Current Landscape of Targeted Therapies for Hormone-Receptor Positive, HER2 Negative Metastatic Breast Cancer

The majority of deaths from MBC are in patients with hormone receptor (HR) positive, HER2 negative disease. Endocrine therapy (ET) remains the backbone of treatment in these cases, improving survival and quality of life. However, treatment can lose effectiveness due to primary or acquired endocrine resistance. Analysis of mechanisms of ET resistance has led to the development of a new generation of targeted therapies for advanced breast cancer. In addition to anti-estrogen therapy with selective estrogen receptor modulators, aromatase inhibitors, and/or selective estrogen receptor degraders, combinations with cyclin dependent kinase (CDK) 4/6 inhibitors have led to substantial progression free survival (PFS) improvements in the first and second line settings. While the PI3K/AKT/mTOR pathway is known to be an important growth pathway in HR positive breast cancer, PI3K inhibitors have been disappointing due to modest effect sizes and significant toxicity. The mTOR inhibitor everolimus significantly improves progression free survival when added to ET, and recent studies have improved supportive care allowing less toxicity. While these combination targeted therapies improve outcomes and often delay initiation of chemotherapy, long term overall survival data are lacking and data for the ideal strategy for sequencing these agents remains unclear. Ongoing research evaluating potential biomarkers and mechanisms of resistance is anticipated to continue to improve outcomes for patients with HR positive metastatic breast cancer. In this review, we will discuss management and ongoing challenges in the treatment of advanced HR positive, HER2 negative breast cancer, highlighting single agent and combination endocrine therapies, targeted therapies including palbociclib, ribociclib, abemaciclib, and everolimus, and sequencing of therapies in the clinic

Impact of primary breast cancer therapy on energetic capacity and body composition

PURPOSE: This observational study was designed to measure baseline energy parameters and body composition in early-stage breast cancer patients, and to follow changes during and after various modalities of treatment. This will provide information to aid in the development of individualized physical activity intervention strategies. METHODS: Patients with newly diagnosed stage 0-III breast cancer were enrolled into three cohorts: A (local therapy alone), B (endocrine therapy), or C (chemotherapy with or without endocrine therapy). At baseline, 6 months, and 12 months, subjects underwent a stationary bicycle protocol to assess power generation and DEXA to assess body composition. RESULTS: Eighty-three patients enrolled. Patients had low and variable levels of power generation at baseline (mean power per kilogram lean mass 1.55 W/kg, SD 0.88). Power normalized to lean body mass (W/kg) decreased significantly, and similarly, by 6 months in cohorts B (1.42-1.04 W/kg, p = 0.008) and C (1.53-1.18 W/kg, p < 0.001). In all cohorts, there was no recovery of power generation by 12 months. Cohort C lost lean body mass (- 1.5 kg, p = 0.007), while cohort B maintained lean body mass (- 0.2 kg, p = 0.68), despite a similar trajectory in loss of power. Seven patients developed sarcopenia during the study period, including four patients who did not receive any chemotherapy (cohort B). CONCLUSIONS: The stationary bike protocol was feasible, easy, and acceptable to patients as a way to measure energetic capacity in a clinical setting. Early-stage breast cancer patients had low and variable levels of power generation, which worsened following primary therapy and did not show evidence of 'spontaneous recovery' by 12 months. Effective physical activity interventions will need to be personalized, accounting for both baseline ability and the effect of treatment

Discerning the clinical relevance of biomarkers in early stage breast cancer

Purpose Prior data suggest that breast cancer patients accept significant toxicity for small benefit. It is unclear whether personalized estimations of risk or benefit likelihood that could be provided by biomarkers alter treatment decisions in the curative setting. Methods A choice-based conjoint (CBC) survey was conducted in 417 HER2-negative breast cancer patients who received chemotherapy in the curative setting. The survey presented pairs of treatment choices derived from common taxane- and anthracycline-based regimens, varying in degree of benefit by risk of recurrence and in toxicity profile, including peripheral neuropathy (PN) and congestive heart failure (CHF). Hypothetical biomarkers shifting benefit and toxicity risk were modeled to determine whether this knowledge alters choice. Previously identified biomarkers were evaluated using this model. Results Based on CBC analysis, a non-anthracycline regimen was the most preferred. Patients with prior PN had a similar preference for a taxane regimen as those who were PN naïve, but more dramatically shifted preference away from taxanes when PN was described as severe/irreversible. When modeled after hypothetical biomarkers, as the likelihood of PN increased, the preference for taxane-containing regimens decreased; similarly, as the likelihood of CHF increased, the preference for anthracycline regimens decreased. When evaluating validated biomarkers for PN and CHF, this knowledge did alter regimen preference. Conclusions Patients faced with multi-faceted decisions consider personal experience and perceived risk of recurrent disease. Biomarkers providing information on likelihood of toxicity risk do influence treatment choices, and patients may accept reduced benefit when faced with higher risk of toxicity in the curative setting

A Personalized, Dynamic Physical Activity Intervention Is Feasible and Improves Energetic Capacity, Energy Expenditure, and Quality of Life in Breast Cancer Survivors

Purpose: Despite survival and quality of life benefits associated with physical activity, many breast cancer survivors remain inactive. Effective, sustainable interventions must account for individual differences in capability, motivation, and environment. Here, we evaluate the feasibility, mechanics, and efficacy of delivering an individualized, dynamic intervention to increase energetic capacity and energy expenditure. Methods: Stage 0-III breast cancer patients who had completed primary treatment were enrolled. Prior to the intervention, detailed movement data was collected with a wearable GPS and accelerometer for 3 weeks to establish baseline activity. Movement data was collected continuously throughout the 12-week intervention, during which patients received electronically delivered, tailored, dynamic activity "prescriptions", adjusted based on demonstrated individual capability, daily movement in their environment, and progress. Results: Of 66 enrolled, 57 participants began and completed the intervention. The intervention resulted in significant improvements in average steps (+558 steps/day, p = 0.01), energetic capacity measured by power generation on a stationary bicycle (1.76 to 1.99 W/kg lean mass, p < 0.01), and quality of life (FACT-B TOI, 72.8 to 74.8, p = 0.02). The greatest improvement in functional energetic capacity was seen in the lowest performing tertile at baseline (0.76 to 1.12 W/kg, p < 0.01). Discussion: Wearable technology delivery of personalized activity prescriptions based on individual capability and movement behaviors demonstrates feasibility and early effectiveness. The high variability seen in baseline activity and function, as well as in response to the intervention, supports the need for future work in precision approaches to physical activity (NCT03158519)

Exercise load monitoring: integrated approaches to advance the individualisation of exercise oncology

Whether slowing disease progression or combatting the ills of advancing age, the extensive utility of exercise training has contributed to the outright declaration by the American College of Sports Medicine that ‘exercise is medicine’. Consistent with general framework of adaptation, the advantages of exercise training are indiscriminate—benefitting even the most susceptible clinical populations. Still, the benefit of exercise training presupposes healthy adaptation wherein progressive overload matches sufficient recovery. Indeed, a difference exists between healthy adaptation and non-functional over-reaching (ie, when internal/external load exceeds recovery capacity)—a difference that may be blurred by cancer treatment and/or comorbidity. Recent advances in smartwatches make them ideally suited to non-invasively monitor the physiological stresses to exercise training. Resolving whether individuals are successfully adapting to exercise training via load monitoring bears clinical and practical relevance. While behaviour-change research aims to identify positive constructs of exercise adherence, further attention is needed to uncover how to optimise exercise prescription among cancer populations. Herein, we briefly discuss the constituents of exercise load monitoring, present examples of internal and external load and consider how such practices can be applied to cancer populations

Evaluation of an Extended-duration Chemoprophylaxis Regimen for Venous Thromboembolism after Microsurgical Breast Reconstruction

Patients undergoing free flap breast reconstruction are at a high risk for venous thromboembolism based upon Caprini scores. Guidelines for venous thromboembolism prophylaxis recommend high-risk groups receive extended chemoprophylaxis for several weeks after gynecological, orthopedic, and surgical oncology cases. Extended prophylaxis has not been studied in free flap breast reconstruction. The purpose of this study was to compare outcomes of free flap breast reconstruction patients who received extended venous thromboembolism (VTE) prophylaxis with those who received standard inpatient-only prophylaxis. Methods: Patients undergoing microsurgical breast reconstruction were divided into two groups: standard VTE prophylaxis (Group I) and extended prophylaxis (Group II). Both groups received prophylactic subcutaneous heparin or enoxaparin preoperatively and enoxaparin 40 mg daily postoperatively while inpatient. Group II was discharged with a home regimen of enoxaparin 40 mg daily for an additional 14 days. Results: In total, 103 patients met inclusion criteria (36 patients in Group I, 67 patients in Group II). The incidence of VTE was 1.5% in Group II compared with 2.8% in Group I (P = 0.6). There was no difference in reoperative hematoma between Group I (n = 0) and Group II (n = 1) (P = 0.7). Total flap loss was 2.2%. Conclusions: Although this retrospective pilot study did not show statistical significance in VTE between those receiving extended home chemoprophylaxis (1.5% incidence) compared with inpatient-only chemoprophylaxis (2.8%), the risk of bleeding complications was similar. These results indicate that a larger, higher powered study is justified to assess if an extended home chemoprophylaxis protocol should be standard of care post free flap breast reconstruction

Protocol of a randomized trial of acceptance and commitment therapy for fatigue interference in metastatic breast cancer

Fatigue interference with activities, mood, and cognition is one of the most prevalent and distressing concerns of metastatic breast cancer patients. To date, there are no evidence-based interventions for reducing fatigue interference in metastatic breast cancer and other advanced cancer populations. In pilot studies, Acceptance and Commitment Therapy (ACT) has shown potential for reducing symptom-related suffering in cancer patients. The current Phase II trial seeks to more definitively examine the efficacy of telephone-based ACT for women with metastatic breast cancer who are experiencing fatigue interference. In this trial, 250 women are randomly assigned to either the ACT intervention or an education/support control condition. Women in both conditions attend six weekly 50-min telephone sessions. The primary aim of this study is to test the effect of telephone-based ACT on fatigue interference. Secondary outcomes include sleep interference, engagement in daily activities, and quality of life. Outcomes are assessed at baseline, 2 weeks post-intervention, and 3 and 6 months post-intervention. This trial also examines whether increases in psychological flexibility, defined as full awareness of the present moment while persisting in behaviors aligned with personal values, account for the beneficial effect of ACT on fatigue interference. After demonstrating ACT's efficacy, the intervention can be widely disseminated to clinicians who care for metastatic breast cancer patients. Our findings will also inform future ACT trials with various cancer populations and functional outcomes

Patient-Reported Outcomes in the Translational Breast Cancer Research Consortium

Members of the Translational Breast Cancer Research Consortium conducted an expert-driven literature review to identify a list of domains and to evaluate potential measures of these domains for inclusion in a list of preferred measures. Measures were included if they were easily available, free of charge, and had acceptable psychometrics based on published peer-reviewed analyses. A total of 22 domains and 52 measures were identified during the selection process. Taken together, these measures form a reliable and validated list of measurement tools that are easily available and used in multiple cancer trials to assess patient-reported outcomes in relevant patients

The bone-muscle connection in breast cancer: implications and therapeutic strategies to preserve musculoskeletal health

Breast cancer and its therapies frequently result in significant musculoskeletal morbidity. Skeletal complications include bone metastases, pain, bone loss, osteoporosis, and fracture. In addition, muscle loss or weakness occurring in both the metastatic and curative setting is becoming increasingly recognized as systemic complications of disease and treatment, impacting quality of life, responsiveness to therapy, and survival. While the anatomical relationship between bone and muscle is well established, emerging research has led to new insights into the biochemical and molecular crosstalk between the skeletal and muscular systems. Here, we review the importance of both skeletal and muscular health in breast cancer, the significance of crosstalk between bone and muscle, and the influence of mechanical signals on this relationship. Therapeutic exploitation of signaling between bone and muscle has great potential to prevent the full spectrum of musculoskeletal complications across the continuum of breast cancer

Impact of Muscle Measures on Outcome in Patients Receiving Endocrine Therapy for Metastatic Breast Cancer: Analysis of ECOG-ACRIN E2112

Background: Observational data investigating the relationship between body habitus and outcomes in breast cancer have been variable and inconsistent, largely centered in the curative setting and focused on weight-based metrics. This study evaluated the impact of muscle measures on outcomes in patients with metastatic breast cancer receiving endocrine-based therapy. Methods: Baseline CT scans were collected from ECOG-ACRIN E2112, a randomized phase III placebo-controlled study of exemestane with or without entinostat. A CT cross-sectional image at the L3 level was extracted to obtain skeletal muscle mass and attenuation. Low muscle mass (LMM) was defined as skeletal muscle index <41 cm2/m2 and low muscle attenuation (LMA) as muscle density <25 HU or <33 HU if overweight/obese by body mass index (BMI). Multivariable Cox proportional hazard models determined the association between LMM or LMA and progression-free survival (PFS) and overall survival (OS). Correlations between LMM, LMA, and patient-reported outcomes were determined using 2-sample t tests. Results: Analyzable CT scans and follow-up data were available for 540 of 608 patients. LMM was present in 39% (n=212) of patients and LMA in 56% (n=301). Those with LMA were more likely to have obesity and worse performance status. LMM was not associated with survival (PFS hazard ratio [HR]: 1.13, P=.23; OS HR: 1.05, P=.68), nor was LMA (PFS HR: 1.01, P=.93; OS HR: 1.00, P=.99). BMI was not associated with survival. LMA, but not LMM, was associated with increased frequency of patient-reported muscle aches. Conclusions: Both low muscle mass and density are prevalent in patients with hormone receptor-positive metastatic breast cancer. Muscle measures correlated with obesity and performance status; however, neither muscle mass nor attenuation were associated with prognosis. Further work is needed to refine body composition measurements and select optimal cutoffs with meaningful endpoints in specific breast cancer populations, particularly those living with metastatic disease