The management of hormone receptor–positive, human epidermal growth factor receptor 2–positive, and triple-negative breast cancers is reviewed, emphasizing changes that occurred in recent years and focusing on potential mechanisms of drug resistance. Strategies to prevent or overcome resistance to specific therapeutic agents are also highlighted.
The management of breast cancer has changed dramatically over the past 20 years. Based on gene expression profiles, or proteomics of three or four biomarkers, it is apparent that there are multiple subtypes with different clinical characteristics, clinical courses, and sensitivities to existing therapies. This manuscript reviews the management of hormone receptor–positive, human epidermal growth factor receptor 2–positive, and triple-negative breast cancers, emphasizing changes that have occurred in recent years and focusing on potential mechanisms of drug resistance. I also highlight strategies to prevent or overcome resistance to specific therapeutic agents. As a result of enhanced biological understanding of the molecular anomalies that drive the development, progression, and dissemination of breast cancer, a number of novel, molecularly targeted agents have been added to standard therapies. Chemotherapy, endocrine therapy, and targeted treatments have markedly reduced the risk for recurrence and mortality after primary treatment of breast cancer and have increased the 5- and 10-year survival rates. The challenges with novel therapeutics include the absence of accurate predictive biomarkers to identify those patient who will derive substantial benefit and those patients whose tumors are resistant to specific antitumor agents. As we move forward with increasing molecular segmentation of breast cancer and develop new, highly targeted agents, molecular diagnostics must accompany molecular therapeutics to implement the concept of personalized cancer therapy.
Clinical correlation studies have clearly shown that obesity is associated with breast cancer risk and patient survival. Although several potential mechanisms linking obesity and cancers have been proposed, the detailed molecular mechanism of obesity-mediated breast tumorigenesis has not yet been critically evaluated. In this study, we evaluated the effects of obesity on mammary tumor initiation and progression using mice with genetic and diet-induced obesity bearing mammary tumor xenografts and mouse mammary tumor virusneu transgenic mice that were fed a high-fat diet. We show that obesity promoted mammary tumor growth and development in these animal models. Moreover, the expressions of TNFα, VEGF, IKKβ, and mTOR are upregulated in mammary tumors of obese mice, suggesting that the IKKβ/ mTOR/VEGF signaling pathway is activated by TNFα in the tumors of obese mice. More importantly, inhibitors (rapamycin, bevacizumab, and aspirin) that target members of the pathway suppressed tumorigenesis and prolonged survival more effectively in obese mice than in nonobese mice. Here, we not only identified a specific signaling pathway that contributes to mammary tumorigenesis in obese mice but also a strategy for treating obesity-mediated breast cancer.
Trastuzumab is an iconic rationally designed targeted therapy for HER2-positive breast cancers. However, the low response rate and development of resistance call for novel approaches for the treatment of patients. Here, we report that concurrent targeting of tumor cells and activation of T cells in the tumor microenvironment results in a synergistic inhibitory effect on tumor growth and overcomes resistance in two distinct PTEN loss–mediated trastuzumab-resistant mammary tumor mouse models. In vivo combination treatment with HER2/Neu antibody and Akt inhibitor triciribine effectively inhibited tumor growth in both models via inhibiting PI3K/AKT and mitogen-activated protein kinase signaling accompanied by increased T-cell infiltration in the tumor microenvironment. We showed that both CD8+ and CD4+ T cells were essential to the optimal antitumor effect of this combination treatment in an IFN- γ–dependent manner. Importantly, the antitumor activities of HER2/Neu antibody and triciribine combination treatment were further improved when coinhibitory receptor cytotoxic T-lymphocyte–associated antigen 4 was blocked to enhance the T-cell response. Our data indicate that multitargeted combinatorial therapies targeting tumor cells and concomitantly enhancing T-cell response in the tumor microenvironment could cooperate to exert maximal therapeutic activity, suggesting a promising clinical strategy for treating trastuzumab-resistant breast cancers and other advanced malignancies.
To determine the patterns of use of anthracycline- and taxane-based chemotherapy for breast cancer treatment.
Claims from a 5% national Medicare sample and from a nationally representative claims database (Marketscan) from 1998 to 2009 were used. Patients with International Classification of Diseases (ICD), ninth revision, codes indicating breast cancer, ICD and Common Procedural Terminology codes indicating breast surgery, and claims for chemotherapy between 3 months before and 12 months after surgery comprised the study cohort. Chemotherapy was classified as anthracycline-based or taxane-based, and the percentages of use were calculated. Piecewise regression models were used to identify the inflection points in the rates of chemotherapy use. The effect of patient characteristics on receiving different types of chemotherapy was estimated by multivariable logistic regression models.
A total of 4,458 patients were included in the Medicare cohort and 30,422 in the private insurance cohort. After 2005, a sharp increase in the use of taxane-based chemotherapy and a decline in anthracycline-based chemotherapy was seen. By 2008 in the Medicare cohort, 51% of patients received taxane-based and 32% received anthracycline-based chemotherapy. By the end of 2008, the majority of patients younger than 65 years were also receiving taxane-based chemotherapy. Patients younger than 35 years were less likely to be treated with a taxane-based regimen, whereas patients who underwent 21-gene recurrence score testing and those treated with trastuzumab were more likely to receive taxane-based chemotherapy.
The use of anthracycline-based chemotherapy has declined, and the majority of patients with breast cancer are instead receiving taxane-based chemotherapy. The potential impact on patient outcomes is unknown.
To evaluate the pathologic complete response (pCR) rates and relapse-free survival (RFS) and overall survival (OS) of patients receiving neoadjuvant systemic therapy (NST) with trastuzumab in combination with an anthracycline- or a non-anthracycline-based regimen.
In this retrospective non-randomized study, we reviewed records of 300 patients with HER2-positive breast cancer treated with either sequential paclitaxel and trastuzumab and FEC75 in combination with trastuzumab (PH-FECH) or docetaxel, carboplatin and trastuzumab (TCH). The Kaplan-Meier product-limit method was used to estimate RFS and OS rates. Logistic regression models and Cox proportional hazards models were fit to determine the associations between NST, pCR and survival.
There was no significant difference in the decline in cardiac ejection fraction, however, patients who received PH-FECH had less cardiac comorbidities at baseline (P = 0.002). pCR rates were 60.6% and 43.3% for patients who received PH-FECH(n=235) and TCH(n=65), respectively (P=0.016). Patients who received PH-FECH were 1.45 times more likely to have a pCR (Odds ratio [OR]:1.45; 95% confidence interval (CI):1.06-1.98; P=0.02). Three-year RFS rates were 93% and 71% (P<0.001), and 3-year OS rates were 96% and 86% (P=0.008) for patients who received PH-FECH and TCH, respectively. Patients who received PH-FECH had a lower risk of recurrence (Hazard ratio [HR]:0.27; 95% CI:0.12-0.60; P=0.001) and death (HR:0.37; 95% CI:0.12-1.13; P=0.08) than those treated with TCH.
The type of NST in HER2-positive breast cancer is predictive of pCR rate independent of disease and patient characteristics. While TCH is active, PH-FECH shows a higher pCR rate and RFS advantage.
HER2-positive breast cancer; neoadjuvant therapy; trastuzumab; anthracyclines; pCR; survival
To evaluate the impact of low ER/PR expression and effect of endocrine therapy on survival outcomes in HER2-negative tumors with ER/PR < 10%, previously labeled as triple negative.
In a retrospective review, 1257 patients were categorized according their ER/PR percentages into three groups, ER/PR <1% (Group A), ER/PR 1–5% (Group B) and ER/PR 6–10% (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.
Group 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 = 0.34) or overall survival (OS): 79%, 81% and 88% (P = 0.33) for groups A, B and C respectively. ER/PR expression was not an independent predictor for RFS (HR=1.10, 95% CI: 0.86–1.39, P=0.46 for group B and HR=0.96, 95% CI: 0.66–1.38, P=0.81 for group C, compared to group A), or OS (HR=1.11, 95% CI: 0.84–1.46, P=0.46 for group B and HR=0.94, 95% CI: 0.63–1.42, P=0.78 for group C, compared to group A). Endocrine therapy had no impact on survival outcomes (RFS: P=0.10; OS: P=0.45) among groups.
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 6–10% is seen. Benefit of endocrine therapy in these patients is unclear.
Estrogen Receptor; Progesterone Receptor; Breast cancer; Prognosis; Immunohistochemistry
Recent observational studies have shown that metformin use in diabetics decreases both cancer incidence and mortality. Metformin use is also independently predictive of pathologic complete response. We explored the association between metformin use and survival outcomes in patients with triple receptor-negative breast cancer (TNBC) receiving adjuvant chemotherapy.
The Breast Cancer Management System database of The University of Texas M.D. 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. 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.
Our study cohort consisted of 63 diabetic patients taking metformin, 67 diabetic patients not taking metformin, and 1318 non-diabetic patients. Patients in the diabetic groups tended to be older (P=0.005); more diabetic patients were postmenopausal (P=0.0007), black (P=0.0001), and obese (P < 0.0001). At a median follow-up of 62 months, there were no significant differences in 5-year DMFS (P=0.23), RFS (P=0.38), and OS (P=0.58) between the three groups. Compared to the metformin group, patients who did not take metformin (Hazard ratio [HR]=1.63; 95% CI:0.87 to 3.06; P=0.13) and nondiabetics (HR=1.62; 95% CI:0.97 to 2.71; P=0.06) tended to have a higher risk of distant metastases.
Our findings suggest that metformin use during adjuvant chemotherapy does not significantly impact survival outcomes in diabetic patients with TNBC.
Triple receptor-negative breast cancer; metformin; diabetes mellitus; survival; recurrence; adjuvant chemotherapy
The Surveillance, Epidemiology, and End Results–Medicare linked database was used to describe the extent of nonadherence to anthracycline-based chemotherapy regimens in older patients with early breast cancer and to explore factors associated with nonadherence.
After completing this course, the reader will be able to:
Describe rates of adherence to anthracycline-based chemotherapy in elderly patients with early breast cancer, using a population-based database.Identify a subset of early breast cancer patients with a higher likelihood of non-adherence to the course of chemotherapy treatment.
This article is available for continuing medical education credit at CME.TheOncologist.com
Rates of anthracycline adherence in breast cancer (BC) patients are unknown, but noncompletion of chemotherapy is associated with worse outcomes.
Using the Surveillance, Epidemiology, and End Results–Medicare database, we obtained demographics, comorbidities, tumor characteristics, and treatment and hospitalization data from stage I–III BC patients diagnosed at age ≥66 years in 1996–2005 treated with surgery who had anthracycline claims. We compared variables between patients with claims for less than four cycles, considered nonadherent cases, and those with claims for four or more cycles using logistic regression analyses.
The sample included 7,399 patients, of whom 1,222 (16.5%) were nonadherent cases. Two hundred forty-three (3.3%) patients had one claim, 298 (4.0%) had two claims, and 681 (9.2%) had three claims. The multivariate regression model showed statistically significant associations between nonadherence and older age, black race, unmarried status, diagnosis before the year 2001, and hospitalizations.
Eighty-three percent of older patients with early-stage BC completed at least four cycles of an anthracycline-based chemotherapy regimen. We identified a subset of patients with a higher likelihood of not adhering to the course of treatment. Further research is warranted to develop interventions to enhance adherence.
Adherence to chemotherapy; Anthracyclines; Early breast cancer; Elderly patients with breast cancer; SEER–Medicare database
We evaluated whether patients with human epidermal growth factor receptor 2 (HER2) –positive primary breast tumors had metastatic tumors that were HER2 positive (concordant) or HER2 negative (discordant). We then evaluated whether treatment with trastuzumab or chemotherapy before biopsy of the metastasis had any effect on the rate of HER2 discordance. We also compared the overall survival durations of patients with HER2-concordant and -discordant tumors.
Patients and Methods
We retrospectively identified all patients who initially had been diagnosed with HER2-positive (immunohistochemistry 3+ and/or fluorescent in situ hybridization positive) primary breast cancer between 1997 and 2008 at MD Anderson Cancer Center who also had metastatic tumor biopsy results available for review.
We included 182 patients who met our criteria. Forty-three (24%) of the 182 patients with HER2-positive primary tumors had HER2-negative metastatic tumors. The HER2 discordance rates differed significantly on the basis of whether patients received chemotherapy (P = .022) but not on the basis of whether patients received trastuzumab (P = .296). Patients with discordant HER2 status had shorter overall survival than did patients with concordant HER2 status (hazard ratio [HR], 0.43; P = .003). A survival difference remained among the 67 patients who received trastuzumab (HR, 0.56; P = .083) and 101 patients who did not (HR, 0.53; P = .033) before their metastasis biopsies.
We confirmed that loss of HER2-positive status in metastatic tumors can occur in patients with primary HER2-positive breast cancer. Our data strongly support the need for biopsies of metastatic lesions to accurately determine patient prognosis and appropriate use of targeted therapy.
Epithelial cancer cells are likely to undergo epithelial mesenchymal transition (EMT) prior to entering the peripheral circulation. By undergoing EMT, circulating tumor cells (CTCs) lose epithelial markers and may escape detection by conventional methods. Therefore, we conducted a pilot study to investigate mRNA transcripts of EMT-inducing transcription factors (TFs) in tumor cells from the peripheral blood (PB) of primary breast cancer (PBC) patients.
Peripheral blood mononuclear cells were isolated from 52 stages I–III PBC patients and 30 healthy donors (HD) and sequentially depleted of EpCAM+ cells and CD45+ leukocytes, henceforth referred to as CD45−. The expression levels of EMT-inducing TFs (TWIST1, SNAIL1, SLUG, ZEB1, and FOXC2) in the CD45− cells were determined using qRT-PCR. The highest level of expression by the CD45− cell fraction of HD was used as “cut off” to determine if samples from PBC patients overexpressed any EMT-inducing TFs. In total, 15.4% of PBC patients overexpressed at least one of the EMT-inducing TF transcripts. Overexpression of any EMT-inducing TF transcripts was more likely to be detected in PBC patients who received neoadjuvant therapies (NAT) than patients who received no NAT (P = 0.003). Concurrently, CTCs were detected in 7 out of 38 (18.4%) patients by CellSearch® and 15 out of 42 (35.7%) patients by AdnaTest™. There was no association between the presence of CTCs measured by CellSearch® or AdnaTest™.
In summary, our results demonstrate that CTCs with EMT phenotype may occur in the peripheral circulation of PBC patients and NAT is unable to eliminate CTCs undergoing EMT.
circulating tumor cells; epithelial-mesenchymal transition; primary breast cancer; neoadjuvant therapy
To examine gene expression differences between pre- and post-NST specimens of breast cancers and identify biological changers that may lead to new therapeutic insights.
Gene expression data from pre-chemotherapy fine needle aspiration specimens were compared to resected residual cancers in 21 patients after 4-6 months of NST. We removed stroma-associated genes to minimize confounding effects. PAM50 was used to assign molecular class. Paired t-test and gene set analysis were used to identify differentially expressed genes and pathways.
The ER and HER2 status based on mRNA expression remained stable in all but two cases and there were no changes in proliferation metrics (Ki67 and PCNA expression). Molecular class changed in 8 cases (33.3%) usually to normal-like class and which was associated with low residual cancer cell cellularity. The expression of 200-600 probe sets changed between baseline and post-NST samples. In basal-like cancers, pathways driven by increased expression of PI3K, small G proteins and CAMK2 and energy metabolism were enriched while immune cell-derived and the sonic hedgehog pathways were depleted in residual cancer. In non-basal-like breast cancers, notch signaling and energy metabolism (e.g. fatty acid synthesis) were enriched and sonic hedgehog signaling and immune-related pathways were depleted in residual cancer. There was no increase in epithelial mesenchymal transition or cancer stem cell signatures.
Our data indicates that energy metabolism related processes are up-regulated and immune related signals are depleted in residual cancers. Targeting these biological processes may represent promising adjuvant treatment strategies for patients with residual cancer.
Breast Cancer; Neaodjuvant chemotherapy; Gene expression; Residual disease
Germline TP53 mutations predispose to early onset breast cancer (BC) in women and are associated with the Li Fraumeni syndrome. Published data on the pathological characteristics of breast cancer among women with TP53 mutations is limited.
We retrospectively reviewed clinical records of women who had genetic testing for suspected germline TP53 mutations and who were diagnosed with BC between 2000 to 2011. The pathological characteristics of the breast tumors from women testing positive (cases) for a mutation were compared to those testing negative (controls).
Patients who tested positive for germline TP53 mutations (N=30) were compared to (N=79) controls. Human epidermal growth factor receptor 2 (HER2) amplification and/or overexpression was found in 67% of the tumors from the cases, compared to 25% for the controls (p=0.0001). Among patients with a mutation, 70% had estrogen receptor and/or progesterone receptor positive tumors, compared to 68% in the control group (p= 0.87). After adjusting for age at BC diagnosis, having a HER2 positive tumor increased the odds of testing positive for a germline TP53 mutation (OR, 6.9, 95% CI, 2.6 to 18.2). For each yearly increments in age at BC diagnosis, there was decreased likelihood of having a TP53 mutation by 5% (OR=0.95, CI 0.91 to 0.99).
This study suggests an association between germline TP53 mutations and early onset HER2 positive breast cancer. If confirmed in a larger cohort, these results could guide genetic testing strategies, lead to chemoprevention trials incorporating HER2 targeted therapies, and elucidate some of the molecular pathways involved in breast cancer.
A simple oral combination of capecitabine and cyclophosphamide for the treatment of patients with metastatic breast cancer was evaluated. The addition of cyclophosphamide did not result in outcomes superior to those seen with capecitabine alone.
After completing this course, the reader will be able to:
Compare outcomes in patients treated with capecitabine plus CPA with those of capecitabine monotherapy and combination therapy with bevacizumab, sorafenib, or ixabepilone.Identify patients for whom single-agent capecitabine is recommended.
This article is available for continuing medical education credit at CME.TheOncologist.com
Interest in oral agents for the treatment of metastatic breast cancer (MBC) has increased because many patients prefer oral to i.v. regimens. We evaluated a simple oral combination of capecitabine with cyclophosphamide (CPA) for MBC.
The trial was designed to determine whether or not combination therapy would achieve a 42% response rate (RR) using the Response Evaluation Criteria in Solid Tumors (RECIST) in MBC. Patients with two or fewer prior chemotherapy regimens for MBC were eligible. Those with estrogen receptor–positive MBC had to have progressed on endocrine therapy. Patients had measurable disease or elevated mucin (MUC)-1 antigen and received CPA, 100 mg daily on days 1–14, and capecitabine, 1,500 mg twice daily on days 8–21, in 21-day cycles.
In 96 eligible patients, the median progression-free survival (PFS) interval was 5.9 months (95% confidence interval [CI], 3.7–8.0 months) and median overall survival (OS) time was 18.8 months (95% CI, 13.1–22.0 months). The RR was 36% (95% CI, 26%–48%) in 80 patients with measurable disease. The MUC-1 antigen RR was 33% (95% CI, 20%–48%), occurring in 15 of 46 patients with elevated MUC-1 antigen. Toxicity was mild, with no treatment-related deaths.
PFS, OS, and RR outcomes with capecitabine plus CPA compare favorably with those of capecitabine monotherapy and combination therapy with bevacizumab, sorafenib, or ixabepilone. The addition of these other agents to capecitabine does not improve OS time in MBC patients, and this single-arm study does not suggest that the addition of CPA to capecitabine has this potential in an unselected MBC population. When OS prolongation is the goal, clinicians should choose single-agent capecitabine.
Metastatic breast cancer; Capecitabine; Cyclophosphamide; Oral therapy
Several studies have suggested that bisphosphonates have an antitumor effect. We sought to evaluate whether the use of bisphosphonates increased the rates of pathological complete response (pCR) in breast cancer patients.
We identified 1449 breast cancer patients receiving taxane and anthracycline-based neoadjuvant chemotherapy between 1995 and 2007 at M.D. Anderson Cancer Center. We also identified those patients that while receiving chemotherapy received bisphosphonates for osteopenia or osteoporosis. Primary outcome was the proportion of patients achieving a pCR. Groups were compared using the chi-squared test. A multivariable logistic regression model was fit to examine the relationship between the use of bisphosphonates and pCR. An exploratory survival analysis using the Kaplan-Meier method was performed; groups were compared using the log-rank test.
From the 1449 patients included, 39 (2.7%) received bisphosphonates. Those receiving bisphosphonates were older (p<0.001) and less likely to be obese (p=0.04). The pCR rate was 25.4% in the bisphosphonate group and 16% in the non-bisphosphonate group (p=.11). In the multivariable model, patients treated with bisphosphonates tended to have higher rates of pCR (OR 2.18; 95%CI 0.90–5.24); however the difference was not statistically significant. With a median follow up of 55 months (3–145), no differences in recurrence or in survival were observed.
The use of bisphosphonates at the time of neoadjuvant chemotherapy was not associated with a statistically significant increase in the rates of pCR. The observed estimates suggest a positive effect; however, the small proportion of patients receiving bisphosphonates likely affected the power to detect a statistically significant difference.
bisphosphonates; neoadjuvant chemotherapy; breast cancer; pathological complete response
The use of supplements during chemotherapy is controversial, partly due to the potential effect of antioxidants on reduced efficacy of chemotherapy-related cytotoxicity. We examined supplement use among breast cancer patients registered to a clinical trial (SWOG 0221) before diagnosis and during treatment. Patients (n = 1,467) completed questionnaires regarding multivitamin and supplement use at trial registration (baseline) to capture use before diagnosis. Of these patients, 1,249 completed a 6-month followup questionnaire to capture use during treatment. We examined the use of vitamins C, D, E, B6, B12, folic acid, and calcium at these timepoints, as well as physician recommendations regarding supplement use. The use of vitamins C, E, folic acid, and calcium decreased during treatment, while the use of vitamin B6 increased. Five hundred seventy four patients (51 %) received no physician recommendations regarding supplement use. Among the remaining 49, 10 % were advised not to take multivitamins and/or supplements, 7 % were advised to use only multivitamins, and 32 % received recommendations to use multivitamins and/or supplements. Among patients who took vitamin C before diagnosis, those who were advised not to take supplements were >5 times more likely not to use of vitamin C during treatment than those not advised to stop use (OR = 5.27, 95 % CI 1.13–24.6). Previous non-users who were advised to take a multivitamin were nearly 5 times more likely to use multivitamins during treatment compared to those who received no recommendation (OR = 4.66, 95 % CI 2.10–10.3). In this clinical trial for high-risk breast cancer, supplement use generally decreased during treatment. Upon followup from the clinical trial, findings regarding supplement use and survival outcomes will better inform physician recommendations for patients on adjuvant chemotherapy.
Antioxidants; Dietary supplements; Epidemiology; Breast cancer; Chemotherapy
BACKGROUND: ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may have anti-tumor properties. We investigated whether the use of ACEI/ARBs affects the clinical outcomes of primary breast cancer patients receiving taxane and anthracycline-based neoadjuvant chemotherapy.
METHODS: We included 1449 patients with diagnosis of invasive primary breast cancer diagnosed at the MD Anderson Cancer Center between 1995 and 2007 who underwent neoadjuvant chemotherapy. Of them, 160 (11%) patients were identified by review of their medical record, as ACEI/ARBs users. We compared pathologic complete response (pCR) rates, relapse-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) between ACEI/ARB users and non-users. Descriptive statistics and Cox proportional hazards model were used in the analyses.
RESULTS: There was no difference in the pCR rates between ACEI/ARB users and non-users (16% vs 18.1%, p-=0.50). After adjustment for important demographic and clinical characteristics, no significant differences between ACEI/ARB users and nonusers were observed in RFS (HR=0.81; 95% CI=0.54-1.21), DSS (HR=0.83; 95% CI=0.52-1.31), or OS (HR=0.91; 95% CI =0.61-1.37). In a subgroup analysis, the 5-year RFS was 82% in ARB only users versus 71% in ACEI/ARB non-users (P=0.03). In the multivariable analysis, ARB use was also associated with a decreased risk of recurrence (HR=0.35; 95% CI=0.14-0.86). No statistically significant differences in DSS or OS were seen.
CONCLUSION: No differences in pCR and survival outcomes were seen between ACEI/ARB users and non-users among breast cancer patients receiving neoadjuvant chemotherapy. ARB use may be associated with improved RFS. Further research is needed to validate this finding.
ACE inhibitor; ARB; breast cancer; neoadjuvant chemotherapy
We assessed SNPS in the Fanconi Anemia (FA)/BRCA pathway in women being was taxanes for breast cancer in an effort to find a prognostic biomarker for neurological toxicities, which while improve survival remain a debilitating outcome.
Patients and Methods
We used data and samples (n=888) from SWOG0221, a phase III adjuvant trial of 4 dose/schedules of cyclophosphamide (C), doxorubicin (A) and paclitaxel (T) for high risk breast cancer. The relationship of SNPs in the (FA)/BRCA pathway with risk grade 3/4 neurotoxicities. In a separate cohort we measured the correlation of significant SNPs in this pathway with corresponding gene expression.
No associations between SNPs in BRCA1 and taxane-induced neuropathy was found. For FANCD2, significant associations between 4 (out of 20) SNPs and neurological toxicities, with risk estimates approaching 2. Two FANCD2 haplotypes were also found to be significantly associated with neurological toxicity, increasing the odds in the overall population 1.8 (95% confidence interval (CI) 1.3–2.5) and 1.7 (95% CI, 1.2–2.4) fold. Although numbers were small, there appeared to be a specific African-American haplotype that was associated with an almost 3-fold increase in risk of neurological toxicity. Expression analyses revealed that significant FANCD2 SNPs were associated with FANCD2 expression levels (p=0.03)
SNPs in FANCD2, were associated with a 70 to 80% increase in the odds of grade 3/4 neurological toxicities and increased expression of the gene. If replicated, women with these genotypes should be closely monitored for toxicities, and could be targeted for preventive measures or alternative therapeutic approaches.
American Joint Committee on Cancer (AJCC) staging is used to determine breast cancer prognosis, yet patient survival within each stage shows wide variation. We hypothesized that differences in biology influence this variation and that addition of biologic markers to AJCC staging improves determination of prognosis.
Patients and Methods
We identified a cohort of 3,728 patients who underwent surgery as the first intervention between 1997 and 2006. A Cox proportional hazards model, with backward stepwise exclusion of factors and stratification on pathologic stage (PS), was used to test the significance of adding grade (G), lymphovascular invasion (L), estrogen receptor (ER) status (E), progesterone receptor (PR) status, combined ER and PR status (EP), or combined ER, PR, and human epidermal growth factor receptor 2 status (M). We assigned values of 0 to 2 to these disease-specific survival (DSS) –associated factors and assessed six different staging systems: PS, PS + G, PS + G L, PS + G E, PS + G EP, and PS + G M. We compared 5-year DSS rates, Akaike's information criterion (AIC), and Harrell's concordance index (C-index) between systems. Surveillance, Epidemiology, and End Results data were used as the external validation cohort (n = 26,711).
Median follow-up was 6.5 years, and 5-year DSS rate was 97.4%. The PS + G E status staging system was most precise, with a low AIC (1,931.9) and the highest C-index (0.80). PS + G E status was confirmed to stratify outcomes in internal bootstrapping samples and the external validation cohort.
Our results validate an improved breast cancer staging system that incorporates grade and ER status. We recommend that biologic markers be incorporated into revised versions of the AJCC staging system.
SWOG trial S0102 showed significant activity of the combination of docetaxel and vinorelbine in HER2-negative metastatic breast cancer (MBC). For HER2-positive patients, additional benefit may occur with the addition of trastuzumab due to its synergy with docetaxel and vinorelbine.
Patients with HER2-positive MBC, but without prior chemotherapy for MBC or adjuvant taxane, were eligible. Docetaxel (60 mg/m2) was given intravenously on Day 1, vinorelbine (27.5 mg/m2) intravenously on Days 8 and 15, and filgrastim (5 μg/kg) on Days 2–21 of a 21-day cycle. Additionally, patients received weekly infusions of trastuzumab (2 mg/kg) after an initial bolus of 4 mg/kg. The primary outcome was one-year overall survival (OS), with secondary outcomes of progression-free survival (PFS), response rate, and toxicity. Due to slow accrual (February 2003-December 2006), enrollment was stopped after 76 of 90 planned patients.
There have been 32 deaths and 51 progressions among the 74 eligible patients who received treatment. The estimated 1-year OS was 93% (95% CI 84%–97%) with a median of 48 months. One-year PFS was 70% (95% CI 58–79%) with a median of 20 months. Response rate for measurable disease was 84%. No deaths were attributed to treatment. Grade 4 toxicities were reported for 19% with neutropenia the most common (15%). The most common grade 3 toxicities (33%) were leucopenia (14%) and fatigue (10%).
The combination of trastuzumab, docetaxel, and vinorelbine is effective as first-line chemotherapy in HER2-positive MBC with minimal toxicity. One-year survival estimates are among the highest reported in this population.
Docetaxel; vinorelbine; trastuzumab; HER2-positive metastatic breast cancer
The most promising breast cancer studies using bevacizumab combined with traditional cytotoxic agents in advanced breast cancer are outlined. The current indications for bevacizumab reviewed by the Oncologic Drug Advisory Committee are discussed and how benefit in patient clinical trials should be measured is proposed.
Significant advances in the treatment of patients with breast cancer have been made in the past 10 years. The current systemic treatment of breast cancer is characterized by the discovery of multiple cancer targets leading to treatments that are more sophisticated and specific than conventional cytotoxic chemotherapy. Two classes of compounds that have helped improve clinical outcomes are small molecules and monoclonal antibodies targeting specific tyrosine kinase receptors. Many novel targets have been discovered, and parallel multiple approaches to anticancer therapy have recently emerged from the literature. One promising strategy is targeting the proangiogenic vascular endothelial growth factors (VEGFs), either by ligand sequestration (preventing VEGF receptor binding) or inhibiting downstream receptor signaling. Bevacizumab, a monoclonal antibody directed against VEGF, has been shown to improve the efficacy of taxanes in frontline treatment of patients with metastatic breast cancer. This review outlines the most promising breast cancer studies using bevacizumab combined with traditional cytotoxic agents in advanced breast cancer. In addition, we discuss the current indications reviewed by the Oncologic Drug Advisory Committee and define our vision of how the benefit of patient clinical trials should be measured.
Antiangiogenesis; Advanced breast cancer; Bevacizumab; FDA
Imatinib mesylate is a potent inhibitor of the Bcr-Abl, c-kit, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases. Based on variable expression of c-kit and PDGFR in breast cancer, and on in vitro data supporting synergy between imatinib and capecitabine, the Southwest Oncology Group conducted a phase II trial of the combination in metastatic breast cancer.
Patients and Methods
Eligible patients had progressive, measurable metastatic breast cancer and received up to two prior chemotherapy regimens for metastatic disease. Prior 5-fluorouracil or capecitabine for metastatic disease was not allowed. Patients were accrued on a 2-stage design and received imatinib mesylate 400 mg by mouth daily and capecitabine at 1000 mg/m2 by mouth twice daily for 14 days of a 21-day cycle. The primary endpoint was the confirmed response rate (RR). Tumors were evaluated for c-kit, PDGFRβ, and hormone receptor expression.
Nineteen fully evaluable patients were enrolled with a confirmed RR of 11% (95% CI 1–33%). Eleven percent had unconfirmed partial responses and 42% had stable disease. The trial did not accrue to the second stage. The estimated 6-month progression-free survival was 16% (95% CI 0–32%) and the median overall survival was 14 months (95% CI 7–15). The combination was well tolerated. Of 8 available tumor samples, 2 stained for c-kit and all had stromal staining for PDGFRβ.
In unselected patients, the combination of imatinib mesylate and capecitabine was well tolerated but did not result in improved response rates compared to that reported with capecitabine alone.
breast cancer; imatinib mesylate; capecitabine
The pathologic complete response rate, delivered dose intensity, disease-free survival and overall survival rates, and toxicity of breast cancer patients treated with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus dose-intense FAC plus G-CSF in the neoadjuvant setting were compared.
After completing this course, the reader will be able to:
Compare outcomes in patients treated with standard fluorouracil, doxorubicin, and cyclophosphamide (FAC) and those treated with dose-intense FAC.Describe toxicity profiles in patients treated with standard fluorouracil, doxorubicin, and cyclophosphamide (FAC) and those treated with dose-intense FAC.
This article is available for continuing medical education credit at CME.TheOncologist.com
To compare the pathologic complete response (pCR) rate of patients treated with 5-fluorouracil (5-FU), doxorubicin, and cyclophosphamide (FAC) versus dose-intense FAC plus G-CSF in the neoadjuvant setting and to compare the delivered dose intensity, disease-free survival (DFS) and overall survival (OS) times, and toxicity between treatment arms in patients with breast cancer.
Patients were randomized to receive preoperative FAC (5-FU, 500 mg/m2; doxorubicin, 50 mg/m2; cyclophosphamide, 500 mg/m2) every 21 days for four cycles or dose-intense FAC (5-FU, 600 mg/m2; doxorubicin, 60 mg/m2; cyclophosphamide, 1,000 mg/m2) plus G-CSF every 18 days for four cycles.
Two hundred two patients were randomly assigned. The median follow-up was 7.5 years. Patients randomized to FAC plus G-CSF had a higher pCR rate as well as clinical complete response rate; however, these differences were not statistically different from those with the FAC arm. Patients in the FAC + G-CSF arm had a higher delivered dose intensity of doxorubicin in the neoadjuvant and adjuvant settings than those in the standard FAC arm. DFS and OS times were not significantly different between the two groups. However, the OS and DFS rates were significantly higher for patients who achieved a pCR than for those who did not. Thrombocytopenia, febrile neutropenia, and infection rates were higher in the FAC + G-CSF arm.
A higher delivered dose intensity of doxorubicin with the FAC + G-CSF regimen did not result in a statistically significant higher pCR rate. However, patients who achieved a pCR experienced longer DFS and OS times.
Breast cancer; Locally advanced; Dose intensity; Disease-free survival; Overall survival; G-CSF
Current options for the management of hot flashes are addressed, key endpoints from recent clinical trials are examined, and future directions are reviewed.
Many therapies are being studied for the treatment of hot flashes for individuals with cancer, yet few studies have demonstrated safe and effective clinical benefit for those who suffer from this distressing symptom. The purpose of this paper is to assess the current options for the management of hot flashes, examining key endpoints from recent clinical trials and reviewing future directions. Hot flashes are a common stressful symptom for individuals with cancer, particularly women with a history of breast cancer and men with prostate cancer. Lifestyle modifications are proposed as the first step in the management of less severe hot flashes. Several publications have addressed nonhormonal agents as a treatment option for hot flashes. Newer antidepressant and anticonvulsant agents have been studied and show potential in treating vasomotor symptoms. Although many complementary and alternative therapies, including herbal medications and phytoestrogens, have been studied for the treatment of hot flashes, none are clinically recommended at this time. Additionally, further evidence is needed for supportive exercise such as yoga and relaxation techniques. Acupuncture may warrant further investigation in the reduction and severity of hot flashes in both men and women. Hormonal therapies, including estrogens and progestogens, are the most well-known and efficient agents in alleviating hot flashes; however, the safety of these agents is disputable.
Vasomotor symptoms; Hot flashes; Menopause; Therapy; Quality of life
To evaluate the patterns of use and the risk of thromboembolic events (TEE) associated with Erythropoietin Stimulating Agents (ESAs) in older patients with metastatic breast cancer receiving chemotherapy.
Retrospective study using the SEER-Medicare linked database. Stage IV breast cancer patients diagnosed from 1995–2005, treated with chemotherapy, ≥66 years old, with full coverage of Medicare A and B were included. ICD-9 and HCPCS codes were used to identify the use of ESAs, chemotherapy, and complications of therapy. Analyses included descriptive statistics and logistic regression.
2,266 women were included, 980 (43.3%) received ESAs and 1,286 (56.7%) did not. Patients diagnosed after 1999 or who received treatment with taxanes, anthracyclines or vinorelbine were more likely to receive ESAs. Patients receiving ESAs had higher rates of stroke (18.5% vs 15.1%, p=0.031); DVT (21.3% vs. 14.4%, p<0.001), other/unspecified TEE (19.8% vs 14.7%; p=0.001) and any clot (31.3% vs. 23.4%, p<0.0001). In multivariable analysis, patients receiving ESAs had increased risk for DVT (OR=1.36; 1.05–1.75), and any clot (OR=1.26; 1.02–1.57). A dose-dependent effect was evident for stroke, DVT, other TEE and any clot.
In this cohort of patients, the use of ESAs increased the risk of TEEs, with a dose-dependent effect for stroke, DVT, other TEE and any clot. Our data shows that among patients treated with chemotherapy and ESAs for metastatic breast cancer, TEEs are a common event. Therefore caution is recommended when using these agents.