Palbociclib or Ribociclib in First-Line Treatment in Patients With Hormone Receptor–Positive/Human Epidermal Receptor 2–Negative Advanced or Metastatic Breast Cancer? A Perspective Based on Pharmacologic Costs

PurposeTo assess the pharmacologic costs of CDK4/6 inhibitors (palbociclib and ribociclib) in hormone receptor–positive (HR⁺)/human epidermal receptor 2–negative (HER2^?) advanced or metastatic breast cancer (BC). Pivotal phase 3 randomized controlled trials (RCTs) were considered.DiscussionTwo phase 3 RCTs including 1334 patients were considered. European Society for Medical Oncology Magnitude of Clinical Benefit Scale reached grade 3 for the PALOMA-2 and MONALEESA-2 trials. Pharmacologic costs of palbociclib and ribociclib at full dose were similar, at €3864 and €4002 per month of progression-free survival (PFS) gained, respectively. The reduction of dose of ribociclib (36.1% in the pivotal RCT vs. 36.0% of palbociclib in pivotal RCT) resulted in €2718 and €1348 per month of PFS gained at 400 and 200 mg daily, respectively.ConclusionWhen pharmacologic costs of drugs are combined with the measure of efficacy represented by PFS, both palbociclib and ribociclib are cost-effective first-line treatments in postmenopausal women with HR⁺/HER2^? advanced or metastatic BC, with a lower cost in favor of ribociclib in patients with dose reduction.     

A 2009 Update on the Treatment of Patients with Hormone Receptor—Positive Breast Cancer

In up to 75% of breast cancers, estrogen receptor (ER) signaling is a key promoter of tumor proliferation, and inhibition of this pathway has clear therapeutic efficacy. The principal clinical means of inhibiting ER signaling comprise selective ER modulators, such as tamoxifen, that act as partial receptor agonists; measures to reduce the circulating level of estrogen, including ovarian ablation, gonadotropin-releasing hormone analogues, and aromatase inhibition; and antagonism and downregulation of ER by the antiestrogen fulvestrant. Each of these therapies is effective in a proportion of ER-positive breast cancers, but de novo and acquired resistance remain significant problems. Emerging knowledge of the biology of ER signaling will provide insights into the mechanisms of resistance and help guide development of therapeutic strategies to maximize response. This review summarizes the contemporary treatment of early-stage and advanced ER-positive breast cancer in premenopausal and postmenopausal women, with an emphasis on recently published or presented data. Mechanisms of resistance to endocrine interventions and trials exploring strategies to overcome them will also be discussed.     

Safety and Efficacy of Everolimus With Exemestane vs. Exemestane Alone in Elderly Patients With HER2-Negative,Hormone Receptor–Positive Breast Cancer in BOLERO-2

BackgroundPostmenopausal women with hormone receptor–positive (HR⁺) breast cancer in whom disease progresses or there is recurrence while taking a nonsteroidal aromatase inhibitor (NSAI) are usually treated with exemestane (EXE), but no single standard of care exists in this setting. The BOLERO-2 trial demonstrated that adding everolimus (EVE) to EXE improved progression-free survival (PFS) while maintaining quality of life when compared with EXE alone. Because many women with HR⁺ advanced breast cancer are elderly, the tolerability profile of EVE plus EXE in this population is of interest.Patients and MethodsBOLERO-2, a phase III randomized trial, compared EVE (10 mg/d) and placebo (PBO), both plus EXE (25 mg/d), in 724 postmenopausal women with HR⁺ advanced breast cancer recurring/progressing after treatment with NSAIs. Safety and efficacy data in elderly patients are reported at 18-month median follow-up.ResultsBaseline disease characteristics and treatment histories among the elderly subsets (≥ 65 years, n = 275; ≥ 70 years, n = 164) were generally comparable with younger patients. The addition of EVE to EXE improved PFS regardless of age (hazard ratio, 0.59 [≥ 65 years] and 0.45 [≥ 70 years]). Adverse events (AEs) of special interest (all grades) that occurred more frequently with EVE than with PBO included stomatitis, infections, rash, pneumonitis, and hyperglycemia. Elderly EVE-treated patients had similar incidences of these AEs as did younger patients but had more on-treatment deaths.ConclusionAdding EVE to EXE offers substantially improved PFS over EXE and was generally well tolerated in elderly patients with HR⁺ advanced breast cancer. Careful monitoring and appropriate dose reductions or interruptions for AE management are recommended during treatment with EVE in this patient population.     

Expanded-Access Study of Palbociclib in Combination With Letrozole for Treatment of Postmenopausal Women With Hormone Receptor–Positive,HER2-Negative Advanced Breast Cancer

Purpose

Palbociclib is a cyclin-dependent kinase (CDK) 4 and 6 inhibitor that was conditionally approved in the United States (February 2015) and Canada (March 2016) with letrozole as initial endocrine-based therapy for postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. A palbociclib expanded-access program (EAP) was initiated as an interim measure to provide drug access before commercial availability of drug.

Clinical Outcomes of Single Versus Double Hormone Receptor–Positive Breast Cancer Patients Treated With Neoadjuvant Chemotherapy

Purpose

To compare tumor response rates and survival outcomes between single and double hormone receptor (HR)-positive breast cancer (BC) patients treated with neoadjuvant chemotherapy.

Clinical Features and Survival of Single Hormone Receptor–Positive Breast Cancer: A Population-Based Study of 531,605 Patients

PurposeTo investigate the prognosis of single hormone receptor–positive (HR⁺) breast cancer (estrogen receptor [ER] positive and progesterone receptor [PR] negative, and ER⁻PR⁺) compared to double HR⁺ (ER⁺PR⁺) and double HR⁻ (ER⁻PR⁻) tumors.MethodsWe included 531,605 cases of invasive breast cancer between 1990 and 2012 from the US Surveillance, Epidemiology, and End Results (SEER) database for study and classified cases into 4 phenotypes according to expression of ER and PR: ER⁺PR⁺, ER⁺PR⁻, ER⁻PR⁺, and ER⁻PR⁻.ResultsOverall, 66,091 ER⁺PR⁻ tumors and 9320 ER⁻PR⁺ tumors were identified. The clinical characteristics of the ER⁺PR⁻ group were similar to those of the double HR⁺ group, while those of the ER⁻PR⁺ and double HR⁻ groups were similar. Overall survival of patients with single HR⁺ tumors was intermediate between that of double HR⁺ and double HR⁻ tumors. However, we observed no differences in disease-specific survival between ER⁻PR⁺ and ER⁻PR⁻ patients. In multivariate analysis, outcomes were similar. Relative to the double HR⁺ patient group, risk of death in the ER⁺PR⁻ group was higher (hazard ratio, 1.422, 95% confidence interval, 1.394-1.452). However, risk of death was comparable between ER⁻PR⁺ and ER⁻PR⁻ patients (hazard ratio, 1.03; 95% confidence interval, 0.98-1.08). Multivariate Cox proportional analysis showed that survival times of patients in the younger age bracket (< 60 years), those positive for human epidermal growth factor receptor 2 (HER2), and patients with tumor stage I-III were longer in the ER⁻PR⁺ group.ConclusionDisease-specific survival of single HR⁺ tumor cases was longer than that of double HR⁻ tumors but poorer than double HR⁺ tumors. However, differences in disease-specific survival were not significant between the ER⁻PR⁺ and ER⁻PR⁻ groups.     

Oncologists' Recommendations for Adjuvant Therapy in Hormone Receptor—Positive Breast Cancer Patients of Varying Age and Health Status

BackgroundCurrently, evidence supports the use of adjuvant endocrine therapy with aromatase inhibitors in post-menopausal patients with hormone receptor (HR)—positive breast cancer. The goal of the current study is to understand the effect of patient age and health status on oncologists' decision to recommend adjuvant treatment (endocrine therapy and chemotherapy) in older women with HR-positive breast cancer.Patients and MethodsAn online survey was conducted, with questions related to a hypothetical patient of varying age and health status with a T2 N2 HR-positive, HER2-negative breast cancer. Treatment options included chemotherapy and endocrine therapy, endocrine therapy alone, or no therapy. Respondents (n = 151) were further asked to specify use of either tamoxifen or aromatase inhibitors. A generalized linear mixed-effects model was used to determine the effect of age and health status on recommendations.ResultsAs the hypothetical patient's age increased or health status deteriorated, oncologists (n = 151) were less likely to recommend a combination of chemotherapy and endocrine therapy (P < .0001 for both). In contrast, oncologists were more likely to recommend endocrine therapy alone with advanced age and deteriorating health status (P < .0001 for both). Oncologists were more likely to choose treatment with aromatase inhibitors as opposed to tamoxifen (P < .01), irrespective of age or health status.ConclusionWith increasing age and declining health status, oncologists were more likely to recommend endocrine therapy alone as opposed to chemotherapy with endocrine therapy. Oncologists were most likely to recommend aromatase inhibitors, irrespective of age or health status.     

Clinical Characteristics and Outcomes of Single Versus Double Hormone Receptor–Positive Breast Cancer in 2 Large Databases

PurposeTo identify biologic and outcome differences between double hormone receptor (HR)-positive (dHR⁺, estrogen receptor (ER)⁺/progesterone receptor [PgR⁺]) and single HR-positive (sHR⁺, either ER⁺/PgR⁻ or ER⁻/PgR⁺) breast cancer; and to explore whether hormone therapy (HT) response in HER2-negative breast cancer correlates with HR status.Patients and MethodsThis retrospective study was conducted by using 2 large breast cancer databases: the Surveillance, Epidemiology, and End Results (SEER) database and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) clinical data set. Cox regression analysis was used to estimate overall survival (OS) and breast cancer–specific survival (BCSS) among sHR⁺ and dHR⁺ patients.ResultsIn the SEER database, dHR⁺ patients had significantly longer OS and BCSS than ER⁺/PgR⁻ patients in short-term follow-up (OS: hazard ratio = 0.620; 95% confidence interval [CI], 0.590, 0.652; P < .001; BCSS: hazard ratio = 0.493; 95% CI, 0.462, 0.526; P < .001). Meanwhile, ER⁻/PgR⁺ patients had younger age, larger tumor size, and higher disease grade than dHR⁺ and ER⁺/PgR⁻ patients. In patients who received HT, dHR⁺ patients had a more favorable OS than ER⁺/PgR⁻ patients (hazard ratio = 0.789; 95% CI, 0.635, 0.982; P = .034), and ER⁻/PgR⁺ patients had a worse OS than ER⁺/PgR⁻ patients at 10 years’ follow-up (hazard ratio = 7.991; 95% CI, 1.053, 60.644; P = .044). However, these groups had similar outcomes over longer periods.ConclusionIn HER2-negative breast cancer, sHR⁺ patients are associated with relatively worse characteristics and worse short-term outcomes than dHR⁺ patients. Additionally, the outcome of patients receiving HT may differ according to the HR status. However, further studies are needed to confirm these conclusions.     

Do Clinical Features and Survival of Single Hormone Receptor Positive Breast Cancers Differ from Double Hormone Receptor Positive Breast Cancers?

The significance of the single hormone receptor positive phenotype of breast cancer is still poorly understood.The use of hormone therapy has been found to be less effective for this type, which has a survival outcome midwaybetween double positive and double negative phenotypes. The aim of this study was to investigate differencesin patient and tumor characteristics and survival between double-receptor positive (ER+PR+), double receptornegative (ER-PR-) and single receptor positive (ER+PR- and ER-PR+) breast cancer in an Asian setting. Atotal of 1,992 patients with newly diagnosed stage I to IV breast cancer between 2003 and 2008, and whereinformation on ER and PR were available, were included in this study. The majority of patients had ER+PR+tumors (n=903: 45.3%), followed by 741 (37.2%) ER-PR-, 247 (12.4%) ER+PR-, and 101 (5.1%) ER-PR+ tumors.Using multivariate analysis, ER+PR- tumors were 2.4 times more likely to be grade 3 compared to ER+PR+tumors. ER+PR- and ER-PR+ tumors were 82% and 86% respectively less likely to be grade 3 compared withER-PR- tumors. ER-PR+ tumours were associated with younger age. There were no survival differences betweenpatients with ER+PR+ and ER-PR+ tumors. However, ER+PR- tumors have poorer survival compared withER+PR+ tumours. ER-PR- tumours had the worst survival. Adjuvant hormonal therapy with tamoxifen wasfound to have identical survival advantage in patients with ER+PR+ and ER-PR+ tumors whereas impact wasslightly lower in patients with ER+PR- tumors. In conclusion, we found ER+PR- tumors to be more aggressiveand have poorer survival when compared to ER+PR+ tumors, while patients with ER-PR+ tumours were younger,but had a similar survival to their counterparts with ER+PR+ tumours.     

Update on Estrogen Receptor–Positive Breast Cancer Risk Reduction

Women who are at increased risk of breast cancer can be identified using individual risk factors or by using validated quantitative risk assessment models. There are millions of such women in the US population alone, and many additional millions of women at increased risk worldwide. Decades of randomized, prospective studies of these women using selective estrogen receptor modulators (SERMs) have shown that risk can be reduced safely and effectively by 50% for all invasive breast cancer and by nearly 70% or more for estrogen receptor–positive breast cancer. Safety and tolerability of the SERMs are acceptable in the published studies, and two SERMs, tamoxifen and raloxifene, are approved by the US Food and Drug Administration for breast cancer risk reduction. Nevertheless, the drugs are not widely used despite reasonable cost per year of life saved (or morbidity avoided). Clinicians must endeavor to identify women who are suitable candidates for these drugs and educate them about their safety and utility.     

Development of a Nomogram to Predict the Recurrence Score of 21-Gene Prediction Assay in Hormone Receptor–Positive Early Breast Cancer

IntroductionA 21-gene prediction assay (Oncotype DX) is helpful to estimate benefit from adjuvant chemotherapy in patients with hormone receptor–positive, lymph node–negative early breast cancer. This study was conducted to develop a model to estimate high recurrence score (RS) using easily available clinicopathologic parameters in limited-resource countries.Patients and MethodsHormone receptor–positive, lymph node–negative early breast cancer patients who underwent Oncotype DX were enrolled onto the training set (n = 192). The risk category range of the RS was the same as in the TAILORx study. The multivariable logistic regression model was used to identify significant variables associated with high RS. The independent validation set (n = 264) was established from patients of a different time period.ResultsThe median age in the training set was 47 years, and 78.0% were premenopausal. The number of patients with low RS (< 11), intermediate RS (11-25), and high RS (> 25) were 42 (22.0%), 122 (63.9%), and 27 (14.1%), respectively. High nuclear grade, no progesterone receptor expression, and high Ki-67 were associated with high RS, and these variables were used to construct the nomogram. It had significant discriminatory power in internal validation (area under the curve = 0.856) and in the validation set (area under the curve = 0.828). The calibration plot showed optimal agreement between predicted and actual probabilities in both sets.ConclusionA nomogram was successfully developed with 3 simple parameters. The probability of high RS can be easily and conveniently estimated using our nomogram. It might be useful to determine whether or not Oncotype DX is conducted in the TAILORx era. Future large-scale prospective studies are warranted.     

Bevacizumab in the Treatment of Metastatic Breast Cancer: Friend or Foe?

Metastatic breast cancer (MBC) is a major cause of death among women worldwide. Progress has been made in treating MBC with the advent of anti-estrogen therapies, potent cytotoxic agents, and monoclonal antibodies. Bevacizumab is a monoclonal antibody against circulating vascular endothelial growth factor (VEGF), which was approved in 2008 by the US Food and Drug Administration (FDA), for first-line treatment of HER-2 negative MBC in combination with paclitaxel. The FDA then reversed this decision in December 2010 by recommending removal of the MBC indication from bevacizumab, citing primarily safety concerns, and that these risks did not outweigh the ability of bevacizumab to significantly prolong progression-free survival. This decision was unexpected in the oncology community and remains controversial. This review looks at all available phase 3 data with bevacizumab in the MBC setting to determine whether the data support this decision by the FDA, and discusses the future of bevacizumab in breast cancer.     

Evaluation of Prognosis in Hormone Receptor–Positive/HER2-Negative and Lymph Node–Negative Breast Cancer With Low Oncotype DX Recurrence Score

Introduction

Hormone receptor–positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancers without lymph node metastasis have good prognosis. We compared the prognosis of hormone receptor–positive, HER2-negative, lymph node–negative cancers with Oncotype DX score ranges of 1 to 10 (1-10 group) and 11 to < 18 (11-18 group).

Can Nomograms Predict Non–Sentinel Lymph Node Metastasis After Neoadjuvant Chemotherapy in Sentinel Lymph Node–Positive Breast Cancer Patients?

BackgroundThe predictive probability of breast cancer nomograms for non–sentinel node metastases (NSLNM) after neoadjuvant chemotherapy (NCT) in patients with a positive sentinel lymph node (SLN) biopsy is unknown. The aim of this study was to evaluate the accuracy of 3 different nomograms in patients receiving NCT.Patients and MethodsBetween 1999 and 2007, 54 patients presented with clinically N0 disease received NCT. Nomograms developed by Memorial Sloan-Kettering Cancer Center (MSKCC), Stanford University, and Tenon Hospital were used to calculate the probability of NSLNM by using tumor size at presentation and after NCT for the same patient. The discrimination of the nomograms was assessed by calculating the area under (AUC) the receiver operating characteristic curve, and it was accepted that AUC values 0.7-0.8 represent considerable discrimination.ResultsThe median patient age was 50.9 years (range, 29–67 years). Twenty-two patients (38.8%) had positive NSLNM. The MSKCC and the Stanford nomograms yielded similar AUC regardless of whether initial or post-NCT tumor size was used to determine predicted probability of NSLNM (AUCs were < 0.70). AUC was 0.74 for the Tenon model using tumor size at presentation. After NCT, the AUCs were 0.64, 0.57, and 0.78 for the MSKCC, the Stanford, and the Tenon nomograms, respectively.ConclusionAlthough the AUC of the Tenon model was acceptable for accuracy, we found a lower rate for predicting negative NSLNM in our group than in the Tenon Hospital report. All of the nomograms developed for use in the non-NCT population need to be used with caution in the NCT population     

Changing Natural History of HER2–Positive Breast Cancer Metastatic to the Brain in the Era of New Targeted Therapies

Background

Given the wide adoption of human epidermal growth factor receptor 2 (HER2)-targeted therapies for advanced HER2–positive breast cancer, we studied the natural history of patients with HER2–positive breast cancer brain metastases (BCBM) over time.

72-Gene Classifier for Predicting Prognosis of Estrogen Receptor–Positive and Node-Negative Breast Cancer Patients Using Formalin-Fixed,Paraffin-Embedded Tumor Tissues

BackgroundThe 95-gene classifier (95-GC) can classify patients with estrogen receptor (ER)–positive and node-negative breast cancer into those with low and high risk of relapse with an accuracy similar to that of 21-GC (Oncotype DX). Because 95-GC uses RNA from fresh-frozen (FF) tumor tissues, we herein attempted to develop a gene classifier that is applicable to RNA from formalin-fixed paraffin-embedded (FFPE) tumor tissues.Patients and Methods25 paired FF and FFPE tumor tissues were subjected to DNA microarray for gene-expression analysis. Of the 95 probes included in the 95-GC, 72 were selected for construction of the gene classifier for FFPE tumor tissues, because the gene expression detected by these 72 probes was well preserved in the FFPE tumor tissues.ResultsThe 72-GC was constructed with these 72 probes for the training set comprising 549 FF tumor tissues and validated with 434 FF tumor tissues (relapse-free survival at 10 years was 91% for the low-risk and 74% for the high-risk group (P = 3.74 × 10⁻⁷). The predictive capability of 72-GC for prognosis was found to be comparable to that of 95-GC. The 25 paired FF and FFPE tumor tissues from each of 25 patients were classified into the same risk group by 72-GC for 23 patients (92% concordance). 72-GC using the FFPE tumor tissues showed that the prognosis for the low-risk group was significantly (P = .007) better than for the high-risk group.Conclusion72-GC is comparable to 95-GC in terms of accuracy of prognosis prediction, and may be effective for FFPE tumor tissues.