogenesis in 3D culture, and for the potential utility of an immunohistochemical assay for DEAR1 expression as an independent prognostic marker for stratification of early-onset disease.
Editors' Summary
Background
Each year, more than one million women discover that they have breast cancer. This type of cancer begins when cells in the breast that line the milk-producing glands or the tubes that take the milk to the nipples (glandular and ductal epithelial cells, respectively) acquire genetic changes that allow them to grow uncontrollably and to move around the body (metastasize). The uncontrolled division leads to the formation of a lump that can be detected by mammography (a breast X-ray) or by manual breast examination. Breast cancer is treated by surgical removal of the lump or, if the cancer has started to spread, by removal of the whole breast (mastectomy). Surgery is usually followed by radiotherapy or chemotherapy. These “adjuvant” therapies are designed to kill any remaining cancer cells but can make patients very ill. Generally speaking, the outlook for women with breast cancer is good. In the US, for example, nearly 90% of affected women are still alive five years after their diagnosis.
Why Was This Study Done?
Although breast cancer is usually diagnosed in women in their 50s or 60s, some women develop breast cancer much earlier. In these women, the disease is often very aggressive. Compared to older women, young women with breast cancer have a lower overall survival rate and their cancer is more likely to recur locally or to metastasize. It would be useful to be able to recognize those younger women at the greatest risk of cancer recurrence so that they could be offered intensive surveillance and adjuvant therapy; those women at a lower risk could have gentler treatments. To achieve this type of “stratification,” the genetic changes that underlie breast cancer in young women need to be identified. In this study, the researchers discover a gene that is genetically altered (by mutations or deletion) in early-onset breast cancer and then investigate whether its expression can predict outcomes in women with this disease.
What Did the Researchers Do and Find?
The researchers used “suppression subtractive hybridization” to identify a new gene in a region of human Chromosome 1 where loss of heterozygosity (LOH; a genetic alteration associated with cancer development) frequently occurs. They called the gene DEAR1 (ductal epithelium-associated RING Chromosome 1) to indicate that it is expressed in ductal and glandular epithelial cells and encodes a “RING finger” protein (specifically, a subtype called a TRIM protein; RING finger proteins such as BRCA1 and BRCA2 have been implicated in early cancer development and in a large fraction of inherited breast cancers). DEAR1 expression was reduced or lost in several ductal carcinomas in situ (a local abnormality that can develop into breast cancer) and advanced breast cancers, the researchers report. Furthermore, many breast tumors carried DEAR1 missense mutations (genetic changes that interfere with the normal function of the DEAR1 protein) or had lost both copies of DEAR1 (the human genome contains two copies of most genes). To determine the function of DEAR1, the researchers replaced a normal copy of DEAR1 into a breast cancer cell that had a mutation in DEAR1. They then examined the growth of these genetically manipulated cells in special three-dimensional cultures. The breast cancer cells without DEAR1 grew rapidly without an organized structure while the breast cancer cells containing the introduced copy of DEAR1 formed structures that resembled normal breast acini (sac-like structures that secrete milk). In normal human mammary epithelial cells, the researchers silenced DEAR1 expression and also showed that without DEAR1, the normal mammary cells lost their ability to form proper acini. Finally, the researchers report that DEAR1 expression (detected “immunohistochemically”) was frequently lost in women who had had early-onset breast cancer and that the loss of DEAR1 expression correlated with reduced local recurrence-free survival, a strong family history of breast cancer and with a breast cancer subtype that has a poor outcome.
What Do These Findings Mean?
These findings indicate that genetic alteration and loss of expression of DEAR1 are common in breast cancer. Although laboratory experiments may not necessarily reflect what happens in people, the results from the three-dimensional culture of breast epithelial cells suggest that DEAR1 may regulate the normal acinar structure of the breast. Consequently, loss of DEAR1 expression could be an early event in breast cancer development. Most importantly, the correlation between DEAR1 expression and both local recurrence in early-onset breast cancer and a breast cancer subtype with a poor outcome suggests that it might be possible to use DEAR1 expression to identify women with early-onset breast cancer who have an increased risk of local recurrence so that they get the most appropriate treatment for their cancer.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000068.
This study is further discussed in a PLoS Medicine Perspective by Senthil Muthuswamy
The US National Cancer Institute provides detailed information for patients and health professionals on all aspects of breast cancer, including information on genetic alterations in breast cancer (in English and Spanish)
The MedlinePlus Encyclopedia provides information for patients about breast cancer; MedlinePlus also provides links to many other breast cancer resources (in English and Spanish)
The UK charities Cancerbackup (now merged with MacMillan Cancer Support) and Cancer Research UK also provide detailed information about breast cancer
doi:10.1371/journal.pmed.1000068
PMCID: PMC2673042  PMID: 19536326
10.  Neoadjuvant Radiotherapy/Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer 
Balkan Medical Journal  2015;32(1):1-7.
Locally advanced non-small cell lung cancer (NSCLC) consists of a heterogeneous group of patients, and the optimal treatment is still controversial. The current standard of care is concurrent chemoradiotherapy. The prognosis is still poor, with high rates of local and distant failure despite multimodality treatment. One of the efforts to improve outcomes in these patients is to use neoadjuvant treatment to improve resectability, and downstaging the nodal disease, which has a clear impact on prognosis. Radiotherapy as the sole neoadjuvant modality has been used historically without any survival benefit, but with increased toxicity. After the demonstrating a survival benefit by combining radiotherapy and chemotherapy, phase II studies were started to determine the neoadjuvant administration of these two modalities together. Although the results of these studies revealed a heterogeneous postinduction pathologic complete response, tumor and nodal down-staging can be achieved at the cost of a slightly higher morbidity and mortality. Subsequent phase III trials also failed to show a survival benefit to surgery, but indicated that there may be a subset of patients with locally advanced disease who can benefit from resection unless pneumonectomy is not provided. In order to increase the efficacy of radiotherapy, hyperfractionated-accelerated schedules have been used with promising complete pathologic response rates, which might improve prognosis. Recently, studies applying high radiotherapy doses in the neoadjuvant setting demonstrated the safety of resection after radiotherapy, with high nodal clearance rates and encouraging long-term survival results.
In conclusion, neoadjuvant treatment of locally advanced NSCLC is one of the most challenging issues in the treatment of this disease, but it can be offered to appropriately selected patients, and should be done by a multidisciplinary team. Individual risk profiles, definite role of radiotherapy with optimal timing, and dose need to be clarified by carefully designed clinical trials.
doi:10.5152/balkanmedj.2014.14573
PMCID: PMC4342120  PMID: 25759765
Locally advanced non-small cell lung cancer; neoadjuvant chemoradiotherapy; neoadjuvant radiotherapy
11.  Imaging for new radiotherapy techniques 
Cancer Imaging  2010;10(1A):S73.
Abstract
Radiotherapy could be considerably improved by the recent development of three-dimensional intensity-modulated radiation therapy. This technique allows the concept of so-called dose painting or adaptive dose distribution to be implemented with improved aligning of the dose distribution along the complex geometric arrangements of the tumour and the surround healthy critical structures. This enables the radiation dose in the tumour to be increasingly enhanced while sparing the normal tissue. Furthermore, many subfields enable the dose distribution within the tumour to be varied considering local differences in the functional tumour characteristics. Tumour heterogeneity or even variations in tumour volume and viability during radiotherapy may be considered. However, the success of the treatment increasingly depends on the capability of oncologic imaging tools to precisely localize and delineate the tumour and to provide information about its functional heterogeneity. The challenge in oncologic imaging is to improve and further develop novel concepts for precise tumour delineation and characterization. Important achievements in biologic imaging with morphologic functional computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET)/CT have the potential to modify the delineation of target volumes and to increase the dose in selected subvolumes. For example, novel PET markers of tumour hypoxia or proliferation have been developed for functional characterization of various tumour entities. Information from several other modalities such as dual energy CT, functional MRI (dynamic contract-enhanced MRI, diffusion-weighted imaging, arterial spin labelling, magnetic resonance spectroscopic imaging (MRSI), etc.) as well as from novel technological advances such as MR/PET may also be integrated in the radiotherapy plan. Data postprocessing with precise spatial coregistration of multimodal morphologic and functional imaging data as well as quality assurance aspects are still challenging. To overcome these problems novel concepts for hardware integration of CT and MRI with linear accelerators (CT/Linac, MR/Linac) are currently under development. The presentation outlines the current concepts of dose painting in radiotherapy for better planning and control of the final dose distribution and discusses the challenges and the potential of modern oncologic imaging in this context.
doi:10.1102/1470-7330.2010.9034
PMCID: PMC2967147
12.  Health-related quality of life in survivors of stage I-II breast cancer: randomized trial of post-operative conventional radiotherapy and hypofractionated tomotherapy 
BMC Cancer  2012;12:495.
Background
Health-related quality of life (HRQOL) assessment is a key component of clinical oncology trials. However, few breast cancer trials comparing adjuvant conventional radiotherapy (CR) and hypofractionated tomotherapy (TT) have investigated HRQOL. We compared HRQOL in stage I-II breast cancer patients who were randomized to receive either CR or TT. Tomotherapy uses an integrated computed tomography scanner to improve treatment accuracy, aiming to reduce the adverse effects of radiotherapy.
Methods
A total of 121 stage I–II breast cancer patients who had undergone breast conserving surgery (BCS) or mastectomy (MA) were randomly assigned to receive either CR or TT. CR patients received 25 × 2 Gy over 5 weeks, and BCS patients also received a sequential boost of 8 × 2 Gy over 2 weeks. TT patients received 15 × 2.8 Gy over 3 weeks, and BCS patients also received a simultaneous integrated boost of 15 × 0.6 Gy over 3 weeks. Patients completed the EORTC QLQ-C30 and BR23 questionnaires. The mean score (± standard error) was calculated at baseline, the end of radiotherapy, and at 3 months and 1, 2, and 3 years post-radiotherapy. Data were analyzed by the 'intention-to-treat' principle.
Results
On the last day of radiotherapy, patients in both treatment arms had decreased global health status and functioning scores; increased fatigue (clinically meaningful in both treatment arms), nausea and vomiting, and constipation; decreased arm symptoms; clinically meaningful increased breast symptoms in CR patients and systemic side effects in TT patients; and slightly decreased body image and future perspective.
At 3 months post-radiotherapy, TT patients had a clinically significant increase in role- and social-functioning scores and a clinically significant decrease in fatigue. The post-radiotherapy physical-, cognitive- and emotional-functioning scores improved faster in TT patients than CR patients. TT patients also had a better long-term recovery from fatigue than CR patients. ANOVA with the Bonferroni correction did not show any significant differences between groups in HRQOL scores.
Conclusions
TT patients had a better improvement in global health status and role- and cognitive-functioning, and a faster recovery from fatigue, than CR patients. These results suggest that a shorter fractionation schedule may reduce the adverse effects of treatment.
doi:10.1186/1471-2407-12-495
PMCID: PMC3492203  PMID: 23098579
Health-related quality of life; Breast cancer; Hypofractionated radiotherapy; Adjuvant treatment; Randomized trial
13.  Primary Tumor Resection as a Component of Multimodality Treatment May Improve Local Control and Survival in Stage IV Inflammatory Breast Cancer 
Cancer  2014;120(9):1319-1328.
Background
The benefit of primary tumor resection for metastatic inflammatory breast cancer (IBC) patients is unknown.
Methods
We reviewed 172 cases of metastatic IBC. All received chemotherapy with or without radiotherapy and/or surgery. Patients were classified as responders or non-responders to chemotherapy. Five-year overall (OS) and distant progression-free survival (DPFS) and local control at last follow-up were evaluated.
Results
Seventy-nine (46%) patients underwent surgery. OS and DPFS were better with surgery vs no surgery (47% vs 10%, respectively, p<0.001 and 30% vs 3%, p<0.001). Surgery plus radiotherapy was associated with better survival compared to treatment with surgery or radiotherapy alone (OS: 50% vs 25% vs 14%, respectively, DPFS: 32% vs 18% vs 15%, p<0.0001 for both). Surgery was associated with better survival for both responders (surgery vs no surgery OS: 49% vs 23%, p<0.0001, DPFS: 31% vs 8%, p<0.0001) and non-responders (surgery vs no surgery OS: 40% vs 6%, p<0.0001, DPFS: 30% vs 0, p<0.0001). On multivariate analysis, treatment with surgery plus radiotherapy and response to chemotherapy were significant predictors of better OS and DPFS. Local control at last follow-up was 4-fold more likely in patients who underwent surgery with or without radiotherapy compared to patients who received chemotherapy alone (81% vs 18%, p<.0001). Surgery and response to chemotherapy independently predicted local control on multivariate analysis.
Conclusion
This study demonstrates that for select patients with metastatic IBC, multimodality treatment including primary tumor resection may result in better local control and survival. A randomized trial is needed to validate these findings.
doi:10.1002/cncr.28550
PMCID: PMC4278570  PMID: 24510381
breast cancer; inflammatory breast cancer; survival; local control; multimodality treatment; combined modality therapy; metastatic breast cancer
14.  Factors that predict early treatment failure for patients with locally advanced (T4) breast cancer 
British Journal of Cancer  2008;98(11):1745-1752.
Locally advanced breast cancer (LABC) is associated with dire prognosis despite progress in multimodal treatments. We evaluated several clinical and pathological features of patients with either noninflammatory (NIBC, cT4a-c) or inflammatory (IBC, cT4d) breast cancer to identify subset groups of patients with high risk of early treatment failure. Clinical and pathological features of 248 patients with LABC, who were treated with multimodality treatments including neoadjuvant chemotherapy followed by radical surgery and radiotherapy were reassessed. Tumour samples obtained at surgery were evaluated using standard immunohistochemical methods. Overall, 141 patients (57%) presented with NIBC (cT4a-c, N0-2, M0) and 107 patients (43%) with IBC (cT4d, N0-2, M0). Median follow-up time was 27.5 months (range: 1.6–87.8). No significant difference in terms of recurrence-free survival (RFS) (P=0.72), disease-free survival (DFS) (P=0.98) and overall survival (OS) (P=0.35) was observed between NIBC and IBC. At the multivariate analysis, patients with ER- and PgR-negative diseases had a significantly worse RFS than patients with ER- and/or PgR-positive diseases (hazard ratio: 2.47, 95% CI: 1.33–4.59 for overall). The worst RFS was observed for the subgroup of patients with endocrine nonresponsive and HER2-negative breast cancer (2-year RFS: 57% in NIBC and 57% in IBC) A high Ki-67 labelling index (>20% of the invasive tumour cells) and the presence of peritumoral vascular invasion (PVI) significantly correlated with poorer RFS in overall (HR 2.69, 95% CI: 1.61–4.50 for Ki-67>20% and HR 2.27, 95% CI: 1.42–3.62 for PVI). Patients with endocrine nonresponsive LABC had the most dire treatment outcome. High degree of Ki-67 staining and presence of PVI were also indicators of higher risk of early relapse. These factors should be considered in therapeutic algorithms for LABC.
doi:10.1038/sj.bjc.6604384
PMCID: PMC2410124  PMID: 18506176
prognostic factors; preoperative therapy; surgery; locally advanced breast cancer
15.  Clinical management of gastroesophageal junction tumors: past and recent evidences for the role of radiotherapy in the multidisciplinary approach 
Gastroesophageal cancers (such as esophageal, gastric and gastroesophageal-junction -GEJ- lesions) are worldwide a leading cause of death being relatively rare but highly aggressive. In the past years, a clear shift in the location of upper gastrointestinal tract tumors has been recorded, both affecting the scientific research and the modern clinical practice. The integration of pre- or peri-operative multimodal approaches, as radiotherapy and chemotherapy (often combined), seems promising to further improve clinical outcome for such presentations. In the past, the definition of GEJ led to controversies and confusion: GEJ tumors have been managed either grouped to gastric or esophageal lesions, following slightly different surgical, radiotherapeutic and systemic approaches. Recently, the American Joint Committee on Cancer (AJCC) changed the staging and classification system of GEJ to harmonize some staging issues for esophageal and gastric cancer. This review discusses the most relevant historical and recent evidences of neoadjuvant treatment involving Radiotherapy for GEJ tumors, and describes the efficacy of such treatment in the frame of multimodal integrated therapies, from the new point of view of the recent classification of such tumors.
doi:10.1186/1748-717X-9-45
PMCID: PMC3942272  PMID: 24499595
Gastroesophageal; Gastric; Esophageal; Review; Radiotherapy; Radiochemotherapy; Chemoradiation; Tumor; Chemotherapy; Management
16.  Fifteen-year median follow-up results after neoadjuvant doxorubicin, followed by mastectomy, followed by adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) followed by radiation for stage III breast cancer: a phase II trial (CALGB 8944) 
Purpose
To describe long-term results of a multimodality strategy for stage III breast cancer utilizing neoadjuvant doxorubicin followed by mastectomy, CMF, and radiotherapy.
Patients and methods
Women with biopsy-proven, clinical stage III breast cancer and adequate organ function were eligible. Neoadjuvant doxorubicin (30 mg/m2 days 1–3, every 28 days for 4 cycles) was followed by mastectomy, in stable or responding patients. Sixteen weeks of postoperative CMF followed (continuous oral cyclophosphamide (2 mg/kg/day); methotrexate (0.7 mg/kg IV) and fluorouracil (12 mg/kg IV) weekly, weeks 1–8, and than biweekly, weeks 9–16). Radiation therapy followed adjuvant chemotherapy.
Results
Clinical response rate was 71% (79/111, 95% CI = 62–79%), with 19% complete clinical response. Pathologic complete response was 5% (95% CI = 2–11%). Median follow-up is 15.6 years. Half of the patients progressed by 2.2 years; half died by 5.4 years (range 6 months–15 years). The hazard of dying was greatest in the first 5 years after diagnosis and declined thereafter. Time to progression and overall survival were predicted by number of pathologically involved lymph nodes (TTP: HR [10 vs. 1 node] 2.40, 95% CI = 1.63–3.53, P < 0.0001; OS: HR 2.50, 95% CI = 1.74–3.58, P < 0.0001).
Conclusions
After multimodality treatment for locally advanced breast cancer, long-term survival was correlated with the number of pathologically positive lymph nodes, but not to clinical response. The hazard of death was highest during the first 5 years after diagnosis and declined thereafter, indicating a possible intermediate endpoint for future trials of neoadjuvant treatment.
doi:10.1007/s10549-008-9943-2
PMCID: PMC4217205  PMID: 18306034
Breast cancer; Chemotherapy; Locally advanced; Long-term follow-up; Neoadjuvant; Stage III
17.  Concurrent chemo-radiotherapy following neoadjuvant chemotherapy in locally advanced breast cancer 
Background
Despite broad advances in multimodal treatment of locally advanced breast cancer (LABC), 30 to 40% of patients develop loco-regional relapse. The aim of this study was to analyze in a retrospective manner the effectiveness of concurrent chemo-radiotherapy (CCRTh) after neoadjuvant chemotherapy (NCT) in patients with LABC.
Methods
One hundred twelve patients with LABC (stage IIB-IIIB) were treated with NCT (5-fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 (FAC), or doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (AC) IV in four 21-day courses) followed by CCRTh (60 Gy breast irradiation and weekly mitomycin 5 mg/m2, 5-fluorouracil 500 mg/m2, and dexamethasone 16 mg, or cisplatin 30 mg/m2, gemcitabine 100 mg/m2 and dexamethasone 16 mg), and 6–8 weeks later, surgery and two additional courses of FAC, AC, or paclitaxel 90 mg/m2 weekly for 12 weeks, and in case of estrogen-receptor positive patients, hormonal therapy.
Results
Stages IIB, IIIA and -B were 21.4, 42.9, and 35.7%, respectively. Pathological complete response (pCR) in the breast was 42% (95% CI, 33.2–50.5%) and, 29.5% (95% CI, 21.4–37.5%) if including both the breast and the axillary nodes. Multivariate analysis showed that the main determinant of pCR was negative estrogen-receptor status (HR = 3.8; 95% CI, 1.5–9; p = 0.016). The 5-year disease-free survival (DFS) was 76.9% (95% CI, 68.2–84.7%). No relationship between pCR and DFS was found. Multivariate analysis demonstrated that the main DFS determinant was clinical stage (IIB and IIIA vs. IIIB, HR = 3.1; 95% CI, 1.02–9.74; p = 0.04). Only one patient had local recurrence. Five-year overall survival was 84.2% (95% CI, 75–93.2%). The toxicity profile was acceptable.
Conclusion
This non-conventional multimodal treatment has good loco-regional control for LABC. Randomized clinical trials of preoperative CCRTh following chemotherapy, in patients with LABC are warranted.
doi:10.1186/1748-717X-4-24
PMCID: PMC2716349  PMID: 19591689
18.  Birth Outcome in Women with Previously Treated Breast Cancer—A Population-Based Cohort Study from Sweden 
PLoS Medicine  2006;3(9):e336.
Background
Data on birth outcome and offspring health after the appearance of breast cancer are limited. The aim of this study was to assess the risk of adverse birth outcomes in women previously treated for invasive breast cancer compared with the general population of mothers.
Methods and Findings
Of all 2,870,932 singleton births registered in the Swedish Medical Birth Registry during 1973–2002, 331 first births following breast cancer surgery—with a mean time to pregnancy of 37 mo (range 7–163)—were identified using linkage with the Swedish Cancer Registry.
Logistic regression analysis was used. The estimates were adjusted for maternal age, parity, and year of delivery. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate infant health and mortality, delivery complications, the risk of preterm birth, and the rates of instrumental delivery and cesarean section.
The large majority of births from women previously treated for breast cancer had no adverse events. However, births by women exposed to breast cancer were associated with an increased risk of delivery complications (OR 1.5, 95% CI 1.2–1.9), cesarean section (OR 1.3, 95% CI 1.0–1.7), very preterm birth (<32 wk) (OR 3.2, 95% CI 1.7–6.0), and low birth weight (<1500 g) (OR 2.9, 95% CI 1.4–5.8). A tendency towards an increased risk of malformations among the infants was seen especially in the later time period (1988–2002) (OR 2.1, 95% CI 1.2–3.7).
Conclusions
It is reassuring that births overall were without adverse events, but our findings indicate that pregnancies in previously treated breast cancer patients should possibly be regarded as higher risk pregnancies, with consequences for their surveillance and management.
The large majority of births from women previously treated for breast cancer had no adverse events, but such pregnancies might benefit from increased surveillance and management.
Editors' Summary
Background.
More women of all ages are developing breast cancer than ever before. In the US, one woman in eight will now develop this disease during her lifetime. For most of these women, their breast cancer diagnosis will come late in life, but a fifth of breast cancers are diagnosed before the age of 50. These days, the long-term outlook for women with breast cancer is quite good; 80% of women who receive a diagnosis of breast cancer survive more than five years. These figures, together with a trend towards starting families later in life—since the late 1970s birth rates for women in their late 30s and 40s have more than doubled in the US, and in Sweden the average age for having a first baby is now 29 years—mean that many women who have had breast cancer want to have children. One estimate is that up to 7% of women who are fertile after treatment for breast cancer will later have children.
Why Was This Study Done?
Pregnancy seems to have no adverse affects on women who have had breast cancer—there is no evidence that pregnancy can trigger a relapse. However, little is known about whether the chemotherapy and radiotherapy used to treat breast cancer have any long-lasting effects that might result in a poor birth outcome such as stillbirth, low birth weight, premature delivery, or abnormalities in the baby (congenital abnormalities). In this study, the researchers assessed the risk of adverse birth outcomes in women previously treated for breast cancer in Sweden.
What Did the Researchers Do and Find?
Nearly three million singleton births that occurred between 1973 and 2002 are recorded in the Swedish Medical Birth Registry. The researchers linked this information with that in the Swedish Cancer Registry to identify 331 first births after treatment for invasive breast cancer (cancer that has spread from where it started to grow in the breast). The birth registry includes details on maternal age and health, child's birth weight, whether the delivery was preterm, and whether the child had any congenital abnormalities, so the researchers were able to compare birth outcomes in these 331 births with those in the general population. They discovered that most births after breast cancer treatment went smoothly. There was no increase in stillbirths, but there were slightly more delivery complications in the women who had had breast cancer than in the general population, and a slight increase in babies born prematurely or with low birth weight. Finally, a few more babies with congenital abnormalities were born to women after breast cancer treatment than to women in the general population.
What Do These Findings Mean?
Overall, these results should reassure women who are thinking about having children after breast cancer about the health of their future offspring. However, they do suggest that these women may need careful monitoring during late pregnancy and delivery. This result was not predicted by the researchers who performed the study. Before starting the study, they thought that there would be no difference in birth outcomes between patients previously treated for breast cancer and the general population. Furthermore, a recently published similar study in Denmark found no increased risk of preterm birth, low birth weight, or congenital abnormalities after breast cancer. Differences between the two countries in the accuracy of their registries or in the use of chemotherapy and radiotherapy treatments may account for this difference in results. Additional studies are now needed in other populations to resolve this discrepancy and to provide more information about how breast cancer treatment might affect birth outcomes. For example, the current study did not provide any information about whether specific chemotherapy regimens or different types of breast cancer might put women at a higher risk of adverse birth outcomes, or whether the time between the cancer diagnosis and treatment and the pregnancy made a difference.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030336.
MedlinePlus encyclopedia entry on breast cancer
National Cancer Institute information for patients and physicians on breast cancer, including links to pages on breast cancer and pregnancy
Cancer Research UK's information on breast cancer for patients, and statistics on breast cancer in the UK
• Wikipedia page on breast cancer (note: Wikipedia is a free online encyclopedia that anyone can edit)
Royal College of Obstetricians and Gynaecologists guidelines for physicians on pregnancy and breast cancer
doi:10.1371/journal.pmed.0030336
PMCID: PMC1564170  PMID: 16968117
19.  Benefits, risks, and safety of external beam radiation therapy for breast cancer 
Breast cancer is a common and complex disease often necessitating multimodality care. Breast cancer may be treated with surgical resection, radiotherapy (RT), and systemic therapy, including chemotherapy, hormonal therapy, and targeted therapies, or a combination thereof. In the past 50 years, RT has played an increasingly significant role in the treatment of breast cancer, resulting in improvements in locoregional control and survival for women undergoing mastectomy who are at high risk of recurrence, and allowing for breast conservation in certain settings. Although radiation provides significant benefit to many women with breast cancer, it is also associated with risks of toxicity, including cardiac and pulmonary toxicity, lymphedema, and secondary malignancy. RT techniques have advanced and continue to evolve dramatically, offering increased precision and reproducibility of treatment delivery and flexibility of treatment schedule. This increased sophistication of RT offers promise of improved outcomes by maintaining or improving efficacy, reducing toxicity, and increasing patient access and convenience. A review of the role of radiation therapy in breast cancer, its associated toxicities and efforts in toxicity reduction is presented.
doi:10.2147/IJWH.S55552
PMCID: PMC4418389  PMID: 25977608
breast malignancy; radiotherapy; toxicity; outcomes
20.  Breast cancer in young women: special considerations in multidisciplinary care 
Breast cancer is one of the most prevalent cancers in females, and 5%–7% of breast cancer cases occur in women under 40 years of age. Breast cancer in the young has gained increased attention with an attempt to improve diagnosis and prognosis. Young patients tend to have different epidemiology, presenting with later stages and more aggressive phenotypes. Diagnostic imaging is also more difficult in this age group. Multidisciplinary care generally encompasses surgeons, medical oncologists, radiation oncologists, radiologists, and social workers. Other special considerations include reconstruction options, fertility, genetics, and psychosocial issues. These concerns enlarge the already diverse multidisciplinary team to incorporate new expertise, such as reproductive specialists and genetic counselors. This review encompasses an overview of the current multimodal treatment regimens and the unique challenges in treating this special population. Integration of diagnosis, treatment, and quality of life issues should be addressed and understood by each member in the interdisciplinary team in order to optimize outcomes.
doi:10.2147/JMDH.S49994
PMCID: PMC4189712  PMID: 25300196
diagnosis; interdisciplinary; quality of life; treatment; premenopausal; fertility preservation
21.  Radiolabeled Nanoparticles for Multimodality Tumor Imaging 
Theranostics  2014;4(3):290-306.
Each imaging modality has its own unique strengths. Multimodality imaging, taking advantages of strengths from two or more imaging modalities, can provide overall structural, functional, and molecular information, offering the prospect of improved diagnostic and therapeutic monitoring abilities. The devices of molecular imaging with multimodality and multifunction are of great value for cancer diagnosis and treatment, and greatly accelerate the development of radionuclide-based multimodal molecular imaging. Radiolabeled nanoparticles bearing intrinsic properties have gained great interest in multimodality tumor imaging over the past decade. Significant breakthrough has been made toward the development of various radiolabeled nanoparticles, which can be used as novel cancer diagnostic tools in multimodality imaging systems. It is expected that quantitative multimodality imaging with multifunctional radiolabeled nanoparticles will afford accurate and precise assessment of biological signatures in cancer in a real-time manner and thus, pave the path towards personalized cancer medicine. This review addresses advantages and challenges in developing multimodality imaging probes by using different types of nanoparticles, and summarizes the recent advances in the applications of radiolabeled nanoparticles for multimodal imaging of tumor. The key issues involved in the translation of radiolabeled nanoparticles to the clinic are also discussed.
doi:10.7150/thno.7341
PMCID: PMC3915092  PMID: 24505237
radiolabeled nanoparticles; molecular imaging; multimodality imaging; tumor diagnosis; cancer; theranostics
22.  A randomized trial of a cognitive-behavioral therapy and hypnosis intervention on positive and negative affect during breast cancer radiotherapy 
Journal of clinical psychology  2009;65(4):443-455.
Breast cancer radiotherapy can be an emotionally difficult experience. Despite this, few studies have examined the effectiveness of psychological interventions to reduce negative affect, and none to date have explicitly examined interventions to improve positive affect among breast cancer radiotherapy patients. The present study examined the effectiveness of a multimodal psychotherapeutic approach, combining cognitive-behavioral therapy and hypnosis (CBTH), to reduce negative affect and increase positive affect in 40 women undergoing breast cancer radiotherapy. Participants were randomly assigned to receive either CBTH or standard care. Participants completed weekly self-report measures of positive and negative affect. Repeated and univariate analyses of variance revealed that the CBTH approach reduced levels of negative affect [F (1, 38) = 13.49; p = .0007], and increased levels of positive affect [F (1, 38) = 9.67; p = .0035, ω2 = .48], during the course of radiotherapy. Additionally, relative to control group, the CBTH group demonstrated significantly more intense positive affect [F (1,38) = 7.09; p = .0113, d = .71] and significantly less intense negative affect [F (1,38) = 10.30; p = .0027, d = .90] during radiotherapy. The CBTH group also had a significantly higher frequency of days where positive affect was greater than negative affect (85% of days assessed for the CBTH group versus 43% of the Control group) [F (1,38) = 18.16; p = .0001, d = 1.16]. Therefore, the CBTH intervention has the potential to improve the affective experience of women undergoing breast cancer radiotherapy.
doi:10.1002/jclp.20559
PMCID: PMC2756503  PMID: 19226611
breast cancer; radiotherapy; cognitive-behavioral therapy; hypnosis; positive affect; negative affect
23.  Breast Imaging in Women Previously Irradiated for Hodgkin Lymphoma 
American journal of clinical oncology  2014;10.1097/COC.0000000000000025.
Background
Women treated with mantle irradiation for Hodgkin Lymphoma (HL) are at an increased risk of developing breast cancer (BC). Current guidelines recommend screening breast magnetic resonance imaging (MRI) as an adjunct to mammography (M) in these patients. There are limited data, however, as to the impact of breast MRI on cancer detection rates. The aim of the current study is to evaluate the use of breast MRI in in survivors of HL treated and followed at a single institution.
Methods
We retrospectively reviewed 980 female patients treated with mantle irradiation for HL between 1961 and 2008. Records were reviewed to determine age at radiotherapy treatment, radiotherapy dose, breast imaging (including M and breast MRI), biopsy results if applicable, and incidence of BC.
Results
118 patients had breast imaging performed at our institution. Median age at HL diagnosis was 28 years (range 10–69). Median radiotherapy dose was 36 Gy (range 20–45 Gy). Seventy-nine patients (67%) underwent M screening only, 1 (1%) breast MRI only, and 38 (32%) both M and breast MRI. Of these 38, 19 (50%) underwent 54 screening MRI studies (range per patient = 1–8), 13 (34%) underwent preoperative MRI for workup of BC, and 6 (16%) initiated screening MRI of the contralateral breast only after diagnosed with BC. Fifty-nine biopsies were performed: 47 were prompted by suspicious M findings only, 10 by palpable findings on physical examination, and 2 by suspicious breast MRI findings. Of the 47 biopsies prompted by M, 24 revealed malignant disease while 23 proved to be benign. All 10 biopsies performed by palpation were malignant. Both biopsies prompted by MRI findings were benign. With M, there were 34 true positive (TP) findings in 32 patients, 23 false positive (FP) findings, and 1 false negative (FN) finding. With screening MRI, there were 2 FP findings, one FN finding, and no TP findings.
Conclusions
The role of screening breast MRI in women previously irradiated for HL is evolving. Further education of patients and physicians is important to increase awareness of more sensitive breast cancer screening modalities in this high-risk population. Future studies are necessary to determine the appropriate integration of screening breast MRI into the ongoing follow up of these women.
doi:10.1097/COC.0000000000000025
PMCID: PMC4079764  PMID: 24390271
Hodgkin Lymphoma (HL); Breast Imaging; Breast Magnetic Resonance Imaging (MRI)
24.  Birth Size and Breast Cancer Risk: Re-analysis of Individual Participant Data from 32 Studies 
PLoS Medicine  2008;5(9):e193.
Background
Birth size, perhaps a proxy for prenatal environment, might be a correlate of subsequent breast cancer risk, but findings from epidemiological studies have been inconsistent. We re-analysed individual participant data from published and unpublished studies to obtain more precise estimates of the magnitude and shape of the birth size–breast cancer association.
Methods and Findings
Studies were identified through computer-assisted and manual searches, and personal communication with investigators. Individual participant data from 32 studies, comprising 22,058 breast cancer cases, were obtained. Random effect models were used, if appropriate, to combine study-specific estimates of effect. Birth weight was positively associated with breast cancer risk in studies based on birth records (pooled relative risk [RR] per one standard deviation [SD] [= 0.5 kg] increment in birth weight: 1.06; 95% confidence interval [CI] 1.02–1.09) and parental recall when the participants were children (1.02; 95% CI 0.99–1.05), but not in those based on adult self-reports, or maternal recall during the woman's adulthood (0.98; 95% CI 0.95–1.01) (p for heterogeneity between data sources = 0.003). Relative to women who weighed 3.000–3.499 kg, the risk was 0.96 (CI 0.80–1.16) in those who weighed < 2.500 kg, and 1.12 (95% CI 1.00–1.25) in those who weighed ≥ 4.000 kg (p for linear trend = 0.001) in birth record data. Birth length and head circumference from birth records were also positively associated with breast cancer risk (pooled RR per one SD increment: 1.06 [95% CI 1.03–1.10] and 1.09 [95% CI 1.03–1.15], respectively). Simultaneous adjustment for these three birth size variables showed that length was the strongest independent predictor of risk. The birth size effects did not appear to be confounded or mediated by established breast cancer risk factors and were not modified by age or menopausal status. The cumulative incidence of breast cancer per 100 women by age 80 y in the study populations was estimated to be 10.0, 10.0, 10.4, and 11.5 in those who were, respectively, in the bottom, second, third, and top fourths of the birth length distribution.
Conclusions
This pooled analysis of individual participant data is consistent with birth size, and in particular birth length, being an independent correlate of breast cancer risk in adulthood.
Editors' Summary
Background.
Last year, more than one million women discovered that they had breast cancer. In the US, nearly 200,000 women will face the same diagnosis this year and 40,000 will die because of breast cancer. Put another way, about one in eight US women will have breast cancer during her lifetime. Like all cancers, breast cancer begins when cells acquire genetic changes that allow them to divide uncontrollably and to move around the body (metastasize). This uncontrolled division leads to the formation of a lump that can be detected by mammography (a breast X-ray) or by manual examination of the breasts. Breast cancer is treated by surgical removal of the lump or, if the cancer has started to spread, by removal of the whole breast (mastectomy). Surgery is usually followed by radiotherapy, chemotherapy, and other treatments designed to kill any remaining cancer cells. Unlike some cancers, the outlook for women with breast cancer is good. In the US, for example, nearly 90% of affected women are still alive five years after their diagnosis.
Why Was This Study Done?
Scientists have identified several factors that increase a woman's risk of developing breast cancer by comparing the characteristics of populations of women with and without breast cancer. Well-established risk factors include increasing age, not having children, and having a late menopause, but another potential risk factor for breast cancer is birth size. A baby's weight, length, and head circumference at birth (three related measures of birth size) depend on the levels of hormones (including estrogen, a hormone that often affects breast cancer growth) and other biological factors to which the baby is exposed during pregnancy—its prenatal environment. The idea that prenatal environment might also affect breast cancer risk in later life was first proposed in 1990, but the findings of studies that have tried to investigate this possibility have been inconsistent. Here, the researchers re-analyze individual participant data from a large number of studies into women's health conducted in Europe, Northern America, and China to get more precise information about the association between birth size and breast cancer risk.
What Did the Researchers Do and Find?
The researchers identified 32 published and unpublished studies that had collected information on birth size and on the occurrence of breast cancer. They then obtained the individual participant data from these studies, which involved more than 22,000 women who had developed breast cancer and more than 600,000 women who had not. Their analyses of these data show that birth weight was positively associated with breast cancer risk in those studies where this measurement was recorded at birth or based on parental recall during the study participant's childhood (but not in those studies in which birth weight was self-reported or maternally recalled during the participant's adulthood). For example, women with recorded birth weights of more than 4 kg or more had a 12% higher chance of developing breast cancer than women who weighed 3–3.5 kg at birth. Birth length and head circumference were also positively associated with breast cancer risk, but birth length was the strongest single predictor of risk. Finally, the amount by which birth size affected breast cancer risk was not affected by allowing for other established risk factors.
What Do These Findings Mean?
These findings provide strong evidence that birth size—in particular, birth length—is a marker of a woman's breast cancer risk in adulthood although the mechanisms underlying this association are unclear. The researchers note that the observed effect of birth size on breast cancer risk is of a similar magnitude to that of other more established risk factors and estimate that 5% of all breast cancers in developed countries could be caused by a high birth size. Because practically all the studies included in this pooled analysis were done in developed countries, these findings may not hold for developing countries. Further investigations into how the prenatal environment may affect breast cancer risk might identify new ways to prevent this increasingly common cancer.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050193.
This study is further discussed in a PLoS Medicine Perspective by Trichopoulos and Lagiou
The US National Cancer Institute provides detailed information for patients and health professionals on all aspects of breast cancer, including information on risk factors for breast cancer (in English and Spanish)
The MedlinePlus Encyclopedia provides information for patients about breast cancer; Medline Plus also provides links to many other breast cancer resources (in English and Spanish)
The UK charity Cancerbackup also provides detailed information about breast cancer
Cancer Research UK is the UK's leading charity dedicated to cancer research
doi:10.1371/journal.pmed.0050193
PMCID: PMC2553821  PMID: 18828667
25.  Concurrent Docetaxel-Based Chemoradiotherapy in Squamous Cell Esophageal Cancer 
Background:
The incidence of esophageal cancer has risen worldwide in recent decades. In Romania, the incidence is 5.3/100,000 population in males and 0.7/100,000 in females, with mortality rates of 4.8/100,000 and 0.5/100,000 in males and females, respectively. Esophageal cancer is a treatable but rarely curable cancer, as many patients have advanced-stage disease at diagnosis. We evaluated a multimodality approach of preoperative radiochemotherapy for patients with squamous cell esophageal carcinoma in terms of safety, tumor response, and resectability rate.
Methods:
From January 2004 to May 2007, 87 patients were included in the study. Inclusion criteria were histologically confirmed squamous esophageal cancer not amenable to curative surgery, no distant metastases, ECOG performance status ≤ 2, and no previous anticancer therapy. The preoperative treatment schedule was conformal radiotherapy (40 Gy) with concomitant weekly docetaxel (25 mg/m2) and carboplatin (AUC=2). Patients were evaluated at baseline, after having received 40 Gy radiotherapy, and 3 months after treatment ended. Endoscopy, barium swallow X-ray, and CT scan of the chest and upper abdomen were used to evaluate patients. Patients whose tumors were resectable underwent surgery; those with unresectable tumors continued radiotherapy to a total dose of 60 Gy and received four cycles of docetaxel (75 mg/m2) and carboplatin (AUC=6) (q3wk regimen). The resected patients received adjuvant chemotherapy with four cycles of the same docetaxel/carboplatin q3wk regimen.
Results:
The median patient age was 53.6 years (range, 32–70 years); 78 of the patients were males and 9 were females. Median follow-up time was 35 months. Survival rate at 1 year was 57.5% and at 2 years, 44.8%. After patients had received 40 Gy radiotherapy, 39 were determined to have resectable disease and 30 underwent surgery (6 patients refused surgery and 3 had contraindications for surgery); 48 patients had tumor regression with clinical benefit but were not operable. No patient progressed. Six of the 30 patients undergoing surgery had complete remissions. The treatment schedule was well tolerated, with no treatment-related deaths or additional hospitalizations. All except 5 of the patients were able to receive the intended chemoradiotherapy regimen. These 5 patients stopped chemoradiotherapy because of hematologic toxicity; radiotherapy was continued (after an approximate 1-week delay) following hematologic recovery. The operated patients had no additional perioperative complications. Radiation therapy was delivered as intended with no toxicity-related interruptions, except in the 5 patients mentioned above. Chemotherapy was delayed in 15 additional cases due to grade 3–4 hematologic effects; a 25% dose reduction was necessary in 9 cases.
Conclusions:
Multimodality treatment of locally advanced esophageal cancer (concurrent radiochemotherapy ± surgery) can be considered superior to each method as single-agent therapy. Radiotherapy and chemotherapy may convert some tumors considered initially unresectable to resectable status. The weekly docetaxel/carboplatin regimen was well tolerated when administered concurrently with radiation therapy. This regimen resulted in a 44.8% resectability rate in patients considered initially unresectable, and 15.4% of patients undergoing surgery had complete remissions. Further investigation of this regimen is warranted.
PMCID: PMC3056309

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