Impact of clinical trial on survival outcomes.

The number of patients with breast cancer who participate in therapeutic clinical trials remains low. One reason is a lack of opportunity; another is health care providers who do not recommend trials because they fear poorer outcome from the use of new drugs. Thus, we compared survival outcome in patients with metastatic breast cancer (MBC) who participated in first-line therapeutic clinical trials with outcome in patients who had never enrolled in a clinical trial and received only standard care. We hypothesized that first-line therapeutic clinical trials does not have a negative survival outcome. We reviewed the records of patients with MBC who were treated at MD Anderson Cancer Center between January 2000, and December 2010. The medical records of 5501 patients with MBC were screened, and 652 patients-285 in the trial arm and 367 in the control arm-met our specific eligible criteria. The median follow-up of our cohort was 7.16 years (95 % confidence interval [CI] 6.53-7.64 years). Among the global population, no significant differences in progression-free survival (PFS) or overall survival (OS) were observed between the treatment arms: for the clinical trial cohort, median PFS was 7 months (95 % CI 5.72-8.71 months), and median OS was 28.48 months (95 % CI 22.70-34.60 months). For the control cohort, median PFS was 10.02 months (95 % CI 7.13-11.99 months), and median OS was 28.71 months (95 % CI 24.41-31.31 months) (P = .089 and .335, respectively). Enrollment in first-line MBC therapeutic clinical trials does not result in less favorable survival outcome than that in MBC patients who never enrolled in a clinical trial.

Recurrence and survival among breast cancer patients achieving a pathological complete response to neoadjuvant chemotherapy.

Patients who achieve a pathological complete response (pCR) after neoadjuvant therapy, including chemotherapy with or without trastuzumab (NAT) have better outcomes than patients with residual disease. Despite the excellent prognosis associated with achieving a pCR, tumors still recur. The objective of this study was to evaluate factors associated with tumor recurrence and survival among patients achieving pCR after NAT. We identified 749 patients with primary breast cancer who achieved pCR after NAT between 1988 and 2009. pCR was defined as no evidence of invasive cancer in the breast and ipsilateral axillary lymph nodes on pathological evaluation. The Kaplan-Meier product limit method and multivariate Cox proportional hazards models were used to determine the association between clinical and demographic factors and outcomes. Median follow-up was 35 months (range, 1-258 months). Overall 5-year distant metastasis-free survival was 93% (95% confidence interval [CI], 90-95%) and 5-year overall survival (OS) was 96% (95% CI, 93-97%). In the multivariable model, we observed that patients >50 years had significantly decreased risk of distant metastasis (hazard ratio [HR] 0.47; 95% CI, 0.22-0.98) and that patients with clinical stage at diagnosis IIIB-C cancer had both an increased risk of distant metastasis (HR 3.92; 95% CI, 1.54-10.00) and lower OS (HR 4.75; 95% CI, 1.60-14.08). Patients with pCR after NAT have excellent outcomes. However, our data show that younger patient and those with clinical stage at diagnosis IIIB and IIIC cancers are at increased risk of developing distant metastasis.

Reverse-phase protein array for prediction of patients at low risk of developing bone metastasis from breast cancer.

BACKGROUND: A biomarker that predicts bone metastasis based on a protein laboratory assay has not been demonstrated. Reverse-phase protein array (RPPA) enables quantification of total and phosphorylated proteins, providing information about their functional status. The aim of this study was to identify bone-metastasis-related markers in patients with primary breast cancer using RPPA analysis. PATIENTS AND METHODS: Tumor samples were obtained from 169 patients with primary invasive breast carcinoma who underwent surgery. The patients were categorized by whether they developed breast cancer bone metastasis (BCBM) during follow-up. Clinical characteristics and protein expression by RPPA were compared and verified by leave-one-out cross-validation. RESULTS: Lymph node status (p = .023) and expression level of 22 proteins by RPPA were significantly correlated with BCBM in logistic regression analysis. These variables were used to build a logistic regression model. After filtering the variables through a stepwise algorithm, the final model, consisting of 8 proteins and lymph node status, had sensitivity of 30.0%, specificity of 90.5%, positive predictive value of 30.0%, and negative predictive value of 90.5% in the cross-validation. Most of the identified proteins were associated with cell cycle or signal transduction (CDK2, CDKN1A, Rb1, Src, phosphorylated-ribosomal S6 kinase, HER2, BCL11A, and MYH11). CONCLUSION: Our validated model, in which the primary tumor is tested with RPPA, can predict patients who are at low risk of developing BCBM and thus who likely would not benefit from receiving a bisphosphonate in the adjuvant setting. Clinical trials excluding these patients have the potential to clarify the benefit of bisphosphonates in the adjuvant setting.

A new hypothesis for the cancer mechanism.

Several observations have led us to a new hypothesis for cancer mechanism. First, that cancer appears only on those multicellular organisms with complicated wound-healing capacities. Second, that wounds considered as risk factors can be identified in all cancers in clinics. And finally, that oncogene activation appears not only in cancer, but also in normal physiology and noncancer pathology processes. Our proposed hypothesis is that cancer is a natural wound healing-related process, which includes oncogene activations, cytokine secretions, stem cell recruitment differentiation, and tissue remodeling. Wounds activate oncogenes of some cells and the latter secrete cytokines to recruit stem cells to heal the wounds. However, if the cause of the wound or if the wound persists, such as under the persistent UV and carcinogen exposures, the continuous wound healing process will lead to a clinical cancer mass. There is no system in nature to stop or reverse the wound healing process in the middle stage when the wound exists. The outcome of the cancer mechanism is either healing the wound or exhausting the whole system (death). The logic of this cancer mechanism is consistent with the rationales of the other physiological metabolisms in the body-for survival. This hypothesis helps to understand many cancer mysteries derived from the mutation theory, such as why cancer only exists in a small proportion of multicellular organisms, although they are all under potential mutation risks during DNA replications. The hypothesis can be used to interpret and guide cancer prevention, recurrence, metastasis, in vitro and in vivo studies, and personalized treatments.

Frequency of mesenchymal-epithelial transition factor gene (MET) and the catalytic subunit of phosphoinositide-3-kinase (PIK3CA) copy number elevation and correlation with outcome in patients with early stage breast cancer.

BACKGROUND: The current study was conducted to determine the frequency and association between recurrence-free survival (RFS) and MET and catalytic subunit of phosphoinositide-3-kinase (PIK3CA) copy number elevations in patients with early stage breast cancer. METHODS: Tumor DNA was extracted from 971 formalin-fixed, paraffin-embedded early breast cancers for molecular inversion probes arrays. Data were segmented using the single-nucleotide polymorphism (SNP)-FASST2 segmentation algorithm. Copy number gains were called when the copy number of each segment was greater than 2.3 or 1.7, respectively. RFS was estimated by the Kaplan-Meier method. Cox proportional hazards models were fit to determine independent associations between copy number and RFS. RESULTS: Of the 971 tumors studied, 82 (8.44%) and 134 (13.8%) had an elevation of the MET or PIK3CA copy number, respectively, and 25.6% of tumors with a MET copy number elevation had a PIK3CA copy number elevation. Patients with either a MET or PI3KCA high copy number tended to have poorer prognostic features (larger tumor size, higher tumor grade, and hormone receptor negativity). Both MET and PIK3CA high copy numbers were more likely to occur in patients with triple receptor-negative disease (P = .019 and P < .001, respectively). At a median follow-up of 7.4 years, there were 252 cases of disease recurrence. The 5-year RFS rates were 63.5% and 83.1% for MET high copy number and MET normal/low copy number, respectively (P = .06) and 73.1%, and 82.3% for PIK3CA high copy number and PIK3CA normal/low copy number, respectively (P = .15). A high copy number for either gene was not found to be an independent predictor of RFS. CONCLUSIONS: A high copy number of MET or PIK3CA was found to be associated with poorer prognostic features and triple receptor-negative disease. Coamplification was frequent. Patients with tumors with high MET copy numbers tended to have a worse RFS.

Impact of chemotherapy sequencing on local-regional failure risk in breast cancer patients undergoing breast-conserving therapy.

OBJECTIVE: This study was performed to evaluate long-term local-regional control rates after breast-conserving therapy (BCT) for patients undergoing surgery before or after neoadjuvant chemotherapy. METHODS: There were 2983 patients who underwent segmental mastectomy with whole-breast irradiation from 1987 to 2005. Clinicopathological and outcome data were reviewed, and comparisons were made between those undergoing surgery before and those undergoing surgery after neoadjuvant chemotherapy. RESULTS: There were 2331 patients (78%) who underwent surgery first and 652 (22%) received neoadjuvant chemotherapy. Patients receiving neoadjuvant chemotherapy had more advanced disease at baseline and more adverse clinicopathological features. The 5- and 10-year local-regional recurrence (LRR)-free survival rates were 97% [95% confidence interval (CI), 96-98) and 94% (95% CI, 93-95) for surgery first and 93% (95% CI, 91-95) and 90% (95% CI, 87-93) after neoadjuvant chemotherapy (P < 0.001). However, there were no differences in LRR-free survival rates when comparing the presenting clinical stage (P = NS). Of 607 patients presenting with clinical stage II/III disease, chemotherapy downstaged 313 patients (52%) to pathological stage 0/I disease; 294 (48%) had residual stage II/III disease. In multivariate analysis, an age less than 50 years, clinical stage III, grade 3, estrogen receptor (ER)-negative disease, estrogen receptor-positive disease without receipt of endocrine therapy, lymphovascular invasion, multifocal disease on pathology, and close/positive margins were associated with LRR. Use of neoadjuvant chemotherapy was not significant when added to the model. Adjusting for adverse factors, there were no differences in LRR between patients who underwent surgery before and those who underwent neoadjuvant chemotherapy after surgery. CONCLUSIONS: LRR after BCT is driven by tumor biology and disease stage. Appropriately selected patients can achieve high rates of local-regional control with BCT with either upfront surgery or surgery after neoadjuvant chemotherapy.

Progress in the biological understanding and management of breast cancer-associated central nervous system metastases.

Metastasis to the central nervous system (CNS) is a devastating neurological complication of systemic cancer. Brain metastases from breast cancer have been documented to occur in approximately 10%-16% of cases over the natural course of the disease with leptomeningeal metastases occurring in approximately 2%-5% of cases of breast cancer. CNS metastases among women with breast cancer tend to occur among those who are younger, have larger tumors, and have a more aggressive histological subtype such as the triple negative and HER2-positive subtypes. Treatment of CNS metastases involves various combinations of whole brain radiation therapy, surgery, stereotactic radiosurgery, and chemotherapy. We will discuss the progress made in the treatment and prevention of breast cancer-associated CNS metastases and will delve into the biological underpinnings of CNS metastases including evaluating the role of breast tumor subtype on the incidence, natural history, prognostic outcome, and impact of therapeutic efficacy.

Locoregional interaction of ixabepilone (ixempra) after breast cancer radiation.

BACKGROUND: Radiation recall is an acute inflammatory reaction within a previously irradiated field triggered by chemotherapy administration. We observed a series of patients with unexpectedly severe reactions that included radiation recall and delayed healing when patients received the microtubule stabilizer ixabepilone (Ixempra; Bristol-Myers Squibb, Princeton, NJ) after radiation. We therefore decided to evaluate our experience in patients receiving ixabepilone following radiotherapy. METHODS: We performed a retrospective chart review of all patients treated with curative intent in the Department of Radiation Oncology at the MD Anderson Cancer Center from 2008-2011 who received any ixabepilone after completion of external-beam radiation therapy. These patients received adjuvant ixabepilone on one of two protocols, either for locally advanced breast cancer or for metastatic breast cancer. In total, 19 patients were identified and their charts were subsequently reviewed for evidence of ixabepilone-related toxicity. RESULTS: Of the 19 patients identified who received ixabepilone following radiation therapy, three (15.8%) had unexpectedly serious reactions in the months following radiation therapy. Complications included delayed wound closure and drain placement into the seroma, intense erythema, and delayed wound closure and grade 4 chest wall necrosis requiring latissimus flap and skin grafting. The average number of days between the end of radiation therapy and documentation of reaction was 99. CONCLUSIONS: Ixabepilone chemotherapy may induce radiation recall and delayed wound healing when used shortly after the completion of external-beam radiotherapy. Significant clinical interactions have not been previously reported and merit further evaluation.

Breast cancer multifocality and multicentricity and locoregional recurrence.

The impact of multifocal (MF) or multicentric (MC) breast cancer on locoregional (LR) control rates is unknown. Methods. MF was defined as two or more separate invasive tumors in the same quadrant of the breast. MC was defined as two or more separate invasive tumors occupying more than one quadrant of the same breast. Patients were categorized by LR treatment: breast conservation therapy (BCT; n = 256), mastectomy (n = 466), or mastectomy plus postmastectomy radiation therapy (PMRT; n = 184). All patients with MC disease had mastectomy (10 patients treated with BCT for MC disease were excluded). The Kaplan-Meier product limit method was used to calculate 5-year LR control rate. Cox proportional hazards models were used to determine independent associations of multifocality or multicentricity with LR control. Results. A total of 906 patients had either MF disease (n = 673) or MC disease (n = 233). With median follow-up of 52 months, the 5-year LR control rate was 99% for MF, 96% for MC, and 98% for unifocal tumors (p = .44). Subset analysis revealed no difference in LR control regardless of the LR treatment (p = .67 for BCT, p = .37 for mastectomy, p = .29 for mastectomy plus PMRT). There were five in-breast recurrences after BCT in the MF group. MF and MC did not have an independent impact on LR control rate on multivariate analysis. Conclusion. MF and MC disease are not independent risk factors for LR recurrence. Patients with MF and MC breast cancer had rates of LR control similar to those of their unifocal counterparts. These data suggest that BCT is a safe option for patients with MF tumors and that MF or MC disease alone is not an indication for PMRT.

Case control study of women treated with chemotherapy for breast cancer during pregnancy as compared with nonpregnant patients with breast cancer.

BACKGROUND: The purpose of this analysis was to compare disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) between pregnant and nonpregnant patients with breast cancer. METHODS: From 1989 to 2009, 75 women were treated with chemotherapy during pregnancy. Each pregnant case was matched on age and cancer stage to two nonpregnant patients with breast cancer (controls). Fisher's exact test, the Kaplan-Meier method, and Cox proportional hazards regression models were used. RESULTS: Median follow-up time for patients who were alive at the end of follow-up (n = 159) was 4.20 years (range: 0.28-19.94 years). DFS at 5 years was 72% (95% confidence interval [CI]: 58.3%-82.1%) for pregnant patients and 57% (95% CI: 46.7%-65.8%) for controls (p = .0115). Five-year PFS was 70% (95% CI: 56.8%-80.3%) for pregnant patients and 59% (95% CI: 49.1%-67.5%) for controls (p = .0252). Five-year OS was 77% (95% CI: 63.9%-86.4%) for pregnant patients and 71% (95% CI: 61.1%-78.3%) for controls (p = .0461). Hazard ratio estimates favored improved survival for pregnant patients in univariate analyses and multivariate analyses, controlling for age, year of diagnosis, stage, and tumor grade. CONCLUSIONS: For patients who received chemotherapy during pregnancy, survival was comparable to-if not better than-that of nonpregnant women. Pregnant patients with breast cancer should receive appropriate local and systemic therapy for breast cancer.

High stearoyl-CoA desaturase 1 expression is associated with shorter survival in breast cancer patients.

Stearoyl-CoA desaturase 1 (SCD1) is an essential regulator of fatty acid synthesis. We have previously shown that overexpression of SCD1 increases the growth of breast cancer cell lines. The purpose of this study was to determine the relationship between SCD1 expression level and clinical-pathologic characteristics and survival of patients with breast cancer. Fine-needle aspirates were collected from the primary tumors of 250 patients with stage I-III breast cancer. Demographic and clinical characteristics including patient age, ethnicity, and menopausal status and tumor clinical stage, grade, and subtype were reviewed. SCD1 expression was analyzed using reverse-phase protein arrays. Samples were divided into high or low SCD1 expression levels based on a cut-off determined from martingale residual plots and regression tree analysis. SCD1 levels were significantly higher in tumors from patients >50-years old compared to patients ≤50-years old and were lower in triple-negative (estrogen/progesterone receptor-negative and human epidermal growth factor receptor-2-negative) breast cancers than other tumor subtypes. After adjusting for patient age, tumor subtype, tumor grade, and clinical stage, we found that patients with primary breast cancers expressing high SCD1 levels had significantly shorter relapse-free survival (RFS) (P = 0.0140) and overall survival (OS) (P = 0.039) in multivariable analysis. We conclude that SCD1 expression varies by breast cancer subtype and that high levels of SCD1 expression are associated with significantly shorter RFS and OS in multivariable analysis. Future studies are needed to define the role of SCD1 in the malignant phenotype of breast cancer and to evaluate the potential for SCD1 as a therapeutic target.

PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer.

PIK3CA mutations are reported to be present in approximately 25% of breast cancer (BC), particularly the estrogen receptor-positive (ER+) and HER2-overexpressing (HER2+) subtypes, making them one of the most common genetic aberrations in BC. In experimental models, these mutations have been shown to activate AKT and induce oncogenic transformation, and hence these lesions have been hypothesized to render tumors highly sensitive to therapeutic PI3K/mTOR inhibition. By analyzing gene expression and protein data from nearly 1,800 human BCs, we report that a PIK3CA mutation-associated gene signature (PIK3CA-GS) derived from exon 20 (kinase domain) mutations was able to predict PIK3CA mutation status in two independent datasets, strongly suggesting a characteristic set of gene expression-induced changes. However, in ER+/HER2- BC despite pathway activation, PIK3CA mutations were associated with a phenotype of relatively low mTORC1 signaling and a good prognosis with tamoxifen monotherapy. The relationship between clinical outcome and the PIK3CA-GS was also assessed. Although the PIK3CA-GS was not associated with prognosis in ER- and HER2+ BC, it could identify better clinical outcomes in ER+/HER2- disease. In ER+ BC cell lines, PIK3CA mutations were also associated with sensitivity to tamoxifen. These findings could have important implications for the treatment of PIK3CA-mutant BCs and the development of PI3K/mTOR inhibitors.

Response to Neoadjuvant Therapy and Long-Term Survival in Patients With Triple-Negative Breast Cancer.

PURPOSE: Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC. PATIENTS AND METHODS: Analysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pCR), survival measurements, and organ-specific relapse rates were compared between patients with TNBC and non-TNBC. RESULTS: Two hundred fifty-five patients (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates (22% v 11%; P = .034), but decreased 3-year progression-free survival rates (P < .0001) and 3-year overall survival (OS) rates (P < .0001). TNBC was associated with increased risk for visceral metastases (P = .0005), lower risk for bone recurrence (P = .027), and shorter postrecurrence survival (P < .0001). Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, patients with TNBC and non-TNBC had similar survival (P = .24). In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC (P < .0001). CONCLUSION: Patients with TNBC have increased pCR rates compared with non-TNBC, and those with pCR have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC, particularly in the first 3 years.

Local-regional control according to surrogate markers of breast cancer subtypes and response to neoadjuvant chemotherapy in breast cancer patients undergoing breast conserving therapy.

INTRODUCTION: Breast cancers of different molecular subtypes have different survival rates. The goal of this study was to identify patients at high risk for local-regional recurrence according to response to neoadjuvant chemotherapy and surrogate markers of molecular subtypes in patients undergoing breast conserving therapy (BCT). METHODS: Clinicopathologic data from 595 breast cancer patients who received neoadjuvant chemotherapy and BCT from 1997 to 2005 were identified. Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expression determined by immunohistochemistry were used to construct the following subtypes: ER+ or PR+ and HER2- (hormone receptor (HR)+/HER2-; 52%), ER+ or PR+ and HER2+ (HR+/HER2+; 9%), ER- and PR- and HER2+ (HR-/HER2+; 7%) and ER- and PR- and HER2- (HR-/HER2-; 32%). Actuarial rates were calculated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards models were used for multivariate analysis (MVA). RESULTS: After a median follow-up of 64 months, the five-year local-regional recurrence (LRR)-free survival rate for all patients was 93.8%. The five-year LRR-free survival rates varied by subtype: HR+/HER2- 97.0%, HR+/HER2+ 95.9%, HR-/HER2+ 86.5% and HR-/HER2- 89.5% (P = 0.001). In addition to subtype, clinical stage III disease (90% vs. 95% for I/II, P = 0.05), high nuclear grade (92% vs. 97% with low/intermediate grade, P = 0.03), presence of lymphovascular invasion (LVI) (89% vs. 95% in those without LVI, P = 0.02) and four or more positive lymph nodes on pathologic examination (87% vs. 95% with zero to three positive lymph nodes, P = 0.03) were associated with lower five-year LRR-free survival on univariate analysis. On MVA, HR-/HER2+ and HR-/HER2- subtypes and disease in four or more lymph nodes were associated with decreased LRR-free survival. A pathologic complete response (pCR) was associated with improved LRR-free survival. CONCLUSIONS: Patients with HR+/HER2- and HR+/HER2+ subtypes had excellent LRR-free survival regardless of tumor response to neoadjuvant chemotherapy. Patients with HR-/HER2+ and HR-/HER2- subtypes with poor response to neoadjuvant chemotherapy had worse LRR-free survival after BCT. Additional study is needed to determine the impact of trastuzumab on local-regional control in HER2+ tumors. Our data suggest that patients with HR-/HER2- subtype tumors not achieving pCR may benefit from novel strategies to improve local-regional control.

Incidence of brain metastases as a first site of recurrence among women with triple receptor-negative breast cancer.

BACKGROUND: This retrospective study sought to define the incidence of brain metastases as a first site of recurrence among women with triple receptor-negative breast cancer (TNBC). METHODS: A total of 2448 patients with stage I through III TNBC who were diagnosed between 1990 and 2010 were identified. We computed the cumulative incidence of developing brain metastases as a first site of recurrence at 2 and 5 years. Cox proportional hazards models were fitted to determine factors that could predict for the development of brain metastases as a first site of recurrence. The Kaplan-Meier product limit method was used to compute survival following a diagnosis of brain metastases. RESULTS: At a median follow-up of 39 months, 115 (4.7%) patients had developed brain metastases as a first site of recurrence. The cumulative incidence at 2 and 5 years was 3.7% (95% confidence interval [CI] = 2.9%-4.5%) and 5.4% (95% CI = 4.4%-6.5%), respectively. Among patients with stage I, II, and III disease, the 2-year cumulative incidence of brain metastases was 0.8%, 3.1%, and 8%, respectively (P < .0001). The 5-year cumulative incidence was 2.8%, 4.6%, and 9.6% among patients with stage I, II, and III disease, respectively (P < .0001). In the multivariable model, patients with stage III disease had a significant increase in the risk of developing brain metastases as a first site of recurrence (hazards ratio = 3.51; 95% CI = 1.85-6.67; P = .0001) compared to patients with stage I disease. Those with stage II disease had a nonsignificant increased risk of developing brain metastases as a first site of recurrence (hazards ratio = 1.61; 95% CI = 0.92-2.81; P = .10) compared with patients with stage I disease. Median survival following a diagnosis of brain metastases was 7.2 months (range, 5.7-9.4 months). CONCLUSIONS: Patients with nonmetastatic TNBC have a high early incidence of developing brain metastases as a first site of recurrence, which is associated with subsequent poor survival. Patients with stage III TNBC in particular would be an ideal cohort in which to research preventive strategies.

Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer.

BACKGROUND: Recent observational studies have shown that metformin use in diabetic patients decreases both cancer incidence and mortality. Metformin use is also independently predictive of pathologic complete response. In the current study, the authors explored the association between metformin use and survival outcomes in patients with triple receptor-negative breast cancer (TNBC) who were receiving adjuvant chemotherapy. METHODS: The Breast Cancer Management System database of The University of Texas MD Anderson Cancer Center identified 1448 women who received adjuvant chemotherapy for TNBC between 1995 and 2007. Patients were categorized by diabetes status and metformin use. The Kaplan-Meier product-limit method was used to calculate distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS). Cox proportional hazards models were fit to determine the association between metformin use and survival outcomes. RESULTS: The study cohort was comprised of 63 diabetic patients receiving treatment with metformin, 67 diabetic patients not receiving metformin, and 1318 nondiabetic patients. Patients in the diabetic groups tended to be older (P = .005); more diabetic patients were postmenopausal (P = .0007), black (P = .0001), and obese (P < .0001). At a median follow-up of 62 months, there were no significant differences with regard to 5-year DMFS (P = .23), RFS (P = .38), and OS (P = .58) between the 3 groups. Compared with the metformin group, patients who did not receive metformin (hazard ratio [HR], 1.63; 95% confidence interval [95% CI], 0.87-3.06 [P = .13]) and nondiabetic patients (HR, 1.62; 95% CI, 0.97-2.71 [P = .06]) tended to have a higher risk of distant metastases. CONCLUSIONS: The findings of the current study suggest that metformin use during adjuvant chemotherapy does not significantly impact survival outcomes in diabetic patients with TNBC.

The use of bevacizumab among women with metastatic breast cancer: a survey on clinical practice and the ongoing controversy.

BACKGROUND: The US Food and Drug Administration's (FDA's) recent decision to remove the indication of bevacizumab for metastatic breast cancer (MBC) has fueled a debate in the breast cancer community. We conducted a survey to assess the perception of health care workers involved in the management of women with MBC on the FDA's decision to ascertain how it will affect practice and to determine how bevacizumab is commonly used in the community for MBC. METHODS: E-mails were sent out between September and November 2010 using a database of 3000 addresses maintained by the United Arab Emirates Cancer Congress. Individuals working for Roche or Genentech were excluded. The survey consisted of 22 questions that were divided into 3 parts addressing each participant's demographic profile, their opinion of the FDA's decision, and the typical use of bevacizumab in the community in the setting of MBC. RESULTS: A total of 564 participants were included in the final analysis, contributing to an 18.8% response rate. Of these participants, 14.6% were from the United States, 7.8% were from Canada, 31.1% were from Europe, 2.0% were from the United Arab Emirates, 11.1% were from Asia, and 33.3% were from other countries. The majority of participants believed progression-free survival to be a surrogate for overall survival, that cost played a role in the FDA's decision, and that the decision would adversely affect the future of newer drugs currently being investigated for MBC. The majority of participants indicated that they would use bevacizumab for triple receptor-negative MBC (46.5%), would use it in a first-line setting (44.7%), and would use it in combination with paclitaxel (51.9%). CONCLUSION: Our survey results highlight the discord between the opinion of community oncologists and the FDA's recent decision to withdraw the indication of bevacizumab for MBC.

Earlier age of onset of BRCA mutation-related cancers in subsequent generations.

BACKGROUND: Women who are diagnosed with a deleterious mutation in either breast cancer (BRCA) gene have a high risk of developing breast and ovarian cancers at young ages. In this study, the authors assessed age at diagnosis in 2 generations of families with known mutations to investigate for earlier onset in subsequent generations. METHODS: Of the 132 BRCA-positive women with breast cancer who participated in a high-risk protocol at The University of Texas MD Anderson Cancer Center (Gen 2), 106 women could be paired with a family member in the previous generation (Gen 1) who was diagnosed with a BRCA-related cancer (either breast cancer or ovarian cancer). Age at diagnosis, location of the mutation, and year of birth were recorded. A previously published parametric anticipation model was applied in these genetically predisposed families. RESULTS: The median age of cancer diagnosis was 42 years (range, 28-55 years) in Gen 2 and 48 years (range, 30-72 years) in Gen 1 (P < .001). [corrected]. In the parametric model, the estimated change in the expected age at onset for the entire cohort was 7.9 years (P < .0001). Statistically significant earlier ages at diagnosis also were observed within subgroups of BRCA1 and BRCA2 mutations, maternal inheritance, paternal inheritance, breast cancer only, and breast cancer-identified and ovarian cancer-identified families. CONCLUSIONS: Breast and ovarian cancers in BRCA mutation carriers appeared to be diagnosed at an earlier age in later generations. The authors concluded that patients who are younger at the onset of BRCA-related cancers should continue to be tracked to offer appropriate screening modalities at appropriate ages.

Impact of low estrogen/progesterone receptor expression on survival outcomes in breast cancers previously classified as triple negative breast cancers.

PURPOSE: To evaluate the impact of low estrogen/progesterone receptor (ER/PR) expression and effect of endocrine therapy on survival outcomes in human epidermal growth factor receptor 2 (HER2)-negative tumors with ER/PR <10%, previously labeled as triple negative. METHODS: In a retrospective review, 1257 patients were categorized according their ER/PR percentages into 3 groups, ER/PR <1% (group A), ER/PR 1% to 5% (group B), and ER/PR 6% to 10% (group C). Kaplan-Meier product limit method was used to estimate survival outcomes. Cox proportional hazards models was used to adjust for patient and tumor characteristics. RESULTS: Groups A, B, and C had 897 (71.4%), 241 (19.2%), and 119 (9.4%) patients, respectively. After a median follow-up of 40 months there was no significant difference in 3-year recurrence-free survival (RFS): 64%, 67%, and 77% (P = .34) or overall survival (OS): 79%, 81%, and 88% (P = .33) for groups A, B, and C, respectively. ER/PR expression was not an independent predictor for RFS (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.86-1.39; P = .46 for group B, and HR, 0.96; 95% CI, 0.66-1.38; P = .81 for group C, compared with group A), or OS (HR, 1.11; 95% CI, 0.84-1.46; P = .46 for group B, and HR, 0.94; 95% CI, 0.63-1.42; P = .78 for group C, compared with group A). Endocrine therapy had no impact on survival outcomes (RFS: P = .10; OS: P = .45) among groups. CONCLUSIONS: In this cohort, a low ER/PR level (1%-5%) does not appear to have any significant impact on survival outcomes. There was a tendency for survival advantages in the ER/PR 6% to 10% is seen. Benefit of endocrine therapy in these patients is unclear.

Effect of CYP2D6 polymorphisms on breast cancer recurrence.

BACKGROUND: Previous studies evaluating the effect of cytochrome P450 2D6 (CYP2D6) polymorphisms on outcomes of adjuvant tamoxifen therapy have been conflicting due to differences in study design, concomitant medications that alter CYP2D6 metabolism, and tamoxifen adherence. METHODS: The authors performed CYP2D6 genotyping from whole blood and fresh frozen tumor samples (n 106) in patients at The University of Texas MD Anderson Cancer Center who were receiving, or had received, tamoxifen as adjuvant therapy for early breast cancer (EBC), using the AmpliChip CYP450 Test. Each patient's medical history was assessed for drugs that affected CYP2D6. Fifty-five patients who had experienced breast cancer recurrence were matched (by date of diagnosis, menopausal status, clinical stage [TNM Staging System], and race) to patients without recurrence. RESULTS: Unadjusted for other patient characteristics, the odds ratio for disease recurrence associated with CYP2D6 functional status was 1.0 (95% confidence interval, 0.35-2.85). After adjustment for stage, CYP2D6 inhibitors (moderate or strong vs none), and follow-up time, no significant association was found between CYP2D6 genotype and breast cancer recurrence in patients who were treated with adjuvant tamoxifen for EBC. CONCLUSIONS: This case-control study demonstrated no significant effect of CYP2D6 genotype on risk of recurrence in breast cancer patients who received adjuvant tamoxifen therapy.