Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in germline ...(g)
/
mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s)
/
mutations or g/s mutations in homologous recombination (HR)-related genes other than
2.
Eligible patients had MBC with measurable disease and germline mutations in non-
/
HR-related genes (cohort 1) or somatic mutations in these genes or
/
(cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS).
Fifty-four patients enrolled. Seventy-six percent had estrogen receptor-positive HER2-negative disease. Eighty-seven percent had mutations in
s
/
,
or
. In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with g
(ORR, 82%) and s
/
(ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable NA) for g
and 6.3 months (90% CI, 4.4 months to NA) for s
/
mutation carriers. No responses were observed with
or
mutations alone.
PARP inhibition is an effective treatment for patients with MBC and g
or s
/
mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond g
/
mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.
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.
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.
This retrospective analysis aimed to determine the relationship between body mass index (BMI) and circulating tumor DNA (ctDNA) in triple-negative breast cancer (TNBC), and to evaluate the impact of ...BMI on disease recurrence and survival in the homogeneous, high-risk population of patients with residual TNBC after neoadjuvant chemotherapy.
BRE12-158 was a phase II trial of genomically directed therapy versus physician's choice in residual TNBC after chemotherapy. ctDNA was isolated from plasma samples, and categorized as positive or negative. BMI (kg/m
) after surgery was analyzed as both a continuous and categorical variable: normal weight, <25; overweight, 25-30; and obese, ≥30. We compared ctDNA category and BMI, and estimated probability of disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) by BMI.
Of 177 patients in BRE12-158, 172 had BMI and 140 had ctDNA data. There was no difference in mean BMI between those with ctDNA positivity versus negativity (
= 0.48). There was no relationship between BMI category and presence of ctDNA (
= 0.31). In multivariate analysis, continuous BMI was not prognostic of DDFS (
= 0.996), DFS (
= 0.41), or OS (
= 0.98). There was no association between BMI categories and survival (
= 0.92, 0.74, and 0.97 for DDFS, DFS, and OS, respectively).
In patients with residual TNBC after neoadjuvant chemotherapy, BMI was not prognostic of DDFS, DFS, or OS. There was no signal of a relationship between BMI and presence of ctDNA. This suggests inherent aggressive tumor biology, in which host phenotype may have less influence and impact of weight loss interventions may be diminished.
We evaluated biochemical changes in skeletal muscle of women with breast cancer initiating aromatase inhibitors (AI), including oxidation of ryanodine receptor RyR1 and loss of stabilizing protein ...calstabin1, and detailed measures of muscle function. Fifteen postmenopausal women with stage I-III breast cancer planning to initiate AI enrolled. Quadriceps muscle biopsy, dual-energy x-ray absorptiometry, isokinetic dynamometry, Short Physical Performance Battery, grip strength, 6-min walk, patient-reported outcomes, and serologic measures of bone turnover were assessed before and after 6 months of AI. Post-AI exposure, oxidation of RyR1 significantly increased (0.23 ± 0.37 vs. 0.88 ± 0.80, p < 0.001) and RyR1-bound calstabin1 significantly decreased (1.69 ± 1.53 vs. 0.74 ± 0.85, p < 0.001), consistent with dysfunctional calcium channels in skeletal muscle. Grip strength significantly decreased at 6 months. No significant differences were seen in isokinetic dynamometry measures of muscle contractility, fatigue resistance, or muscle recovery post-AI exposure. However, there was significant correlation between oxidation of RyR1 with muscle power (r = 0.60, p = 0.02) and muscle fatigue (r = 0.57, p = 0.03). Estrogen deprivation therapy for breast cancer resulted in maladaptive changes in skeletal muscle, consistent with the biochemical signature of dysfunctional RyR1 calcium channels. Future studies will evaluate longer trajectories of muscle function change and include other high bone turnover states, such as bone metastases.
Background
African ancestry (AA) and obesity are associated with worse survival in early‐stage breast cancer. Obesity disproportionately affects women of AA; however, the intersection between ...ancestry and obesity on breast cancer outcomes remains unclear.
Methods
A total of 2854 patients in the adjuvant trial E5103 were analyzed. Genetic ancestry was determined using principal components from a genome‐wide array. The impact of continuous or binary body mass index (BMI) on disease‐free survival (DFS) and overall survival (OS) was evaluated by multivariable Cox proportional hazards models in AA patients and European ancestry (EA) patients.
Results
There were 2471 EA patients and 383 AA patients. Higher BMI was significantly associated with worse DFS and OS only in AA patients (DFS hazard ratio HR, 1.25; 95% CI, 1.07‐1.46; OS HR, 1.38; 95% CI, 1.10‐1.73), not in EA patients (DFS HR, 0.97; 95% CI, 0.90‐1.05; OS HR, 1.03; 95% CI, 0.93‐1.14). Severe obesity (BMI ≥40) was significantly associated with worse survival in AA patients (DFS HR, 2.04; 95% CI, 1.21‐3.43; OS HR, 2.21; 95% CI, 1.03‐4.75) but had no impact on that of EA patients. In the estrogen receptor–positive (ER+) and triple‐negative breast cancer subgroups, BMI was significantly associated with worse outcomes only in those AA patients with ER+ disease. Within the AA group, BMI remained associated with worse survival regardless of the AA proportion.
Conclusions
Higher BMI was statistically significantly associated with worse breast cancer outcomes in AA but not EA patients. This association was most significant for severe obesity and those with ER+ disease. These observations help define optimal populations for weight change interventions designed to affect disparities and survival in early‐stage breast cancer.
Lay Summary
African ancestry and obesity are both risk factors for worse survival after early‐stage breast cancer.
Women of African descent are also disproportionately affected by obesity; however, it is unclear what impact body weight has on racial disparities in breast cancer.
Data from a large phase 3 clinical trial in high‐risk, early‐stage breast cancer were used to determine how body weight affects survival outcomes in European versus African Americans.
Study results demonstrate that a higher body mass index is associated with increased risk of breast cancer recurrence and worse survival in women of African ancestry but not in women of European ancestry.
In this post hoc analysis of a large randomized clinical trial, body mass index was associated with worse disease‐free and overall survival only in patients of genetically determined African descent, with no impact on survival in those of European descent. Interventions that are focused on social determinants of health and lifestyle factors associated with weight gain in patients with high‐risk breast cancer may reduce racial disparities and improve outcomes.
A significant proportion of patients with early-stage triple-negative breast cancer (TNBC) are treated with neoadjuvant chemotherapy. Sequencing of circulating tumor DNA (ctDNA) after surgery, along ...with enumeration of circulating tumor cells (CTCs), may be used to detect minimal residual disease and assess which patients may experience disease recurrence.
To determine whether the presence of ctDNA and CTCs after neoadjuvant chemotherapy in patients with early-stage TNBC is independently associated with recurrence and clinical outcomes.
A preplanned secondary analysis was conducted from March 26, 2014, to December 18, 2018, using data from 196 female patients in BRE12-158, a phase 2 multicenter randomized clinical trial that randomized patients with early-stage TNBC who had residual disease after neoadjuvant chemotherapy to receive postneoadjuvant genomically directed therapy vs treatment of physician choice. Patients had blood samples collected for ctDNA and CTCs at time of treatment assignment; ctDNA analysis with survival was performed for 142 patients, and CTC analysis with survival was performed for 123 patients. Median clinical follow-up was 17.2 months (range, 0.3-58.3 months).
Circulating tumor DNA was sequenced using the FoundationACT or FoundationOneLiquid Assay, and CTCs were enumerated using an epithelial cell adhesion molecule-based, positive-selection microfluidic device.
Primary outcomes were distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS).
Among 196 female patients (mean SD age, 49.6 11.1 years), detection of ctDNA was significantly associated with inferior DDFS (median DDFS, 32.5 months vs not reached; hazard ratio HR, 2.99; 95% CI, 1.38-6.48; P = .006). At 24 months, DDFS probability was 56% for ctDNA-positive patients compared with 81% for ctDNA-negative patients. Detection of ctDNA was similarly associated with inferior DFS (HR, 2.67; 95% CI, 1.28-5.57; P = .009) and inferior OS (HR, 4.16; 95% CI,1.66-10.42; P = .002). The combination of ctDNA and CTCs provided additional information for increased sensitivity and discriminatory capacity. Patients who were ctDNA positive and CTC positive had significantly inferior DDFS compared with those who were ctDNA negative and CTC negative (median DDFS, 32.5 months vs not reached; HR, 5.29; 95% CI, 1.50-18.62; P = .009). At 24 months, DDFS probability was 52% for patients who were ctDNA positive and CTC positive compared with 89% for those who were ctDNA negative and CTC negative. Similar trends were observed for DFS (HR, 3.15; 95% CI, 1.07-9.27; P = .04) and OS (HR, 8.60; 95% CI, 1.78-41.47; P = .007).
In this preplanned secondary analysis of a randomized clinical trial, detection of ctDNA and CTCs in patients with early-stage TNBC after neoadjuvant chemotherapy was independently associated with disease recurrence, which represents an important stratification factor for future postneoadjuvant trials.
ClinicalTrials.gov Identifier: NCT02101385.
Significant advances in the management of metastatic breast cancer (MBC) have guided more personalized treatment according to disease biology and led to improved survival outcomes and quality of life ...for patients. In this review, we discuss landmark clinical trials in medical oncology that have shaped the current standard of care for MBC. Combinations of endocrine therapy with cyclin-dependent kinase 4/6 inhibitors have led to substantial improvements in overall survival, thus becoming standard first-line treatment for patients with HR-positive MBC. Inhibition of the PI3K and mTOR pathway is another promising strategy to overcome resistance to endocrine therapy. HER2-targeted therapies have also evolved with the addition of pertuzumab to trastuzumab plus a taxane demonstrating remarkable overall survival advantage in patient with HER2-positive MBC. In second or later line therapies, novel anti-HER2 antibody-drug conjugates and TKIs have durable antitumor activity, survival benefit, and encouraging efficacy in the subgroup of patients with brain metastases. Triple negative breast cancer remains the most challenging subtype due to lack of druggable targets. Immunotherapy for patients with PDL-1 expression on tumor infiltrating immune cells and poly (ADP-ribose) polymerase inhibitors for those with germline BRCA1/2 mutations are the latest approved targeted strategies in this population. Numerous obstacles still exist in treating MBC, especially for patients whose disease develops resistance to available agents. Future research is eagerly awaited to address the optimal sequence or combination of therapies and to identify better biomarkers to guide precision medicine.
Abstract Clinical decision-making in the treatment of breast cancer depends on an accurate determination and understanding of human epidermal growth factor receptor 2 (HER2) status. The guidelines ...for HER2 testing were recently updated in late 2013, but limitations continue to exist in the interpretation and clinical application of results when the tumor specimens do not fall neatly into positive or negative categories with immunohistochemistry and fluorescence in situ hybridization testing. The issues, including discordance between pathologists or laboratories, polysomy, and genetic heterogeneity, present challenging situations that are difficult to translate into clinical significance. The present review discussed the changes in the updated American Society of Clinical Oncology/College of American Pathologists guidelines, the clinical relevance of complex issues in HER2 testing, and the implications of the results on the response to HER2-targeted therapies. Great advances have been made in the treatment of HER2-positive breast cancer; however, the challenge remains to determine the best testing analysis that will identify patients who will benefit the most from these therapies.
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