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1.  Thymosin beta 15A (TMSB15A) is a predictor of chemotherapy response in triple-negative breast cancer 
British Journal of Cancer  2012;107(11):1892-1900.
Biomarkers predictive of pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) of breast cancer are urgently needed.
Using a training/validation approach for detection of predictive biomarkers in HER2-negative breast cancer, pre-therapeutic core biopsies from four independent cohorts were investigated: Gene array data were analysed in fresh frozen samples of two cohorts (n=86 and n=55). Quantitative reverse transcription polymerase chain reaction (qRT–PCR) was performed in formalin-fixed, paraffin-embedded (FFPE) samples from two neoadjuvant phase III trials (GeparTrio, n=212, and GeparQuattro, n=383).
A strong predictive capacity of thymosin beta 15 (TMSB15A) gene expression was evident in both fresh frozen cohorts (P<0.0001; P<0.0042). In the GeparTrio FFPE training cohort, a significant linear correlation between TMSB15A expression and pCR was apparent in triple-negative breast cancer (TNBC) (n=61, P=0.040). A cutoff point was then defined that divided TNBC into a low and a high expression group (pCR rate 16.0% vs 47.2%). Both linear correlation of TMSB15A mRNA levels (P=0.017) and the pre-defined cutoff point were validated in 134 TNBC from GeparQuattro (pCR rate 36.8% vs 17.0%, P=0.020). No significant predictive capacity was observed in luminal carcinomas from GeparTrio and GeparQuattro.
In TNBC, TMSB15A gene expression analysis might help to select patients with a high chance for pCR after NACT.
PMCID: PMC3504944  PMID: 23079573
predictive factor; neoadjuvant chemotherapy; triple negative; breast cancer; thymosin beta 15
2.  Extending neoadjuvant care through multi-disciplinary collaboration: proceedings from the fourth annual meeting of the Canadian Consortium for Locally Advanced Breast Cancer 
Current Oncology  2012;19(2):106-114.
The use of systemic therapy before surgery (“neoadjuvant therapy”) is the standard of care for the treatment of locally advanced and nonoperable breast cancer. The advantages of neoadjuvant therapy include improved rates of breast-conserving surgery, the possibility of early measurement of response, and potentially improved outcomes for certain subgroups of high-risk patients. The use of neoadjuvant therapy in operable breast cancer is increasing, although there are no clear guidelines in Canada to help guide patient selection and management.
Multidisciplinary experts in the diagnosis and treatment of locally advanced breast cancer (labc) converged at the fourth annual meeting of the Canadian Consortium for LABC (colab) to further their goals of improved standards for neoadjuvant care and clinical research through education and collaboration. Canadian clinical researchers were joined by Dr. Michael Untch of the Helios Hospital Berlin–Buch—representing the German neoadjuvant treatment groups German Gynecologic Oncology Working Group (Arbeitsgemeinschaft Gynakologische Onkologie) and German Breast Group—to discuss the advancement of research in the neoadjuvant setting and important issues of clinical care and investigator-led research. The group reached a consensus on the importance of multidisciplinary collaboration, the use of clips to mark tumour location, and core biopsy testing for the estrogen and progesterone receptors and the human epidermal growth factor receptor 2 at the time of diagnosis. Other initiatives—including creation of a prospective database, inception of the colab Neoadjuvant Network, and development of a clinical survey to evaluate current practice—continue to further the colab mandate of transforming the neoadjuvant treatment landscape in Canada.
PMCID: PMC3320223
Breast neoplasms; cancer treatment; clinical research; translational research; neoadjuvant therapy; surgery; radiation oncology; pathology
3.  Serum biomarker profiles and response to neoadjuvant chemotherapy for locally advanced breast cancer 
Neoadjuvant chemotherapy has become the standard of care for the diverse population of women diagnosed with locally advanced breast cancer. Serum biomarker levels are increasingly being investigated for their ability to predict therapy response and aid in the development of individualized treatment regimens. Multianalyte profiles may offer greater predictive power for neoadjuvant treatment response than the individual biomarkers currently in use.
Serum samples were collected from 44 patients enrolled in a phase I–II, open-label study of liposomal doxorubicin and paclitaxel in combination with whole breast hyperthermia for the neoadjuvant treatment of locally advanced breast cancer (stage IIB or stage III). Samples were collected prior to each of four rounds of treatment and prior to definitive surgery. Samples were assayed by Luminex assay for 55 serum biomarkers, including cancer antigens, growth/angiogenic factors, apoptosis-related molecules, metastasis-related molecules, adhesion molecules, adipokines, cytokines, chemokines, hormones, and other proteins.
Biomarker levels were compared retrospectively with clinical and pathologic treatment responses. Univariate analysis of the data identified several groups of biomarkers that differed significantly among treatment outcome groups early in the course of neoadjuvant chemotherapy. Multivariate statistical analysis revealed multibiomarker panels that could differentiate between treatment response groups with high sensitivity and specificity.
We demonstrate here that serum biomarker profiles may offer predictive power concerning treatment response and outcome in the neoadjuvant setting. The continued development of these findings will be of considerable clinical utility in the design of treatment regimens for individual breast cancer patients.
Trial registration
PMCID: PMC2481492  PMID: 18474099
4.  Prognostic significance of VEGF expression in patients with bulky cervical carcinoma undergoing neoadjuvant chemotherapy 
BMC Cancer  2008;8:295.
The prediction of response to treatment would be valuable for managing cervical carcinoma with neoadjuvant chemotherapy.
To this end, the expression of VEGF was analyzed by immunohistochemistry using paraffin-embedded pre-treatment cervical biopsy tissues. This study included 29 patients with bulky IB to IIA cervical squamous cell carcinoma treated with neoadjuvant chemotherapy.
Fifteen (51.7%) of 29 patients were scored as VEGF-positive. Response to chemotherapy (complete response or residual tumor with less than 3 mm stromal invasion) was observed in eight patients (27.6%), and it was negatively associated with VEGF expression (P = 0.009). With logistic regression analysis, VEGF positivity continued to be an independent predictor for poor response (P = 0.032). In addition, the progression-free survival rate was significantly lower in patients with VEGF-positive tumors (P = 0.033).
Pretreatment assessment of VEGF expression may provide additional information for identification of patients with cervical cancer who had a low likelihood of response to neoadjuvant chemotherapy and an unfavorable prognosis.
PMCID: PMC2572070  PMID: 18847499
5.  The potential prognostic value of connexin 26 and 46 expression in neoadjuvant-treated breast cancer 
BMC Cancer  2013;13:50.
Several classification systems are available to assess pathological response to neoadjuvant chemotherapy in breast cancer, but reliable biomarkers to predict the efficiency of primary systemic therapy (PST) are still missing. Deregulation of gap junction channel forming connexins (Cx) has been implicated in carcinogenesis and tumour progression through loss of cell cycle control. In this study we correlated Cx expression and cell proliferation with disease survival and pathological response to neoadjuvant chemotherapy in breast cancers using existing classification systems.
The expression of Cx26, Cx32, Cx43, Cx46 and Ki67 was evaluated in 96 breast cancer patients prior to and after neoadjuvant chemotherapy using duplicate cores in tissue microarrays (TMA). Cx plaques of <1μm were detected with multilayer, multichannel fluorescence digital microscopy. Current classifications to assess residual tumour burden after primary systemic therapy included the EWGBSP, CPS-EG, Miller-Payne, Sataloff and NSABP systems.
In our cohort dominated by hormone receptor (ER/PR) positive and HER2 negative cases, only the CPS-EG classification showed prognostic relevance: cases with scores 1–2 had significantly better overall survival (p=0.015) than cases with scores 3–5. Pre-chemotherapy Cx43 expression correlated positively with hormone receptor status both before and after chemotherapy and had a negative correlation with HER2 expression pre-chemotherapy. There was a positive correlation between Cx32 and HER2 expression pre-chemotherapy and between Cx32 and Ki67 expression post-chemotherapy. A negative correlation was found between post-chemotherapy Cx46 and Ki67 expression. Decreased post-chemotherapy Cx26 expression (<5%) statistically correlated with better overall survival (p=0.011). Moderate or higher Cx46 expression (>20%) pre- and post-chemotherapy correlated with significantly better survival in the intermediate prognostic subgroups of EWGBSP TR2b (ppre-chemo=0.006; Sataloff TB (ppre-chemo=0.005; ppost-chemo=0.029) and in Miller-Payne G3 (ppre-chemo=0.002; ppost-chemo=0.012) classifications. Pre-chemotherapy, Cx46 expression was the only marker that correlated with overall survival within these subgroups.
Our results suggest that Cx46 and Cx26 expression in breast cancer may improve the assessment of pathological response and refine intermediate prognostic subgroups of residual tumour classifications used after neoadjuvant chemotherapy.
PMCID: PMC3583680  PMID: 23374644
Breast cancer; Connexin; Gap junction; Preoperative chemotherapy; Prognosis
6.  Assessment of Ki67 in Breast Cancer: Recommendations from the International Ki67 in Breast Cancer Working Group 
Uncontrolled proliferation is a hallmark of cancer. In breast cancer, immunohistochemical assessment of the proportion of cells staining for the nuclear antigen Ki67 has become the most widely used method for comparing proliferation between tumor samples. Potential uses include prognosis, prediction of relative responsiveness or resistance to chemotherapy or endocrine therapy, estimation of residual risk in patients on standard therapy and as a dynamic biomarker of treatment efficacy in samples taken before, during, and after neoadjuvant therapy, particularly neoadjuvant endocrine therapy. Increasingly, Ki67 is measured in these scenarios for clinical research, including as a primary efficacy endpoint for clinical trials, and sometimes for clinical management. At present, the enormous variation in analytical practice markedly limits the value of Ki67 in each of these contexts. On March 12, 2010, an international panel of investigators with substantial expertise in the assessment of Ki67 and in the development of biomarker guidelines was convened in London by the cochairs of the Breast International Group and North American Breast Cancer Group Biomarker Working Party to consider evidence for potential applications. Comprehensive recommendations on preanalytical and analytical assessment, and interpretation and scoring of Ki67 were formulated based on current evidence. These recommendations are geared toward achieving a harmonized methodology, create greater between-laboratory and between-study comparability, and allow earlier valid applications of this marker in clinical practice.
PMCID: PMC3216967  PMID: 21960707
7.  Modulation of plasma complement by the initial dose of epirubicin/docetaxel therapy in breast cancer and its predictive value 
British Journal of Cancer  2010;103(8):1201-1208.
Despite the widespread use of neoadjuvant chemotherapy in breast cancer patients, prediction of individual response to treatment remains an unsolved clinical problem. Particularly, administration of an inefficient chemotherapeutic regimen should be avoided. Therefore, a better understanding of the molecular mechanisms underlying response to neoadjuvant chemotherapy is of particular clinical interest. Aim of the present study was to test whether neoadjuvant chemotherapy with epirubicin/docetaxel induces early changes in the plasma proteome of breast cancer patients and whether such changes correlate with response to therapy.
Plasma samples of 25 breast cancer patients obtained before and 24 h after initiation of epirubicin/docetaxel-based neoadjuvant chemotherapy were analysed using two-dimensional differential gel electrophoresis (2D-DIGE). Protein spots found to be differentially expressed were identified using mass spectrometry and then correlated with the pathological response after six cycles of therapy. Markers identified in a discovery set of patients (n=12) were confirmed in an independent validation set (n=13).
2D-DIGE revealed 33 protein spots to be differentially expressed in response to chemotherapy, including the complement factors C1, C3 and C4, inter-α-trypsin inhibitor, α-1-antichymotrypsin and α-2-Heremans-Schmid glycoprotein (AHSG). With respect to cytokines, only interleukin (IL)-6, IL-10 and soluble intracellular adgesion molecule 3 (sICAM3) were minimally modulated. Moreover, two protein spots within the complement component C3 significantly correlated with response to therapy.
We have identified acute phase proteins and the complement system as part of the early host response to epirubicin/docetaxel chemotherapy. As complement C3 cleavage correlates with the efficacy of docetaxel/epirubicin-based chemotherapy, it has the potential as an easily accessible predictive biomarker.
PMCID: PMC2967072  PMID: 20877360
breast cancer; response to therapy; epirubicin; docetaxel; complement system
8.  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.
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.
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).
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.
PMCID: PMC4039021  PMID: 23218766
Breast cancer; Chemotherapy; Class III β-tubulin; Neoadjuvant; Predictive biomarker
9.  Apoptosis – associated genes and their role in predicting responses to neoadjuvant breast cancer treatment 
Neoadjuvant chemotherapy is used in the treatment of breast carcinoma because it substantially reduces the size of the primary tumor and lymph node metastases. The present study investigated biomarkers that can predict a pathologic response to the therapy.
The role of apoptosis in regression of the tumors after neoadjuvant chemotherapy was determined by TUNEL and anti-active caspase 3 assay. The transcriptional profile of 84 key apoptosis genes was evaluated in both pre-therapeutically obtained tumor tissue by core needle biopsy and in specimens removed by final surgery, using a pathway-specific real-time PCR assay. Obtained data were analyzed by hierarchical cluster analysis and correlation analysis. The immunohistochemical profile of each tumor was determined using the standard ABC method.
On the basis of a hierarchical cluster analysis of 13 significantly changed genes, we divided patients into good and poor prognosis groups, which correlate well with progression-free survival. In the good prognosis group, we found a statistically significant down-regulation of the expression of MCL1 and IGF1R genes after neoadjuvant treatment. We also found a statistically significant overexpression of BCL2L10, BCL2AF1, CASP8, CASP10, CASP14, CIDEB, FADD, HRK, TNFRSF25, TNFSF8 and CD70 genes. In contrast, we found up-regulation of IGF1R after the treatment in the group with poor prognosis.
Gene expression profiling using real-time PCR assay is a valuable research tool for the investigation of molecular markers, which reflect tumor biology and treatment response.
PMCID: PMC3560664  PMID: 22207111
biomarkers; apoptosis; breast cancer; neoadjuvant chemotherapy
10.  PAX8: a sensitive and specific marker to identify cancer cells of ovarian origin for patients prior to neoadjuvant chemotherapy 
Neoadjuvant chemotherapy followed by cytoreduction surgery has been used where an accurate cytologic or pathologic diagnosis is usually required before the initiation of neoadjuvant chemotherapy. However, it is difficult to make definitive diagnosis of presence of cancer cells, particularly gynecologic versus non-gynecologic origin, from those ascites specimens due to the absence of specific biomarkers of gynecologic cancers. In the present study, we evaluated if, in addition to the routine morphologic diagnosis, the biomarker PAX8 could be useful in recognition of ovarian epithelial cancer cells prior to the neoadjuvant chemotherapy.
Two hundred and two cytology specimens including 120 pretreatment ovarian cancer samples, 60 benign controls, and 22 malignant non-gynecologic cases were studied. All cytology slides were morphologically reviewed in a blinded fashion without knowing corresponding pathology diagnosis, if present. A total of 168 cytology specimens with a cell block were stained with PAX8 and Calretinin. These included patients with potential for ovarian cancer neoadjuvant chemotherapy (n = 96), metastatic cancers (n = 22), and benign controls (n = 50).
Among the 96 ascitic samples prior to neoadjuvant chemotherapy, 76 (79%) showing morphologic features consistent with cancers of ovarian primary were all PAX+/Calretinin-. The remaining 20 (21%) cases were positive for adenocarcinoma, but morphologically unable to be further classified. Among the 22 metastatic cancers into the pelvis, one case with PAX8+/Calretinin- represented a renal cell carcinoma and the remaining 21 PAX8-/Calretinin- metastatic cancers were either breast metastasis (n = 4) and the metastasis from gastrointestinal tract (n = 17). Among the 50 benign control pelvic washing cases, 5 PAX8+/Calretinin-cases represented endosalpingiosis (n = 4) and endometriosis (n = 1), 25 PAX8-/Calretinin + cases showed reactive mesothelial cells, and the remaining 20 specimens with PAX8-/Calretinin- phenotype typically contained inflammatory or blood cells without noticeable diagnostic epithelia.
PAX8 identifies all Müllerian derived benign or malignant epithelia. When combining with Calretinin, PAX8 is a sensitive marker to diagnose the carcinomas of ovarian origin, which will be ideal to be used for those patients with a possible advanced ovarian cancer prior to receiving neoadjuvant chemotherapy.
PMCID: PMC3751714  PMID: 23958394
PAX8; Ascitic fluid; Ovarian cancer; Neoadjuvant chemotherapy; Origin; Marker
11.  Retrospective analysis of 119 Chinese noninflammatory locally advanced breast cancer cases treated with intravenous combination of vinorelbine and epirubicin as a neoadjuvant chemotherapy: a median follow-up of 63.4 months 
BMC Cancer  2009;9:375.
This study is a retrospective evaluation of the efficacy of neoadjuvant chemotherapy (NC) with a vinorelbine (V) and epirubicin (E) intravenous combination regimen and is aimed at identification of predictive markers for the long-term outcome in noninflammatory locally advanced breast cancer (NLABC).
One-hundred-and-nineteen patients with NLABC were identified from September 2001 to May 2006. Analysis was performed in March 2008, with a median follow-up of 63.4 months (range, 9-76 months). All patients were diagnosed with invasive breast cancer using 14 G core needle biopsy and treated with three cycles of VE before surgery. Local-regional radiotherapy was offered to all patients after the completion of chemotherapy followed by hormonal therapy according to hormone receptor status. Tissue sections cut from formalin-fixed paraffin-embedded blocks from biopsy specimens and postoperative tumor tissues were stained for the presence of estrogen receptor (ER), progesterone receptor (PgR), HER-2 (human epidermal growth factor receptor-2), and MIB-1(Ki-67).
Patients characteristics were median age 52 years (range: 25-70 years); clinical TNM stage, stage IIB (n = 32), stage IIIA (n = 56), stage IIIB (n = 22) and stage IIIC (n = 9). All patients were evaluable for response: clinically complete response was documented in 27 patients (22.7%); 78 (65.6%) obtained partial response; stable disease was observed in 13 (10.9%); 1 patient (0.8%) had progressive disease. Pathological complete response was found in 22 cases (18.5%). Seventy-five patients were alive with no recurrence after a median follow-up of 63.4 months, the 5-year rates for disease-free survival and overall survival were 58.7% and 71.3%, respectively, after the start of NC. On multivariate analysis, the independent variables associated with increased risk of relapse and death were high pre-Ki-67(p = 0.012, p = 0.017, respectively), high post-Ki-67 expression (p = 0.045, p = 0.001, respectively), and non-pCR (p = 0.034, p = 0.027, respectively). A significantly increased risk of death was associated with lack of pre-ER expression (p = 0.002). Among patients with non-pCR, those with a pathological response at the tumor site with special involvement (i.e. skin, vessel and more than one quadrant) were at a higher risk of disease relapse and death (p < 0.001, p = 0.001, respectively).
This study suggests the promising use of a VE regimen as NC for Chinese NLABC after a median follow-up of 63.4 months. Pathological response in the tumor site, pre-Ki-67 and post-Ki-67 expression, and pre-ER expression were the important variables that predicted long-term outcome. Patients with pathological special involvement at the primary site after NC had the lowest survival rates.
PMCID: PMC2770573  PMID: 19845944
12.  Patient and tumor characteristics associated with breast cancer recurrence after complete pathological response to neoadjuvant chemotherapy 
Breast cancer patients whose tumors achieve a pathological complete response (pCR) with neoadjuvant chemotherapy have a prognosis which is better than that predicted for the stage of their disease. However, within this subgroup of patients, recurrences have been observed. We sought to examine factors associated with recurrence in a population of breast cancer patients who achieved a pCR with neoadjuvant chemotherapy. A retrospective chart review was conducted of all patients with unilateral breast cancer treated with neoadjuvant chemotherapy from January 1, 2000 to December 31, 2010 at one comprehensive cancer center. A pCR was defined as no residual invasive cancer in the breast in the surgical specimen following neoadjuvant therapy. Recurrence was defined as visceral or bony reappearance of cancer after completion of all therapy. Of 818 patients who completed neoadjuvant chemotherapy, 144 (17.6 %) had pCR; six with bilateral breast cancer were excluded from further analysis. The mean time to follow-up was 47.2 months. Among the 138 patients with unilateral breast cancer, there were 14 recurrences (10.1 %). Using a binary multiple logistic regression model, examining types of chemotherapy and surgery, race, lymph node assessment, and lymph node status, breast cancer side, triple-negative status, and radiation receipt, only African-American patients (OR: 5.827, 95 % CI: 1.280–26.525; p = 0.023) were more likely to develop distant recurrence. The mean time to recurrence was 31.9 months. In our study, race was the only independent predictor of recurrence after achieving pCR with neoadjuvant chemotherapy. The reasons for this observation require further study.
PMCID: PMC3801189  PMID: 23149464
Neoadjuvant chemotherapy; Breast cancer; Complete pathological response; Recurrence
13.  Optical imaging correlates with magnetic resonance imaging breast density and reveals composition changes during neoadjuvant chemotherapy 
In addition to being a risk factor for breast cancer, breast density has been hypothesized to be a surrogate biomarker for predicting response to endocrine-based chemotherapies. The purpose of this study was to evaluate whether a noninvasive bedside scanner based on diffuse optical spectroscopic imaging (DOSI) provides quantitative metrics to measure and track changes in breast tissue composition and density. To access a broad range of densities in a limited patient population, we performed optical measurements on the contralateral normal breast of patients before and during neoadjuvant chemotherapy (NAC). In this work, DOSI parameters, including tissue hemoglobin, water, and lipid concentrations, were obtained and correlated with magnetic resonance imaging (MRI)-measured fibroglandular tissue density. We evaluated how DOSI could be used to assess breast density while gaining new insight into the impact of chemotherapy on breast tissue.
This was a retrospective study of 28 volunteers undergoing NAC treatment for breast cancer. Both 3.0-T MRI and broadband DOSI (650 to 1,000 nm) were obtained from the contralateral normal breast before and during NAC. Longitudinal DOSI measurements were used to calculate breast tissue concentrations of oxygenated and deoxygenated hemoglobin, water, and lipid. These values were compared with MRI-measured fibroglandular density before and during therapy.
Water (r = 0.843; P < 0.001), deoxyhemoglobin (r = 0.785; P = 0.003), and lipid (r = -0.707; P = 0.010) concentration measured with DOSI correlated strongly with MRI-measured density before therapy. Mean DOSI parameters differed significantly between pre- and postmenopausal subjects at baseline (water, P < 0.001; deoxyhemoglobin, P = 0.024; lipid, P = 0.006). During NAC treatment measured at about 90 days, significant reductions were observed in oxyhemoglobin for pre- (-20.0%; 95% confidence interval (CI), -32.7 to -7.4) and postmenopausal subjects (-20.1%; 95% CI, -31.4 to -8.8), and water concentration for premenopausal subjects (-11.9%; 95% CI, -17.1 to -6.7) compared with baseline. Lipid increased slightly in premenopausal subjects (3.8%; 95% CI, 1.1 to 6.5), and water increased slightly in postmenopausal subjects (4.4%; 95% CI, 0.1 to 8.6). Percentage change in water at the end of therapy compared with baseline correlated strongly with percentage change in MRI-measured density (r = 0.864; P = 0.012).
DOSI functional measurements correlate with MRI fibroglandular density, both before therapy and during NAC. Although from a limited patient dataset, these results suggest that DOSI may provide new functional indices of density based on hemoglobin and water that could be used at the bedside to assess response to therapy and evaluate disease risk.
PMCID: PMC3672664  PMID: 23433249
14.  Ki-67 biomarker in breast cancer of Indian women 
Biological markers that reliably predict clinical or pathological response to primary systemic therapy early during a course of chemotherapy may have considerable clinical potential.
Aims of study to evaluated changes in Ki-67 (MIB-1) labeling index and apoptotic index (AI) before, during, and after neoadjuvant anthracycline chemotherapy in breast cancer in Indian women.
Materials and Methods:
Breast cancer tissues were collected from Grant Medical College and Sir J.J. Group of Hospitals, Mumbai, India. Twenty-seven patients receiving neoadjuvant FEC (5-fluorouracil, epirubicin, and cyclophosphamide) chemotherapy for operable breast cancer underwent repeat core biopsy after 21 days of treatment.
The objective clinical response rate was 56%. Eight patients (31%) achieved a pathological response by histopathological criteria; two patients had a near-complete pathological response. Increased day-21 AI was a statistically significant predictor of pathological response (p = 0.049). A strong trend for predicting pathological response was seen with higher Ki-67 indices at day 21 and AI at surgery (p = 0.06 and 0.06, respectively).
The clinical utility of early changes in biological marker expression during chemotherapy remains unclear. Until further prospectively validated evidence confirming the reliability of predictive biomarkers is available, clinical decision-making should not be based upon individual biological tumor biomarker profiles.
PMCID: PMC3336898  PMID: 22540077
Ki-67 (MIB-1); breast cancer; prognostic factor; proliferative labeling index; apoptotic index; chemotherapy; primary systemic therapy
15.  Major clinical research advances in gynecologic cancer 2008 
Journal of Gynecologic Oncology  2008;19(4):209-217.
In this review, we summarized 14 major clinical advances in gynecology which occurred in 2008. For cervical cancer, clinical impact of HPV vaccine, prognostic value of imaging during radiotherapy, and oncologic/obstetric outcomes of fertility-sparing surgery were chosen. For uterine cancer, optimal method of adjuvant radiotherapy in intermediate-risk patients, extent of lymph node dissection, outcome of robot-assisted staging surgery, new standard chemotherapy regimen for leiomyosarcoma were selected. For ovarian cancer, recent changes in adjuvant therapy, feasibility of neoadjuvant chemotherapy, prediction of optimal secondary cytoreduction, studies on new biomarkers, advances in screening and treatment of women with BRCA mutations were included. For other cancers, the safety of sentinel lymph node dissection in vulvar cancer and chemotherapy regimens for low-risk gestational trophoblastic tumors were reviewed.
PMCID: PMC2676488  PMID: 19471658
Gynecology; Urogenital neoplasms; Biomedical research
16.  Diffuse optical spectroscopic imaging correlates with final pathological response in breast cancer neoadjuvant chemotherapy 
Diffuse optical spectroscopic imaging (DOSI) non-invasively and quantitatively measures tissue haemoglobin, water and lipid. Pilot studies in small groups of patients demonstrate that DOSI may be useful for longitudinal monitoring and predicting breast cancer neoadjuvant chemotherapy pathological response. This study evaluates the performance of a bedside DOSI platform in 34 breast cancer patients followed for several months. DOSI optical endpoints obtained at multiple timepoints are compared with final pathological response. Thirty-six stage II/III breast cancers (34 patients) were measured in vivo with DOSI prior to, in the middle of and after the completion of pre-surgical neoadjuvant chemotherapy. Cancer therapies ranged from standard anthracyclines to targeted therapies. Changes in DOSI-measured parameters at each timepoint were compared against final surgical pathology. Absolute changes in the tumour-to-normal (T/N) ratio of tissue deoxyhaemoglobin concentration (ctHHb) and relative changes in the T/N ratio of a tissue optical index (TOI) were most sensitive and correlate to pathological response. Changes in ctHHb and TOI were significantly different between tumours that achieved pathological complete response (pCR) versus non-pCR. By therapy midpoint, mean TOI-T/N changes were 47±8 versus 20±5 per cent for pCR versus non-pCR subjects, respectively (Z=0.011). Changes in ctHHb and TOI scaled significantly with the degree of pathological response (non-, partial and complete). DOSI measurements of TOI separated pCR from non-pCR by therapy midpoint regardless of drug or dosing strategy. This approach is well suited to monitoring breast tumour response and may provide feedback for optimizing therapeutic outcomes and minimizing side-effects.
PMCID: PMC3263790  PMID: 22006904
near-infrared; tissue spectroscopy; multiple scattering; therapeutic monitoring; photon migration; cancer imaging
17.  Changes in aldehyde dehydrogenase-1 expression during neoadjuvant chemotherapy predict outcome in locally advanced breast cancer 
Although neoadjuvant chemotherapy (NAC) for locally advanced breast cancer can improve operability and local disease control, there is a lack of reliable biomarkers that predict response to chemotherapy or long-term survival. Since expression of aldehyde dehydrogenase-1 (ALDH1) is associated with the stem-like properties of self-renewal and innate chemoresistance in breast cancer, we asked whether expression in serial tumor samples treated with NAC could identify women more likely to benefit from this therapy.
Women with locally advanced breast cancer were randomly assigned to receive four cycles of anthracycline-based chemotherapy, followed by four cycles of taxane therapy (Arm A), or the same regimen in reverse order (Arm B). Tumor specimens were collected at baseline, after four cycles, and then at surgical resection. ALDH1 expression was determined by immunohistochemistry and correlated with tumor response using Fisher’s exact test while Kaplan-Meier method was used to calculate survival.
A hundred and nineteen women were enrolled into the study. Fifty seven (48%) were randomized to Arm A and 62 (52%) to Arm B. Most of the women (90%) had ductal carcinoma and 10% had lobular carcinoma. Of these, 26 (22%) achieved a pathological complete response (pCR) after NAC. There was no correlation between baseline ALDH1 expression and tumor grade, stage, hormone receptor, human epidermal growth factor receptor 2 (HER2) status and Ki67 index. ALDH1 negativity at baseline was significantly associated with pCR (P = 0.004). The presence of ALDH1(+) cells in the residual tumor cells in non-responding women was strongly predictive of worse overall survival (P = 0.024). Moreover, serial analysis of specimens from non-responders showed a marked increase in tumor-specific ALDH1 expression (P = 0.028). Overall, there was no survival difference according to the chemotherapy sequence. However, poorly responding tumours from women receiving docetaxel chemotherapy showed an unexpected significant increase in ALDH1 expression.
ALDH1 expression is a useful predictor of chemoresistance. The up-regulation of ALDH1 after NAC predicts poor survival in locally advanced breast cancer. Although the chemotherapy sequence had no effect on overall prognosis, our results suggest that anthracycline-based chemotherapy may be more effective at targeting ALDH1(+) breast cancer cells.
Trial registration
PMCID: PMC4053180  PMID: 24762066
18.  State of the art of neoadjuvant chemotherapy in breast cancer: rationale, results and recent developments 
Aims, results, advantages and possible disadvantages of preoperative chemotherapy (pCHT) for breast cancer are discussed in this review. Established chemotherapeutic regimens are described with respect to new drugs that are added to combinations now and in the future. Illustrating the potential of new components, trastuzumab and cytotoxic chemotherapy, were combined in neoadjuvant trials for the first time. This approach yielded impressing and unprecedented high pathological response rates. An overview regarding current neoadjuvant cytostatic and immunotherapy trials is given.
Established prognostic factors like axillary lymph-nodal status are altered during pCHT, which causes the need for new prognostic markers. The consequences of these changes for clinical decision making are demonstrated. It seems possible that the advances of gene array and protein expression profile technologies will lead to improved prognostic and predictive statements. Tumor tissue can be analyzed before during and after treatment in this regard recent studies investigating the response to specific, chemotherapeutics in correlation to molecular markers are reviewed. These approaches might enable us to identify chemoresistance of specific tumors. Furthermore pCHT allows testing of chemosensitivity in vivo in an early stage, which might lead to a more individualized cancer therapy.
We discuss radiotherapy after neoadjuvant therapy and the risk of local relapse after breast conserving surgery, which was made feasible by pCHT. It is shown how the evaluation of efficacy of new cancer drugs, using the neoadjuvant situation, can be done more rapidly than in the metastatic and adjuvant setting.
PMCID: PMC2703246  PMID: 19675725
preoperative/neoadjuvant chemotherapy; breast cancer; local recurrence; prognostic factors; cancer biology
19.  Predictive Factors of Response in HER2-Positive Breast Cancer Treated by Neoadjuvant Therapy 
Journal of Oncology  2013;2013:854121.
Since 2005, major progresses have been made in the neoadjuvant treatment of HER2-positive breast cancer. Trastuzumab introduction associated with chemotherapy has been the first major step leading to the improvement of the complete pathological response rate and, like in the adjuvant studies, better survivals. Dual HER2 blockade has been the next step and trastuzumab is associated now with other anti-HER2 therapies like lapatinib or pertuzumab, the latter being much more easy to use in combination with chemotherapy. Additional knowledge is necessary to better define within the HER2 tumor subgroup which patients could benefit more from targeted therapies. Different biomarkers have been studied to predict the response after anti-HER2 neoadjuvant therapies but until now none has been validated.
PMCID: PMC3657410  PMID: 23737784
20.  Role of neo-adjuvant hormonal therapy in the treatment of breast cancer: a review of clinical trials 
The clinical benefits of endocrine therapy for patients with hormonosensitive breast cancer are well established. For many years, 5 years of tamoxifen was the gold standard of adjuvant treatment. The recent development of new endocrine agents provides physicians with a more effective therapeutic approach. Nevertheless, the success of neoadjuvant endocrine therapy is much more recent and less reported in the literature. This article reviews the studies published about neoadjuvant endocrine treatment (tamoxifen and aromatase inhibitors). According to the literature, neoadjuvant endocrine therapy seems to be effective. In contrast to neoadjuvant chemotherapy, neoadjuvant endocrine therapy is well tolerated, with very few patients having to discontinue the treatment because of side effects. It does not constitute a standard treatment but could have potential for elderly women with operable, hormonosensitive, well differentiated and slowly progressing (SBR I) tumor or for patients with lobular MSBR 1 carcinoma (low chemosensitivity). The newer generation of aromatase inhibitors (letrozole, anastrozole, exemestane) appears to be more active (in terms of overall response rates and conservative surgery rate) than tamoxifen. Patients with an estrogen receptor Allred score of 6 and over are more likely to respond and gain a clinical benefit. The optimal duration of neoadjuvant therapy has not yet been investigated in detail. These preliminary results should be confirmed by further studies.
PMCID: PMC2840558  PMID: 20360896
aromatase inhibitors; breast cancer; endocrine therapy; neoadjuvant; tamoxifen
21.  MicroRNAs as a potential prognostic factor in gastric cancer 
AIM: To compare the microRNA (miR) profiles in the primary tumor of patients with recurrent and non-recurrent gastric cancer.
METHODS: The study group included 45 patients who underwent curative gastrectomies from 1995 to 2005 without adjuvant or neoadjuvant therapy and for whom adequate tumor content was available. Total RNA was extracted from formalin-fixed paraffin-embedded tumor samples, preserving the small RNA fraction. Initial profiling using miR microarrays was performed to identify potential biomarkers of recurrence after resection. The expression of the differential miRs was later verified by quantitative real-time polymerase chain reaction (qRT-PCR). Findings were compared between patients who had a recurrence within 36 mo of surgery (bad-prognosis group, n = 14, 31%) and those who did not (good-prognosis group, n = 31, 69%).
RESULTS: Three miRs, miR-451, miR-199a-3p and miR-195 were found to be differentially expressed in tumors from patients with good prognosis vs patients with bad prognosis (P < 0.0002, 0.0027 and 0.0046 respectively). High expression of each miR was associated with poorer prognosis for both recurrence and survival. Using miR-451, the positive predictive value for non-recurrence was 100% (13/13). The expression of the differential miRs was verified by qRT-PCR, showing high correlation to the microarray data and similar separation into prognosis groups.
CONCLUSION: This study identified three miRs, miR-451, miR-199a-3p and miR-195 to be predictive of recurrence of gastric cancer. Of these, miR-451 had the strongest prognostic impact.
PMCID: PMC3199555  PMID: 22046085
MicroRNA; Prognosis; Recurrence; Gastric cancer
22.  Neoadjuvant endocrine treatment for breast cancer: from bedside to bench and back again? 
Current Oncology  2014;21(1):e122-e128.
In recent years, considerable attention has been paid to the role of neoadjuvant chemotherapy as a pluripotential test bed for the treatment of breast cancer. Although traditionally reserved to render inoperable disease operable, neoadjuvant chemotherapy is increasingly being used to improve the chance for breast-conserving surgery, to gain information on pathologic response rates for a more rapid assessment of new chemotherapy–biologic regimens, and also to study in vivo tumour sensitivity or resistance to the agent being used.
Similarly, use of neoadjuvant endocrine treatment was also traditionally restricted to elderly or frail patients who were felt to be unsuitable for chemotherapy. It is therefore not surprising that, given the increasing realization of the pivotal role of endocrine therapy in patient care, there is enhanced interest in neoadjuvant endocrine therapy not only as a less-toxic alternative to chemotherapy, but also to assess tumour sensitivity or resistance to endocrine agents.
The availability of newer endocrine manipulations and increasing evidence that the benefits of chemotherapy are frequently marginal in many hormone-positive patients is making endocrine therapy increasingly important in the clinical setting. The hope is that, one day, instead of preoperative endocrine therapy being restricted to the infirm and the elderly, it will be used in the time between biopsy diagnosis and surgery to predict which patients will or will not benefit from chemotherapy in the adjuvant setting.
PMCID: PMC3921036  PMID: 24523609
Medical oncology; breast cancer; neoadjuvant therapy; endocrine therapy
23.  Advancements in the Treatment of Metastatic Breast Cancer (MBC): The Role of Ixabepilone 
Journal of Oncology  2012;2012:703858.
Successful management of breast cancer in the metastatic setting is often confounded by resistance to chemotherapeutics, in particular anthracyclines and taxanes. The limited number of effective treatment options for patients with more aggressive biological subtypes, such as triple-negative metastatic breast cancer, is especially concerning. As such, a therapy clinically proven to be effective in this subtype would be of great value. Ixabepilone, a novel synthetic lactam analog of epothilone B, demonstrated better clinical outcomes in metastatic disease, particularly in triple-negative breast cancer. Most recently, studies have shown the activity of ixabepilone in the neoadjuvant setting, suggesting a role for this drug in primary disease. Notably, treating in the neoadjuvant setting might allow clinicians to explore the predictive value of biomarkers and response to treatment, as pharmacogenomic approaches to therapy continue to evolve. In this article, we review the efficacy and safety data of ixabepilone as a monotherapy and as a component of combination therapy for metastatic and primary breast cancer.
PMCID: PMC3356906  PMID: 22645612
24.  Triple-negative breast cancer: bridging the gap from cancer genomics to predictive biomarkers 
Triple-negative breast cancer (TNBC) represents a challenge clinically due to a lack of response to hormonal and HER2-targeted agents coupled with an aggressive disease course. As the biology of this breast cancer subtype is better understood, it is clear that TNBC is a heterogeneous disease and one targeted therapy is unlikely to be active in all patients. Biomarkers predictive of response to treatment are thus of great importance in TNBC. This review outlines studies evaluating biomarkers predictive of response to neoadjuvant chemotherapy and to targeted therapies in the advanced setting. The development of validated biomarkers in conjunction with novel targeted therapies represents an opportunity to improve patient outcomes in TNBC.
PMCID: PMC3987651  PMID: 24790649
biomarkers; targeted therapy; triple-negative breast cancer
25.  Bevacizumab and breast cancer: current therapeutic progress and future perspectives 
Bevacizumab is a humanized monoclonal antibody to VEGF, and the incorporation of bevacizumab to chemotherapy is one of the rapidly evolving areas in the treatment of breast cancer. Bevacizumab in combination with chemotherapy versus chemotherapy alone improves progression-free survival and increases the response rate in first-line therapy for locally recurrent or metastatic breast cancer. This approach has been and is still being evaluated for early breast cancer in neoadjuvant and adjuvant settings. Bevacizumab is well tolerated and has an established tolerability profile. Both tumor- and host-related biomarkers of bevacizumab activity, response and benefit are emerging from Phase I, II and III clinical trials. The biomarkers of benefit will ultimately help identify the subgroups of patients who specifically benefit from anti-VEGF therapy with bevacizumab.
PMCID: PMC2819039  PMID: 19954282
bevacizumab; breast cancer; chemotherapy; clinical trials; first-line therapy; VEGF

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