Abemaciclib plus fulvestrant in East Asian women with HR+, HER2− advanced breast cancer: Overall survival from MONARCH 2

MONARCH 2 is a global, randomized, double-blind, phase 3 study of abemaciclib/placebo + fulvestrant in patients with hormone receptor positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The East Asian population comprised 212 (31.7%) of the 669 intent-to-treat population in the MONARCH 2 trial. Consistent with the primary analysis, this subpopulation analysis of East Asian patients indicated progression-free survival benefit in the abemaciclib arm. The median overall survival was not reached in the abemaciclib arm and was 48.9 months in the placebo arm (hazard ratio 0.80; 95% confidence interval 0.52–1.24; p = 0.377). In addition, other efficacy endpoints, including time to chemotherapy, chemotherapy free survival, and time to second disease progression, indicated benefit in the abemaciclib arm. This analysis found no new safety concerns with longer follow-up. These findings support the positive benefit–risk balance of the MONARCH 2 regimen in East Asian patients with hormone receptor positive, human epidermal growth factor receptor 2-negative advanced breast cancer.     

Abemaciclib in combination with endocrine therapy for East Asian patients with HR+, HER2− advanced breast cancer: MONARCH 2 & 3 trials

This post hoc analysis of MONARCH 2 and MONARCH 3 assesses the efficacy, safety, and pharmacokinetics (PK) of abemaciclib in combination with endocrine therapy (ET) in East Asian patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer. MONARCH 2 and MONARCH 3 are global, randomized, double-blind, phase 3 studies of abemaciclib/placebo + fulvestrant and abemaciclib/placebo + nonsteroidal aromatase inhibitor (NSAI, anastrozole or letrozole), respectively. The East Asian population comprised 212 (31.7%) of the 669 intent-to-treat (ITT) population in the MONARCH 2 trial and 144 (29.2%) of the 493 ITT patients in the MONARCH 3 trial. In the East Asian population, median progression-free survival (PFS) was significantly prolonged in the abemaciclib arm compared with placebo in both MONARCH 2 (hazard ratio [HR], 0.520; 95% confidence interval [CI], 0.362 to 0.747; P < .001; median: 21.2 vs 11.6 months) and MONARCH 3 (HR, 0.326; 95% CI, 0.200 to 0.531, P < .001; median: not reached vs 12.82 months). Diarrhea (MONARCH 2: 90%; MONARCH 3: 88%) and neutropenia (MONARCH 2: 68%; MONARCH 3: 58%) were the most frequent adverse events observed in the East Asian populations. Abemaciclib exposures and PK were similar in East Asians and the non-East Asian populations of both trials. Abemaciclib in combination with ET in the East Asian populations of MONARCH 2 and MONARCH 3 provided consistent results with the ITT populations, demonstrating improvements in efficacy with generally tolerable safety profiles for patients with HR+, HER2− advanced breast cancer.     

Relationship of Optimism–Pessimism and Health-Related Quality of Life in Breast Cancer Survivors

ABSTRACT

Few studies have investigated the influence of optimism–pessimism in breast cancer survivors. This study used a retrospective design with 268 adult women who completed the Minnesota Multiphasic Personality Inventory (MMPI) as part of their medical care approximately 10 years prior to their breast cancer diagnosis and Medical Outcome Study Short-Form General Health Survey (SF-36 or SF-12), on average, 8 years after diagnosis. MMPI pessimism scores were divided into quartiles, and t tests were used to determine differences between those highest and lowest in pessimism on health-related quality-of-life (QOL) measures, demographics, and disease status. The mean age at diagnosis of breast cancer was 63 years, and 74% had early-stage breast cancer. Patients age 65 years and older were significantly lower on physical health–related QOL scales. There were no significant differences in health-related QOL scores by stage of disease. Patients with a pessimistic explanatory style were significantly lower on all of the health-related QOL scores, compared to those with a nonpessimistic style. Breast cancer survivors who exhibit a pessimistic explanatory style report lower health-related QOL for years after receiving a cancer diagnosis, compared to nonpessimistic women.     

Everolimus plus exemestane as first-line therapy in HR+, HER2− advanced breast cancer in BOLERO-2

The present exploratory analysis examined the efficacy, safety, and quality-of-life effects of everolimus (EVE) + exemestane (EXE) in the subgroup of patients in BOLERO-2 whose last treatment before study entry was in the (neo)adjuvant setting. In BOLERO-2, patients with hormone-receptor-positive (HR⁺), human epidermal growth factor receptor-2-negative (HER2^?) advanced breast cancer recurring/progressing after a nonsteroidal aromatase inhibitor (NSAI) were randomly assigned (2:1) to receive EVE (10 mg/day) + EXE (25 mg/day) or placebo (PBO) + EXE. The primary endpoint was progression-free survival (PFS) by local assessment. Overall, 137 patients received first-line EVE + EXE (n = 100) or PBO + EXE (n = 37). Median PFS by local investigator assessment nearly tripled to 11.5 months with EVE + EXE from 4.1 months with PBO + EXE (hazard ratio = 0.39; 95 % CI 0.25–0.62), while maintaining quality of life. This was confirmed by central assessment (15.2 vs 4.2 months; hazard ratio = 0.32; 95 % CI 0.18–0.57). The marked PFS improvement in patients receiving EVE + EXE as first-line therapy for disease recurrence during or after (neo)adjuvant NSAI therapy supports the efficacy of this combination in the first-line setting. Furthermore, the results highlight the potential benefit of early introduction of EVE + EXE in the management of HR⁺, HER2^? advanced breast cancer in postmenopausal patients.     

Everolimus Plus Letrozole for Treatment of Patients With HR+, HER2– Advanced Breast Cancer Progressing on Endocrine Therapy: An Open-label,Phase II Trial

Purpose

In the Breast cancer trials of OraL EveROlimus-2 (BOLERO-2) trial, everolimus plus exemestane improved progression-free survival (PFS) in patients with hormone receptor-positive (HR⁺), human epidermal growth factor receptor 2-negative (HER2^?) advanced breast cancer (ABC) recurring or progressing on/after prior endocrine therapy (ET), suggesting that dual blockade using targeted therapy and ET was an effective treatment option. Here, we investigated the clinical benefit of combining everolimus with different endocrine partner, letrozole, in a similar patient population.

CDK4/6 Inhibitors in Combination With Hormone Therapy for HR+/HER2− Advanced Breast Cancer: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Background

This meta-analysis of randomized controlled trials aimed to comprehensively assess the efficacy and toxicity of cyclin-dependent kinase (CDK) 4/6 inhibitors in advanced breast cancer (ABC) with hormone-receptor positive (HR⁺) and human epidermal growth factor receptor 2 negative (HER2^?) disease.

Practical Treatment Strategies and Future Directions After Progression While Receiving CDK4/6 Inhibition and Endocrine Therapy in Advanced HR+/HER2− Breast Cancer

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with backbone endocrine therapy have markedly improved progression-free survival and overall survival over endocrine therapy alone in advanced hormone receptor–positive, HER2-negative (HR⁺/HER2⁻) breast cancer and are the standard of care in the first- or second-line setting. There are few data to drive decision making for subsequent treatment strategies after inevitable disease progression after CDK4/6i. Information about the genomic landscape of CDK4/6i-resistant disease is emerging. Resistance mechanisms appear to be varied, but mutations in PIK3CA and ESR1, which can be acquired while receiving treatment, are frequent. Activating PIK3CA mutations are present in up to 35% of patients and are now the most actionable genomic alteration in HR⁺/HER2⁻ advanced breast cancer with the recent approval of alpelisib and fulvestrant. Everolimus-based combinations and chemotherapy appear to have continued efficacy after progression while receiving CDK4/6i, although historical data on benefit include CDK4/6i-naive patients. Use of selective estrogen down-regulators over aromatase inhibitors is best once the patient has an acquired ESR1 mutation. Tumor biopsy with genomic sequencing and repeat biomarker analysis in patients with CDK4/6i- and endocrine-resistant disease will be integral to guide subsequent treatment strategies and to inform clinical trial eligibility. Promising novel therapeutics in CDK4/6i-resistant disease including oral selective estrogen down-regulators, fibroblast growth factor receptor antagonists, and immunotherapy will be discussed.     

HER2+ Breast Cancer Therapy: By CPP-ZFN Mediated Targeting of mTOR?

A significant fraction of HER2+ patients develop resistance to available therapies such as trastuzumab. The acquired resistance is primarily due to hyper activation of HER2 downstream PI3K/Akt/mTOR signalling pathway. Hence, identification of inhibitors of components of this pathway, particularly mTOR, is an area of intense investigation. Interestingly, mTOR specific inhibitors (rapamycin/rapalogs) have been tested and shown to potentiate the effect of HER2 inhibitors. However, the use of mTOR inhibitors will also be associated with the limitations inherently linked with extensive use of anticancer drugs e.g., toxicity and acquired drug resistance. Hereby, we hypothesize development of an alternative novel molecular therapeutic intervention based on cell penetrating peptide (CPP), a highly efficient carrier, conjugated to zinc finger nuclease (ZFN), a precise molecular scissor. The use of HER2 specific CPP conjugated to mTOR specific ZFN, will make the mTOR locus non-functional and inhibit the PI3K/Akt/mTOR pathway, essential for growth and proliferation of cancerous cells. With the availability of HER21 cancerous cell specific CPP and proved applications of ZFN in targeted genome engineering of over 11 species, the prospects of success of CPP-ZFN anti-cancer therapy are very high.     

Quality-Adjusted Survival with Ribociclib Plus Fulvestrant Versus Placebo Plus Fulvestrant in Postmenopausal Women with HR±HER2− Advanced Breast Cancer in the MONALEESA-3 Trial

BackgroundMONALEESA-3 demonstrated an overall survival (OS) benefit for ribociclib plus fulvestrant (R+F) in postmenopausal women with hormone receptor (HR) positive, HER2 negative advanced breast cancer (ABC). This study estimated quality-adjusted (QA) survival outcomes for patients receiving R+F vs. placebo (P)+F in MONALEESA-3.MethodsKaplan-Meier OS was partitioned into health states: (1) toxicity (TOX)=time spent with grade 3 –4 adverse events before progression (DP); (2) progression (PROG)=time between DP and death; and (3) time without symptoms or toxicity (TWiST)=time not in TOX or PROG. QA time was calculated by combining estimated mean time in each health state with treatment-group specific health-state utility values estimated using EQ-5D-5L questionnaire. Outcomes included QA progression-free survival (QAPFS), QAOS, and QA TWiST (Q-TWiST). Q-TWiST was calculated with health-state utility values for TOX and PROG defined relative to TWiST.ResultsMean PFS and OS were significantly greater with R+F vs. P+F (difference 0.56 and 0.19 years). Mean time in TOX and TWiST were greater with R+F; mean time in PROG was greater with P+F. QAPFS was 0.45 years (95% CI 0.27 –0.63) greater with R+F than P+F (P <.001). QAOS was numerically greater with R+F vs. P+F (0.16 years, 95% CI 0.07 –0.45, P = .0569). Q-TWiST was 0.23 years greater with R+F (95% CI 0.07 –0.45, P = .0069). In a sensitivity analysis using an estimate of disutility for PROG, the difference in QAOS was 0.23 years (95% CI 0.08 –0.41, P = .0022).ConclusionR+F in postmenopausal women with HR+/HER2- ABC improves QAPFS, resulting in clinically important improvements in Q-TWiST and may improve QAOS.     

Omission of Chemotherapy in HR+/HER2− Early Invasive Breast Cancer Based on Combined 6-IHC Score?

PurposeCurrent methods of judging whether HR+/HER2− breast cancer (BC) require adjuvant therapy, such as Ki67 and multigene prognostic tests, cannot balance accuracy with the price most patients can afford.MethodsA retrospective analysis of 330 HR+/HER2− BC patients was conducted. Six BC-related genes (Cathepsin L2, MMP11, CyclinB1, Aurora A, Survivin, and Ki67) were screened using univariate and multivariate COX regression, and correlate clinical follow-up with immunohistochemical expression (designated as 6-IHC). All the included patients were divided randomly at a 7:3 ratio into training and testing cohorts. The cutoff prognosis index (PI) of 6-IHC was determined by multivariate Cox risk regression analysis after calculating the PI of each patient in training cohort and confirmed in testing cohort. Kaplan-Meier (KM) method was used to analyze Disease-free survival (DFS) and overall survival (OS). Six-IHC score and other factors associated with survival benefit of adjuvant chemotherapy were compared with Ki67 index.ResultsThe receiver operating characteristic curve analysis showed that the patients can be divided into 6-IHC score “High” and “Low” risk groups. The 8-year DFS and OS of the KM curves showed that chemotherapy did not significantly improve the DFS in the 6-IHC score “Low” risk group (P= 0.830), but significantly improved the DFS in the 6-IHC score “High” risk group (P = 0.012).ConclusionsCombined 6-IHC score could be a reliable tool in predicting cancer-specific recurrences and survival in HR+/HER2-breast cancer patients, with additional advantages over using immunohistochemical expression of Ki67.     

A Systematic Literature Review of the Prognostic and Predictive Value of PIK3CA Mutations in HR+/HER2− Metastatic Breast Cancer

PIK3CA mutations may have prognostic value for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer, representing an important potential target for systemic therapy. Prognostic and predictive values associated with PIK3CA mutations are not well understood.A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and conference abstracts was performed for English-language articles published January 1993 through April 2019. Articles were categorized by treatment arms based on experimental and treatment drug classes. Information on progression-free survival (PFS), hazard ratios, overall survival, response rate, and clinical benefit rate was obtained. A total of 17 studies were included. Among those evaluating non-PI3Ki based therapies, 91% showed numerically shorter median PFS, ranging from 1.5 to 19.2 months and 1.8 to 29.6 months for the mutant versus non-mutant subgroups, respectively. Where reported (n = 13 studies), PFS was shorter between those arms offering endocrine monotherapy (range, 1.6-14.7 months) compared with a corresponding targeted therapy + endocrine monotherapy (range, 3.9-29.6 months). Of 5 PI3Ki-based arms comparing PFS, higher median PFS in PIK3CA mutant versus non-mutant cases was demonstrated. PFS was shorter for patients with PIK3CA mutant (range, 1.6-19.2 months) compared with PIK3CA wild-type (range, 1.8-29.6 months) in 10 (71%) of 14 treatment arms reporting PFS. Studies (n = 4) not reporting PFS reported response rate, but there were no clear directional trends.The presence of PIK3CA mutations may be associated with worse clinical outcomes in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. Clinical outcomes such as PFS may be improved using a combination of PI3Ki-based therapies and endocrine therapies among this population. However, more research is warranted to fully elucidate this association.