José Bines

Double-Blind, Randomized Placebo Controlled Trial of Fulvestrant Compared With Exemestane After Prior Nonsteroidal Aromatase Inhibitor Therapy in Postmenopausal Women With Hormone Receptor–Positive, Advanced Breast Cancer: Results From EFECT

PURPOSE The third-generation nonsteroidal aromatase inhibitors (AIs) are increasingly used as adjuvant and first-line advanced therapy for postmenopausal, hormone receptor-positive (HR+) breast cancer. Because many patients subsequently experience progression or relapse, it is important to identify agents with efficacy after AI failure. MATERIALS AND METHODS Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) is a randomized, double-blind, placebo controlled, multicenter phase III trial of fulvestrant versus exemestane in postmenopausal women with HR+ advanced breast cancer (ABC) progressing or recurring after nonsteroidal AI. The primary end point was time to progression (TTP). A fulvestrant loading-dose (LD) regimen was used: 500 mg intramuscularly on day 0, 250 mg on days 14, 28, and 250 mg every 28 days thereafter. Exemestane 25 mg orally was administered once daily. RESULTS A total of 693 women were randomly assigned to fulvestrant (n = 351) or exemestane (n = 342). Approximately 60% of patients had received at least two prior endocrine therapies. Median TTP was 3.7 months in both groups (hazard ratio = 0.963; 95% CI, 0.819 to 1.133; P = .6531). The overall response rate (7.4% v 6.7%; P = .736) and clinical benefit rate (32.2% v 31.5%; P = .853) were similar between fulvestrant and exemestane respectively. Median duration of clinical benefit was 9.3 and 8.3 months, respectively. Both treatments were well tolerated, with no significant differences in the incidence of adverse events or quality of life. Pharmacokinetic data confirm that steady-state was reached within 1 month with the LD schedule of fulvestrant. CONCLUSION Fulvestrant LD and exemestane are equally active and well-tolerated in a meaningful proportion of postmenopausal women with ABC who have experienced progression or recurrence during treatment with a nonsteroidal AI.

Phase III, Double-Blind, Randomized Study Comparing Lapatinib Plus Paclitaxel With Placebo Plus Paclitaxel As First-Line Treatment for Metastatic Breast Cancer

PURPOSE Lapatinib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR/ErbB1) and human epidermal growth factor receptor 2 (HER-2/ErbB2), is effective against HER-2-positive locally advanced or metastatic breast cancer (MBC). This phase III trial evaluated the efficacy of lapatinib in HER-2-negative and HER-2-uncharacterized MBC. PATIENTS AND METHODS Women with MBC were randomly assigned to first-line therapy with paclitaxel 175 mg/m(2) every 3 weeks plus lapatinib 1,500 mg/d or placebo. A preplanned retrospective evaluation of HER-2 status was performed using fluorescence in situ hybridization and immunohistochemistry. The primary end point was time to progression (TTP); secondary end points were objective response rate (ORR), clinical benefit rate (CBR), event-free survival (EFS), and overall survival (OS). RESULTS In the intent-to-treat population (n = 579), there were no significant differences in TTP, EFS, or OS between treatment arms, although differences in ORR and CBR were noted. In 86 HER-2-positive patients (15%), treatment with paclitaxel-lapatinib resulted in statistically significant improvements in TTP, EFS, ORR, and CBR compared with paclitaxel-placebo. No differences between treatment groups were observed for any end point in HER-2-negative patients. The most common adverse events were alopecia, rash, and diarrhea. The incidence of diarrhea and rash was significantly higher in the paclitaxel-lapatinib arm. The rate of cardiac events was low, and no difference was observed between treatment arms. CONCLUSION Patients with HER-2-negative or HER-2-untested MBC did not benefit from the addition of lapatinib to paclitaxel. However, first-line therapy with paclitaxel-lapatinib significantly improved clinical outcomes in HER-2-positive patients. Prospective evaluation of the efficacy and safety of this combination is ongoing in early and metastatic HER-2-positive breast cancer patients.

Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer.

BACKGROUND Pertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)–positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2‐positive early breast cancer. METHODS We randomly assigned patients with node‐positive or high‐risk node‐negative HER2‐positive, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed a 3‐year invasive‐disease–free survival rate of 91.8% with pertuzumab and 89.2% with placebo. RESULTS In the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node‐positive disease and 36% had hormone‐receptor–negative disease. Disease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The estimates of the 3‐year rates of invasive‐disease–free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node‐positive disease, the 3‐year rate of invasive‐disease–free survival was 92.0% in the pertuzumab group, as compared with 90.2% in the placebo group (hazard ratio for an invasive‐disease event, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In the cohort of patients with node‐negative disease, the 3‐year rate of invasive‐disease–free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive‐disease event, 1.13; 95% CI, 0.68 to 1.86; P=0.64). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Diarrhea of grade 3 or higher occurred almost exclusively during chemotherapy and was more frequent with pertuzumab than with placebo (9.8% vs. 3.7%). CONCLUSIONS Pertuzumab significantly improved the rates of invasive‐disease–free survival among patients with HER2‐positive, operable breast cancer when it was added to trastuzumab and chemotherapy. Diarrhea was more common with pertuzumab than with placebo. (Funded by F. Hoffmann–La Roche/Genentech; APHINITY ClinicalTrials.gov number, NCT01358877.)

Breast Cancer in Limited‐Resource Countries: Treatment and Allocation of Resources

Abstract:  Treating breast cancer under the constraints of significantly limited health care resources poses unique challenges that are not well addressed by existing guidelines. We present evidence‐based guidelines for systematically prioritizing cancer therapies across the entire spectrum of resource levels. After consideration of factors affecting the value of a given breast cancer therapy (contribution to overall survival, disease‐free survival, quality of life, and cost), we assigned each therapy to one of four incremental levels—basic, limited, enhanced, or maximal—that together map out a sequential and flexible approach for planning, establishing, and expanding breast cancer treatment services. For stage I disease, basic‐level therapies are modified radical mastectomy and endocrine therapy with ovarian ablation or tamoxifen; therapies added at the limited level are breast‐conserving therapy, radiation therapy, and standard‐efficacy chemotherapy (cyclophosphamide, methotrexate, and 5‐fluorouracil [CMF], or doxorubicin and cyclophosphamide [AC], epirubicin and cyclophosphamide [EC], or 5‐fluorouracil, doxorubicin, and cyclophosphamide [FAC]); at the enhanced level, taxane chemotherapy and endocrine therapy with aromatase inhibitors or luteinizing hormone–releasing hormone (LH‐RH) agonists; and at the maximal level, reconstructive surgery, dose‐dense chemotherapy, and growth factors. For stage II disease, the therapy allocation is the same, with the exception that standard‐efficacy chemotherapy is a basic‐level therapy. For locally advanced breast cancer, basic‐level therapies are modified radical mastectomy, neoadjuvant chemotherapy (CMF, AC, or FAC), and endocrine therapy with ovarian ablation or tamoxifen; the therapy added at the limited level is postmastectomy radiation therapy; at the enhanced level, breast‐conserving therapy, breast‐conserving whole‐breast radiation therapy, taxane chemotherapy, and endocrine therapy with aromatase inhibitors or LH‐RH agonists; and at the maximal level, reconstructive surgery and dose‐dense chemotherapy and growth factors. For metastatic or recurrent disease, basic‐level therapies are total mastectomy for ipsilateral in‐breast recurrence, endocrine therapy with ovarian ablation or tamoxifen, and analgesics; therapies added at the limited level are radiation therapy and CMF or anthracycline chemotherapy; at the enhanced level, chemotherapy with taxanes, capecitabine, or trastuzumab, endocrine therapy with aromatase inhibitors, and bisphosphonates; and at the maximal level, chemotherapy with vinorelbine, gemcitabine, or carboplatin, growth factors, and endocrine therapy with fulvestrant. Compared with the treatment of early breast cancer, the treatment of advanced breast cancer is more resource intensive and generally has poorer outcomes, highlighting the potential benefit of earlier detection and diagnosis, both in terms of conserving scarce resources and in terms of reducing morbidity and mortality. Use of the scheme outlined here should help ministers of health, policymakers, administrators, and institutions in limited‐resource settings plan, establish, and gradually expand breast cancer treatment services for their populations.

Guideline implementation for breast healthcare in low- and middle-Income countries: Treatment resource allocation†

A key determinant of breast cancer outcome is the degree to which newly diagnosed cancers are treated correctly in a timely fashion. Available resources must be applied in a rational manner to optimize population‐based outcomes. A multidisciplinary international panel of experts addressed the implementation of treatment guidelines and developed process checklists for breast surgery, radiation treatment, and systemic therapy. The needed resources for stage I, stage II, locally advanced, and metastatic breast cancer were outlined, and process metrics were developed. The ability to perform modified radical mastectomy is the mainstay of locoregional treatment at the basic level of breast healthcare. Radiation therapy allows for consideration of breast‐conserving therapy, postmastectomy chest wall irradiation, and palliation of painful or symptomatic metastases. Systemic therapy with cytotoxic chemotherapy is effective in the treatment of all biologic subtypes of breast cancer, but its provision is resource intensive. Although endocrine therapy requires few specialized resources, it requires knowledge of hormone receptor status. Targeted therapy against human epidermal growth factor receptor 2 (anti‐HER‐2) is very effective in tumors that overexpress HER‐2/neu receptors, but cost largely prevents its use in resource‐limited environments. Incremental allocation of resources can help address economic disparities and ensure equity in access to care. Checklists and allocation tables can support the objective of offering optimal care for all patients. The use of process metrics can facilitate the development of multidisciplinary, integrated, fiscally responsible, continuously improving, and flexible approaches to the global enhancement of breast cancer treatment. Cancer 2008;113(8 suppl):2269–81.

Effective but Cost-Prohibitive Drugs in Breast Cancer Treatment A Clinician's Perspective

New pharmacologic treatments for early‐stage breast cancer have been proven effective, but many of them are cost prohibitive in low economic settings. Differences in breast cancer mortality rates between developed and developing countries may be because of differences in screening and treatment options, some of which may be unavailable or limited by cost constraints in countries with limited resources. It is well recognized that treatment choices have to be made within budgetary constraints, and treatment guidelines that address the need to stratify treatment options by available resources have been published by the Breast Health Global Initiative. Practical treatment choices need to be made based on the best available cost–effective information. This article reviews new and emerging medical strategies that may improve the cost‐effectiveness equation. Cancer 2008;113(8 suppl):2353–8.

Quality-of-life and quality-adjusted survival (Q-TWiST) in patients receiving lapatinib in combination with paclitaxel as first-line treatment for metastatic breast cancer

Abstract Background: In a phase 3 randomized, multicenter, double-blind, placebo-controlled study, first-line therapy with lapatinib plus paclitaxel significantly improved clinical outcomes based on a pre-planned analysis of ErbB2+ metastatic breast cancer patients (GSK Study #EGF30001; ClinicalTrials.gov identifier: NCT00075270). Patients with ErbB2− or untested did not significantly benefit. This article focuses on the quality of life (QOL) and quality-adjusted survival outcomes (Q-TWiST) in the study. Methods: QOL was assessed using the Functional Assessment of Cancer Therapy–Breast (FACT-B). Changes from baseline were analyzed using ANCOVAs, repeated measures and pattern mixture modeling. The Q-TWiST method was used to examine the trade-off between toxicities and delayed progression. Trial registration: ClinicalTrials.gov identifier: NCT00075270. Results: The study included 579 subjects, of whom 86 were ErbB2+. In the ITT population, no significant differences in QOL or Q-TWiST scores were observed. In the ErbB2+ subgroup, the lapatinib plus paclitaxel (L + P) arm demonstrated stable FACT-B scores over the first year, while average scores for patients on P + placebo (P + pla) monotherapy decreased (change from baseline: L + P, p = 0.99; P + pla, p = 0.01). Clinically meaningful differences were observed between treatment arms on the FACT-B, Trial Outcome Index and breast cancer subscale scores. Pattern mixture models suggested more QOL differentiation between treatments among patients who progressed or withdrew early. Q-TWiST differences between the arms in the ErbB2+ subgroup ranged from 2 to 15 weeks with an L + P advantage across all utility weight combinations. Conclusions: In the ITT population, results provide no evidence of QOL differences between treatment groups. In a small, prospectively-defined subgroup of ErbB2+ patients, L + P resulted in more stable QOL and more quality-adjusted survival than paclitaxel monotherapy, representing clinically important differences between treatments.

Clinical Implications of ESR1 Mutations in Hormone Receptor-Positive Advanced Breast Cancer

Hormone receptor-positive breast cancer is the most frequent breast cancer subtype. Endocrine therapy (ET) targeting the estrogen receptor (ER) pathway represents the main initial therapeutic approach. The major strategies include estrogen deprivation and the use of selective estrogen modulators or degraders, which show efficacy in the management of metastatic and early-stage disease. However, clinical resistance associated with progression of disease remains a significant therapeutic challenge. Mutations of the ESR1 gene, which encodes the ER, have been increasingly recognized as an important mechanism of ET resistance, with a prevalence that ranges from 11 to 39%. The majority of these mutations are located within the ligand-binding domain and result in an estrogen-independent constitutive activation of the ER and, therefore, resistance to estrogen deprivation therapy such as aromatase inhibition. ESR1 mutations, most often detected from liquid biopsies, have been consistently associated with a worse outcome and are being currently evaluated as a potential biomarker to guide therapeutic decisions. At the same time, targeted therapy directed to ESR1-mutated clones is an appealing concept with preclinical and clinical work in progress.

Multidisciplinary Approach to Neoadjuvant Endocrine Therapy in Breast Cancer: A Comprehensive Review

Breast cancer is the most common type of cancer and the leading cause of cancer-related death among women worldwide. Hormone receptor-positive (HR+) tumors represent the most common form of this disease, with more than 70% of breast cancers expressing these receptors. Response and benefit to neoadjuvant chemotherapy (NCT) varies according to HR expression, with lower responses in luminal tumors as compared with hormone receptor-negative (HR-) and human epidermal growth factor receptor 2-positive (HER2+) tumors. Neoadjuvant endocrine therapy (NET) is an option for selected patients with HR+ locally advanced breast cancer. Neoadjuvant endocrine therapy has a favorable toxicity profile, and is associated with benefits such as having low cost and being more easily available even for cancer care professionals outside major urban areas or tertiary centers. These factors are particularly relevant, as 70% of breast cancer deaths occur in women from low-income and middle-income countries. Additionally, NET is being increasingly explored, not simply to allow for less extensive surgery, but also as a scientific tool, with the use of biomarkers to predict outcomes in adjuvant trials and for the individual patient. This review details the current and most relevant evidence about NET for breast cancer as well as the future directions of this field.

A Phase II Randomized Study of Lapatinib Combined with Capecitabine, Vinorelbine, or Gemcitabine in Patients with HER2-Positive Metastatic Breast Cancer with Progression after a Taxane (Latin American Cooperative Oncology Group 0801 Study)

BACKGROUND Novel targeted agents and combinations have become available in multiple lines of treatment for human epidermal growth factor receptor 2-positive (HER2(+)) metastatic breast cancer (MBC). In this context, alternatives to the lapatinib (L) and capecitabine (C) regimen, evaluating L combined with other cytotoxic drugs, are warranted. PATIENTS AND METHODS In the present phase II, multicenter study, patients with HER2(+) MBC with progression after taxane were randomized between L, 1250 mg, combined with C, 2000 mg/m(2) on days 1 to 14 (LC), vinorelbine (V), 25 mg/m(2) on days 1 and 8 (LV), or gemcitabine (G), 1000 mg/m(2) on days 1 and 8 (LG), every 21 days. The primary endpoint was the overall response rate. RESULTS A total of 142 patients were included from 2009 to 2012. No differences were found in the patient baseline characteristics. The median age was 51 years, 69% were postmenopausal, 32% had liver metastasis, 57% were hormone receptor negative, and 48% had been previously treated with trastuzumab. The overall response rate was 49% (95% confidence interval [CI], 34.8%-63.4%), 56% (95% CI, 40%-70.4%), and 41% (95% CI, 27%-56.8%) in the LC, LV, and LG groups, respectively. The median progression-free survival was 9 months in the LC arm and 7 months in the other 2 arms (P = .28). The most common grade 3 and 4 adverse events were hand-foot syndrome (18%), diarrhea (6%), and increased alanine aminotransferase/aspartate aminotransferase (4%) in the LC arm; neutropenia (36%), diarrhea (9%), and febrile neutropenia (6%) in the LV arm; and neutropenia (47%), alanine aminotransferase/aspartate aminotransferase (13%), and rash (4%) in the LG arm. CONCLUSION LV and LG seem to be active combinations in patients with HER2(+) MBC after taxane failure. The overall toxicity was manageable in all regimens.