PURPOSE; Pertuzumab, a human epidermal growth factor receptor 2 (HER2) -targeted monoclonal antibody, potently inhibits HER2 dimerization and HER-mediated signaling pathways. Pertuzumab and the ...approved HER2-targeted monoclonal antibody trastuzumab have complementary mechanisms of action and result in enhanced antitumor activity when combined. This phase II trial assessed the efficacy and safety profile of the combination in patients with HER2-positive breast cancer whose disease had progressed during prior trastuzumab-based therapy.
This was a multicenter, open-label, single-arm, Simon two-stage study. Patients with advanced HER2-positive breast cancer in whom disease progression had occurred during prior trastuzumab-based therapy received trastuzumab weekly (4 mg/kg loading dose, then 2 mg/kg every week) or every 3 weeks (8 mg/kg loading dose, then 6 mg/kg every 3 weeks) and pertuzumab every 3 weeks (840 mg loading dose, then 420 mg every 3 weeks). Treatment continued until disease progression or excessive toxicity.
All 66 patients were assessable for efficacy and safety. The objective response rate was 24.2%, and the clinical benefit rate was 50%. Five patients (7.6%) experienced a complete response, 11 patients (16.7%) experienced a partial response, and 17 patients (25.8%) experienced stable disease of > or = 6 months. Median progression-free survival was 5.5 months. Overall, the combination of pertuzumab and trastuzumab was well tolerated, and adverse events were mild to moderate. Cardiac dysfunction was minimal, and no patients withdrew as a result of cardiac-related adverse events.
The combination of pertuzumab and trastuzumab is active and well tolerated in patients with metastatic HER2-positive breast cancer who had experienced progression during prior trastuzumab therapy.
To determine whether the patterns of relapse according to estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status changed in the contemporary era.
Female patients referred ...to the British Columbia Cancer Agency with biopsy-proven stage I to III breast cancer (BC), diagnosed between 1986 and 1992 (cohort 1 C1) and between mid-2004 and 2008 (cohort 2 C2), and with known ER and HER2 status were eligible. Data were prospectively collected. C2 patients were matched to C1 patients for stage, grade, and ER and HER2 status. The primary end point was hazard rate of relapse (HRR) for BC by study cohort according to biomarker status. Secondary outcomes included HRR according to stage, grade, and age and hazard rate of death (HRD).
After matching, 7,178 patients were included (3,589 patients in each cohort). BC subtype distribution was as following ER positive/HER2 negative, 70.8%; ER positive/HER2 positive, 6.9%; ER negative/HER2 positive, 6.6%; and ER negative/HER2 negative, 15.8%. For the overall population, the HRR approximately halved in all yearly intervals to year 9 in C2 compared with C1. Differences in HRR between cohorts were greater in the initial five intervals for HER2-positive and ER-negative/HER2-negative BC. The HRR decreased in C2 compared with C1 for all disease stages and grades. The HRD in C2 also decreased compared with C1, although to a lesser extent.
Although the pattern of relapse remains similar, there has been a significant improvement in BC relapse-free survival. Outcomes have improved for all BC subtypes, especially HER2-positive and ER-negative/HER2-negative BC, with the early spike in disease recurrence markedly decreased. These contemporary hazard rates are important for treatment decisions, patient discussions, and planning clinical trials of early BC.
The efficacy of lapatinib versus trastuzumab combined with taxanes in the first-line setting of human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (BC) is unknown.
The ...MA.31 trial compared a combination of first-line anti-HER2 therapy (lapatinib or trastuzumab) and taxane therapy for 24 weeks, followed by the same anti-HER2 monotherapy until progression. Stratification was by prior (neo)adjuvant anti-HER2 therapy, prior (neo)adjuvant taxane, planned taxane, and liver metastases. The primary end point was intention-to-treat (ITT) progression-free survival (PFS), defined as time from random assignment to progression by RECIST (version 1.0) criteria, or death for patients with locally assessed HER2-positive tumors. The primary test statistic was a stratified log-rank test for noninferiority. PFS was also assessed for patients with centrally confirmed HER2-positive tumors.
From July 17, 2008, to December 1, 2011, 652 patients were accrued from 21 countries, resulting in 537 patients with centrally confirmed HER2-positive tumors. Median follow-up was 21.5 months. Median ITT PFS was 9.0 months with lapatinib and 11.3 months with trastuzumab. By ITT analysis, PFS was inferior for lapatinib compared with trastuzumab, with a stratified hazard ratio (HR) of 1.37 (95% CI, 1.13 to 1.65; P = .001). In patients with centrally confirmed HER2-positive tumors, median PFS was 9.1 months with lapatinib and 13.6 months with trastuzumab (HR, 1.48; 95% CI, 1.20 to 1.83; P < .001). More grade 3 or 4 diarrhea and rash were observed with lapatinib (P < .001). PFS results were supported by the secondary end point of overall survival, with an ITT HR of 1.28 (95% CI, 0.95 to 1.72; P = .11); in patients with centrally confirmed HER2-positive tumors, the HR was 1.47 (95% CI, 1.03 to 2.09; P = .03).
As first-line therapy for HER2-positive metastatic BC, lapatinib combined with taxane was associated with shorter PFS and more toxicity compared with trastuzumab combined with taxane.
IMPORTANCE: Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical ...studies. OBJECTIVE: To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes. DESIGN, SETTING, AND PARTICIPANTS: MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020. INTERVENTIONS: Patients were randomized (stratified for hormone receptor estrogen receptor and/or progesterone receptor {ER/PgR} status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 ERBB2, formerly HER2 or HER2/neu, positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years. MAIN OUTCOMES AND MEASURES: The primary outcome was invasive disease–free survival in hormone receptor–positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse–free survival, and breast cancer–free interval were analyzed. RESULTS: Of the 3649 randomized patients (mean age, 52.4 years; 3643 women 99.8%), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR−, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease–free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease–free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio HR, 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR−, followed up for a median of 94.1 months, incidence of invasive disease–free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%). CONCLUSIONS AND RELEVANCE: Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease–free survival. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01101438
In postmenopausal women at increased risk for breast cancer, exemestane reduced the annual incidence of invasive breast cancer by 65% after a median follow-up of only 3 years. Exemestane caused no ...serious toxic effects and only minimal changes in quality of life.
Estrogens contribute to normal breast development but can also promote breast cancer in preclinical models and in women with high circulating plasma estrogen levels.
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4
To date, chemoprevention of breast cancer has focused on the selective estrogen-receptor modulators (SERMs) tamoxifen and raloxifene, which exert antiestrogenic effects on the breast, as well as agonist or antagonist effects on other organs. In the National Surgical Adjuvant Breast and Bowel Project P-1 trial, tamoxifen significantly reduced the number of invasive breast cancers, by 49% (P<0.001) as compared with placebo.
5
A meta-analysis of trials comparing tamoxifen with placebo showed that tamoxifen reduced the incidence . . .
To evaluate the safety and efficacy of oral everolimus, a mammalian target of rapamycin (mTOR) inhibitor, in two different schedules in minimally pretreated patients with metastatic breast cancer and ...to explore for possible biologic correlates of response.
Patients who received no or one prior chemotherapy regimen for metastatic breast cancer were entered onto this multicenter, noncomparative, randomized phase II study of everolimus 10 mg daily versus 70 mg weekly; the multinomial end points of response and progression were evaluated at 8 weeks. A two-stage accrual design was used, with 15 evaluable patients in each schedule in stage 1. Only daily therapy met criteria for continuing, and another 15 patients were added. pAKT, PTEN, carbonic anhydrase 9, estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) were evaluated for possible correlation with response.
The most common drug-related toxicities were fatigue, rash, anorexia, diarrhea, stomatitis, cough, and pneumonitis. Pneumonitis occurred at higher than expected rates and seemed to be schedule dependent, with the highest incidence on the daily schedule. Response rate with daily therapy was 12% (95% CI, 3.4% to 28.2%) compared with 0% (95% CI, 0.0% to 20.6%) for weekly therapy. Twenty-seven percent of patients on daily therapy discontinued treatment compared with 13% on weekly therapy (16% v 6% with pneumonitis, respectively). No biologic correlates of response could be identified, although there were trends favoring benefit in ER-positive and HER2-negative metastatic breast cancer.
Oral everolimus has activity in metastatic breast cancer that is schedule dependent. Daily therapy with 10 mg is worthy of further study in this patient population.
In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor ...exemestane is partially non-cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss.
We designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease-free survival, incidence of contralateral new primary breast cancer, and safety.
In the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease-free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms.
This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor-positive breast cancer.
Adjuvant! (www.adjuvantonline.com) is a web-based tool that predicts 10-year breast cancer outcomes with and without adjuvant systemic therapy, but it has not been independently validated.
Using the ...British Columbia Breast Cancer Outcomes Unit (BCOU) database, demographic, pathologic, staging, and treatment data on 4,083 women diagnosed between 1989 and 1993 in British Columbia with T1-2, N0-1, M0 breast cancer were abstracted and entered into Adjuvant! to calculate predicted 10-year overall survival (OS), breast cancer-specific survival (BCSS), and event-free survival (EFS) for each patient. Individual BCOU observed outcomes at 10 years were independently determined. Predicted and observed outcomes were compared.
Across all 4,083 patients, 10-year predicted and observed outcomes were within 1% for OS, BCSS, and EFS (all P > .05). Predicted and observed outcomes were within 2% for most demographic, pathologic, and treatment-defined subgroups. Adjuvant! overestimated OS, BCSS, and EFS in women younger than age 35 years (predicted-observed = 8.6%, 9.6%, and 13.6%, respectively; all P < .001) or with lymphatic or vascular invasion (LVI; predicted-observed = 3.6%, 3.8%, and 4.2%, respectively; all P < .05); these two prognostic factors were not automatically incorporated within the Adjuvant! algorithm. After adjusting for the distribution of LVI, using the prognostic factor impact calculator in Adjuvant!, 10-year predicted and observed outcomes were no longer significantly different.
Adjuvant! performed reliably. Patients younger than age 35 or with known additional adverse prognostic factors such as LVI require adjustment of risks to derive reliable predictions of prognosis without adjuvant systemic therapy and the absolute benefits of adjuvant systemic therapy.
Background
The MA32 study investigated whether 5 years of metformin (versus placebo) improves invasive disease-free survival in early-stage breast cancer (BC). Non-adherence to endocrine therapy (ET) ...and medications for chronic conditions is common and increases with drug toxicity and polypharmacy. This secondary analysis evaluates rates and predictors of early discontinuation of metformin, placebo, and ET among participants with HR-positive BC.
Methods
Patients with high-risk non-metastatic BC were randomized to 60 months of metformin (850 mg BID) or placebo BID. Patients were administered bottles of metformin/placebo every 180 days. Metformin/placebo adherence was defined as a bottle dispensed at month 48 or later. The ET adherence analysis included patients with HR-positive BC who received ET with start and stop date reported, with adherence defined as > 48 months of use. Associations of covariates with study drug and ET adherence were examined using multivariable models.
Results
Among the 2521 HR-positive BC patients, 32.9% were non-adherent to study drug. Non-adherence was higher among patients on metformin vs placebo (37.1% vs 28.7%,
p
< 0.001). Reassuringly, ET discontinuation rates were similar between treatment arms (28.4% vs 28.0%,
p
= 0.86). Patients who were non-adherent to ET were more likely to discontinue study therapy (38.8% vs 30.1%,
p
< 0.0001). In a multivariable analysis, study drug non-adherence was increased with metformin vs placebo (OR: 1.50, 95% CI 1.25–1.80;
p
< 0.0001); non-adherence to ET (OR: 1.47, 95% CI 1.20–1.79,
p
< 0.0001); grade 1 or greater GI toxicity during the first 2 years; lower age; and higher body mass index.
Conclusion
While non-adherence was higher among patients on metformin, it was still considerable among patients on placebo. Reassuringly, treatment arm allocation did not impact ET adherence. Attention to global medication adherence is needed to improve BC and non-oncological outcomes in cancer survivors.
Trial registration
ClinicalTrials.gov: NCT01.
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