Real-World Evaluation of Disease Progression After CDK 4/6 Inhibitor Therapy in Patients With Hormone Receptor-Positive Metastatic Breast Cancer.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDKi) have changed the landscape for treatment of patients with hormone receptor positive, human epidermal growth factor receptor 2-negative (HR+/HER-) metastatic breast cancer (MBC). However, next-line treatment strategies after CDKi progression are not yet optimized. We report here the impact of clinical and genomic factors on post-CDKi outcomes in a single institution cohort of HR+/HER2- patients with MBC. METHODS: We retrospectively reviewed the medical records of patients with HR+/HER2- MBC that received a CDKi between April 1, 2014 and December 1, 2019 at our institution. Data were summarized using descriptive statistics, the Kaplan-Meier method, and regression models. RESULTS: We identified 140 patients with HR+/HER2- MBC that received a CDKi. Eighty percent of patients discontinued treatment due to disease progression, with a median progression-free survival (PFS) of 6.0 months (95% CI, 5.0-7.1), whereas those that discontinued CDKi for other reasons had a PFS of 11.3 months (95% CI, 4.6-19.4) (hazard ratio (HR) 2.53, 95% CI, 1.50-4.26 [P = .001]). The 6-month cumulative incidence of post-CDKi progression or death was 51% for the 112 patients who progressed on CDKi. Patients harboring PTEN mutations pre-CDKi treatment had poorer clinical outcomes compared to those with wild-type PTEN. CONCLUSION: This study highlights post-CDKi outcomes and the need for further molecular characterization and novel therapies to improve treatments for patients with HR+/HER2- MBC.

Predictors of long-term durable response in de novo HER2-positive metastatic breast cancer and the real-world treatment experience at two institutions.

PURPOSE: HER2-directed therapies enable some patients with de novo HER2+ metastatic breast cancer (MBC) to achieve long-term, durable responses (DR). Expert opinion dictates indefinite HER2-directed therapies for patients who achieve DRs, but real-world examples of this practice are lacking in the literature. Patient factors that predict DR continue to be elucidated. METHODS: This is a retrospective study of patients with de novo HER2 + MBC. DR is defined as absence of progression/death at any point after diagnosis. Controls are patients with evidence of progression/death. Age, ER/PR status, sites of metastasis, surgical resection of primary tumor, and initial treatment were analyzed. RESULTS: 96 patients with de novo HER2 + MBC, 28 with DR, and 68 with progression were identified. 75% of patients with DR had a single metastatic site, compared with 47% of patients with progression (OR 3.7, p = 0.01). 64% of patients with DR received a regimen containing trastuzumab, pertuzumab, and a taxane, while 28% of patients who progressed did (OR 4.5, p < 0.001). 57% of patients with DR underwent surgical removal of breast primary, compared with 24% of patients who progressed (OR 4.3, p = 0.002.) Among patients with DR, nine patients have been receiving trastuzumab for over ten years with no evidence of disease and one patient opted to discontinue trastuzumab. CONCLUSION: Nearly a third of patients with de novo HER2 + MBC achieved DR. Factors that correlate with DR include single metastatic site, initial trastuzumab, pertuzumab and taxane therapy, and surgical resection of primary tumor. Among patients with DR, indefinite trastuzumab administration is the norm.

Delivering exercise medicine to cancer survivors: has COVID-19 shifted the landscape for how and who can be reached with supervised group exercise?

PURPOSE: Due to stay-at-home orders during COVID-19, we transitioned supervised, group, in-person resistance training interventions in two clinical trials in cancer survivors to live, online delivery using video-conferencing technology. We describe the feasibility, preliminary efficacy, and safety of live online group training and compare to in-person training. METHODS: Adherence (% sessions attended), retention (% participants completing intervention), and safety (# adverse events) data of resistance training groups from two randomized controlled trials in cancer survivors that participated before or during the COVID-19 pandemic were collated. Participants were post-treatment breast cancer survivors and their spouses (n = 62) and prostate cancer survivors (n = 32) (age range: 38-82 years). During COVID-19, delivery of supervised, group resistance exercise sessions was delivered live online via video-conference. Preliminary evidence for training efficacy was assessed by chair stand performance over the 6-month intervention. RESULTS: Feasibility of online resistance training was better than in-person for both studies (adherence: 86% vs 82% and 91% vs. 81% and retention 95% vs. 80% and 92% vs. 84% for online and in-person classes). Improvements in chair stand time were similar in prostate cancer and spouse groups that trained online vs. in-person, except for breast cancer survivors who improved more with in-person training (7% vs. 14% for online vs. in-person). Safety was similar between formats (12 vs. 11 adverse events for online vs. in-person). CONCLUSION: Supervised, in-person group resistance training can be feasibly adapted for live, online delivery and could help broaden approaches to exercise delivery in cancer survivors, including older adults. TRIAL REGISTRATION: The studies described in this commentary were registered on ClinicalTrials.gov on August 3, 2018 (NCT03630354) and on October 30, 2018 (NCT03741335).

Quantitative DCE-MRI prediction of breast cancer recurrence following neoadjuvant chemotherapy: a preliminary study.

INTRODUCTION: Breast cancer patients treated with neoadjuvant chemotherapy (NACT) are at risk of recurrence depending on clinicopathological characteristics. This preliminary study aimed to investigate the predictive performances of quantitative dynamic contrast-enhanced (DCE) MRI parameters, alone and in combination with clinicopathological variables, for prediction of recurrence in patients treated with NACT. METHODS: Forty-seven patients underwent pre- and post-NACT MRI exams including high spatiotemporal resolution DCE-MRI. The Shutter-Speed model was employed to perform pharmacokinetic analysis of the DCE-MRI data and estimate the Ktrans, ve, kep, and τi parameters. Univariable logistic regression was used to assess predictive accuracy for recurrence for each MRI metric, while Firth logistic regression was used to evaluate predictive performances for models with multi-clinicopathological variables and in combination with a single MRI metric or the first principal components of all MRI metrics. RESULTS: Pre- and post-NACT DCE-MRI parameters performed better than tumor size measurement in prediction of recurrence, whether alone or in combination with clinicopathological variables. Combining post-NACT Ktrans with residual cancer burden and age showed the best improvement in predictive performance with ROC AUC = 0.965. CONCLUSION: Accurate prediction of recurrence pre- and/or post-NACT through integration of imaging markers and clinicopathological variables may help improve clinical decision making in adjusting NACT and/or adjuvant treatment regimens to reduce the risk of recurrence and improve survival outcome.

Everolimus Plus Exemestane Treatment in Patients with Metastatic Hormone Receptor-Positive Breast Cancer Previously Treated with CDK4/6 Inhibitor Therapy.

BACKGROUND: The combination of everolimus (EVE) and exemestane (EXE) is approved for the treatment of patients with metastatic hormone receptor-positive breast cancer (mHRBC) who progress on nonsteroidal aromatase inhibitor (NSAI) therapy. However, none of the patients enrolled in the trial that led to this approval (BOLERO-2) had previously received CDK4/6 inhibitors (CDK4/6is), which have since become a frontline standard of care for mHRBC. As such, the clinical benefit of EVE plus EXE in patients who have previously received CDK4/6is remains unknown. MATERIALS AND METHODS: Adult patients with mHRBC at our institution who progressed on an NSAI plus CDK4/6i or NSAI therapy alone and were treated with at least one cycle of EVE plus EXE between 2012 and 2018 were analyzed. Collected data included patient demographics, treatment history, adverse events, and clinical outcomes. Primary objectives were to compare progression-free survival (PFS) and overall survival (OS) between patients who received prior NSAI plus CDK4/6i therapy versus an NSAI alone. RESULTS: Among 43 patients, 17 had prior CDK4/6i exposure. With the exception of de novo metastatic disease, patient and disease characteristics were comparable across treatment cohorts. There was no significant difference in PFS (median, 3.6 vs. 4.2 months) or OS (median, 15.6 vs. 11.3 months) between patients who had received prior CDK4/6is and those who had not, respectively. CONCLUSION: Prior exposure to CDK4/6i therapy did not impact survival outcomes for patients with mHRBC taking EVE plus EXE. However, there was a trend toward improved OS in the CDK4/6i cohort that should be evaluated in larger cohorts. IMPLICATIONS FOR PRACTICE: The use of CDK4/6 inhibitors in combination with a nonsteroidal aromatase inhibitor has become a standard frontline therapy in metastatic hormone receptor-positive breast cancer. An approved subsequent line of therapy is everolimus plus exemestane; however, the original data supporting this therapy predated approval of CDK4/6 inhibitors. As such, the clinical benefit of everolimus and exemestane in patients previously treated with a CDK4/6 inhibitor was unknown. This retrospective cohort study offers real-world data demonstrating prior CDK4/6 inhibitor exposure does not impact survival outcomes for everolimus plus exemestane.

Ado-trastuzumab for the treatment of metastatic HER2-positive breast cancer in patients previously treated with Pertuzumab.

BACKGROUND: Docetaxel in combination with two HER2-directed therapies, trastuzumab and pertuzumab, is the current standard frontline therapy for patients with metastatic HER2-positive breast cancer. Ado-trastuzumab (T-DM1), an antibody-drug conjugate of trastuzumab and a cytotoxic microtubule-inhibitory agent, emtansine, is approved in patients that have progressed with prior trastuzumab-based therapy. However, the benefit of T-DM1 in patients previously treated with pertuzumab therapy for metastatic breast cancer remains unclear. METHODS: We identified thirty-three adults with metastatic HER2-positive breast cancer treated between March 2013 and July 2018 with T-DM1 either as subsequent therapy after progression on a pertuzumab-based regimen (i.e., "pertuzumab-pretreated") or without prior exposure to pertuzumab (i.e., "pertuzumab-naïve"). Collected data included patient demographics, treatment history, adverse events, and clinical outcomes. For both cohorts receiving T-DM1, the primary endpoint was PFS and secondary endpoints were overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and T-DM1-related toxicity rate. RESULTS: Pertuzumab-pretreated patients (n = 23, with 21 evaluable for T-DM1 efficacy) had a median PFS of 9.5 months (95% CI: 2.9-NA), 1-year OS rate of 67.4% (95% CI: 50.0-90.9%) with an unreached median, ORR of 14.3% (95% CI: 3.0-36.3%), and CBR of 52.4% (95% CI: 29.8-74.3%), with none of these measures being statistically different than those estimated for the pertuzumab-naïve group (n = 10). Treatment with T-DM1 after prior pertuzumab exposure (median T-DM1 duration 2.9 months) resulted in no grade ≥ 3 adverse events. CONCLUSIONS: In our cohort, prior exposure to pertuzumab did not significantly impact T-DM1's clinical efficacy or safety profile as second- or later-line therapy in patients with metastatic HER2-positive breast cancer.

CDK 4/6 inhibitors are associated with a high incidence of thrombotic events in women with breast cancer in real-world practice.

PURPOSE: Cyclin-dependent kinase (CDK) 4/6 inhibitors are integral treatment for advanced hormone receptor positive breast cancer; however, venous thromboembolic events (VTE) occurred in 1%-5% of clinical trial patients. Thrombosis rates in the real-world setting remain unclear. We aimed to define the rate of thromboembolic events, risk factors for thrombosis on CDK 4/6 inhibitors and evaluate the Khorana VTE risk score as a predictive tool for VTE in patients on CDK 4/6 therapy. METHODS: Multicenter retrospective analysis of adult breast cancer patients prescribed palbociclib, ribociclib, or abemaciclib. The primary endpoint was thrombosis during treatment or within 30 days of CDK inhibitor discontinuation. Cox regression was used to model time-to-thrombosis, starting from a patient's initiation of CDK 4/6 therapy. The extended Kaplan-Meier method and Cox modeling were used to assess the effect of time-varying thrombosis status on overall survival. RESULTS: Two hundred and sixty-six patients were included (89% on palbociclib, 14% on abemaciclib, 7% on ribociclib). Twenty-nine thrombotic events occurred in 26 (9.8%) women. Of these events, 72% were venous and 34% were arterial. The 1-year incidence of thrombosis was 10.4% overall, 10.9% on palbociclib, 8.3% on ribociclib, and 4.8% on abemaciclib. Hemoglobin less than 10 g/dL was a statistically significant predictor of thrombosis (HR 3.53, P: .014). Khorana score ranged from 0-3, with the majority between 0 and 1 and was not predictive of VTE. Thrombosis was associated with reduced overall survival (HR 1.28, P: .128, median 7.3 months) compared to not having a CDK-associated clot (median 35.7 months). DISCUSSION: VTE in our analysis is higher than reported in clinical trials and arterial thrombosis comprised over one-third of events. The highest incidence was with palbociclib, followed by ribociclib. Khorana score did not predict VTE risk. Larger, real-world studies are needed. The role for prophylactic anticoagulation is yet to be defined in this patient population.

Using Reverse Phase Protein Array (RPPA) to Identify and Target Adaptive Resistance.

Tumor cells and the tumor ecosystem rapidly evolve in response to therapy. This tumor evolution results in the rapid emergence of drug resistance that limits the magnitude and duration of response to therapy including chemotherapy, targeted therapy, and immunotherapy. Thus, there is an urgent need to understand and interdict tumor evolution to improve patient benefit to therapy. Reverse phase protein array (RPPA) provides a powerful tool to evaluate and develop approaches to target the processes underlying one form of tumor evolution: adaptive evolution. Tumor cells and the tumor microenvironment rapidly evolve through rewiring of protein networks to bypass the effects of therapy. In this review, we present the concepts underlying adaptive resistance and use of RPPA in understanding resistance mechanisms and identification of effective drug combinations. We further demonstrate that this novel information is resulting in biomarker-driven trials aimed at targeting adaptive resistance and improving patient outcomes.

Implementing a comprehensive translational oncology platform: from molecular testing to actionability.

BACKGROUND: In order to establish the workflows required to implement a real-time process involving multi-omic analysis of patient samples to support precision-guided therapeutic intervention, a tissue acquisition and analysis trial was implemented. This report describes our findings to date, including the frequency with which mutational testing led to precision-guided therapy and outcome for those patients. METHODS: Eligible patients presenting to Oregon Health and Science University Knight Cancer Institute were enrolled on the study. Patients with biopsy proven metastatic or locally advanced unresectable prostate cancer, breast cancer, pancreatic adenocarcinoma, or refractory acute myelogenous leukemia receiving standard of care therapy were eligible. Metastatic site biopsies were collected and analyzed using the Knight Diagnostic Lab GeneTrails comprehensive solid tumor panel (124 genes). CLIA certified genomic information was made available to the treating physician. RESULTS: Between 1/26/2017 and 5/30/2018, 38 patients were enrolled, with 28 successfully undergoing biopsy. Of these, 25 samples yielded sufficient tumor for analysis. The median biopsy cellularity and number of cores collected were 70% (15-90%) and 5 (2-20), respectively. No procedure-related complications occurred. GeneTrails analysis revealed that 22 of 25 (88%) tumor samples harbored at least one potentially actionable mutation, and 18 (72%) samples harbored 2 or more potentially actionable mutations. The most common genetic alterations identified involved: DNA damage repair genes, cell cycle regulating genes, PIK3CA/Akt/mTOR pathway, and FGF gene family. To date, CLIA certified genomic results were used by treating physicians for precision-guided therapy in 5 (23%) patients. CONCLUSION: We report the feasibility of real-time tissue acquisition and analysis to support a successful translational oncology platform. The workflow will provide the foundation to improve access and accrual to biomarker driven precision oncology trials.

BRCAPRO 6.0 Model Validation in Male Patients Presenting for BRCA Testing.

BACKGROUND: BRCAPRO is a risk assessment model to estimate the risk of carrying a BRCA mutation. BRCA mutation carriers are at higher risk of developing breast, ovarian, pancreatic, and prostate cancer. BRCAPRO was developed for women and found to be superior to other risk assessment models. The present study evaluated the validity of BRCAPRO at predicting the risk of male patients carrying a BRCA mutation. PATIENTS AND METHODS: A total of 146 men who presented for genetic counseling and testing from February1997 to September 2011, and their test results were included in the present study. BRCAPRO risk assessment for all patients was calculated using the BRCAPRO clinical CancerGene assessment software. RESULTS: The mean age at presentation was 57 years. Of the 146 patients, 48 had breast cancer, 18 had pancreatic cancer, 39 had prostate cancer, 27 had other primary cancers, and 37 had no cancer. Fifty patients (34%) tested positive for a BRCA mutation (22 BRCA1, 27 BRCA2, and 1 BRCA1 and BRCA2). The mean BRCAPRO score for all patients was 24.96%. The BRCAPRO score was significantly higher for patients who tested positive for a BRCA mutation (46.19% vs. 13.9%, p < .01). The area under the receiver operating characteristics curve was 0.83 for all patients for the BRCAPRO score to predict the risk of carrying a BRCA mutation. At a cutoff point of 30.02%, the sensitivity, specificity, positive predictive value, and negative predictive value were 0.74, 0.81, 0.67, and 0.86, respectively. CONCLUSION: BRCAPRO appears to be a valid risk assessment tool for determining the risk of carrying a BRCA mutation in men. IMPLICATIONS FOR PRACTICE: Men carrying genetic mutations in the BRCA gene have a greater risk than the general population of developing certain types of cancer, including breast, pancreatic, and prostate cancer. BRCAPRO is a risk assessment model that predicts the risk of carrying a BRCA mutation. The present study aimed at validating BRCAPRO for use with men seen for genetic counseling, whether affected by cancer or not. The data available for 146 patients revealed that BRCAPRO was effective at identifying patients at risk of BRCA mutation. These findings could help in identifying a subset of high-risk patients who should proceed to genetic testing.

A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer.

PURPOSE: Low molecular weight cyclin E (LMW-E) isoforms, overexpressed in a majority (~70 %) of triple-negative breast cancers (TNBC), were found in preclinical models to mediate tumorigenesis through binding and activation of CDK2. CDK1/CDK2 inhibitors, such as dinaciclib, combined with anthracyclines, were synergistic in decreasing viability of TNBC cell lines. Based on this data, a phase 1 study was conducted to determine the maximum tolerated dose of dinaciclib in combination with epirubicin in patients with metastatic TNBC. METHODS: Cohorts of at least 2 patients were treated with escalating doses of dinaciclib given on day 1 followed by standard dose of epirubicin given on day 2 of a 21 day cycle. No intra-patient dose escalation was allowed. An adaptive accrual design based upon toxicity during cycle 1 determined entry into therapy cohorts. The target acceptable dose limiting toxicity (DLT) to advance to the next treatment level was 30 %. RESULTS: Between 9/18/2012 and 7/18/2013, 9 patients were enrolled and treated at MD Anderson Cancer Center. DLTs included febrile neutropenia (grade 3, n = 2), syncope (grade 3, n = 2) and vomiting (grade 3, n = 1). Dose escalation did not proceed past the second cohort due to toxicity. After further accrual, the first dose level was also found to be too toxic. No treatment responses were noted, median time to progression was 5.5 weeks (range 3-12 weeks). Thus, accrual was stopped rather than explore the -1 dose level. CONCLUSION: The combination of dinaciclib and epirubicin is associated with substantial toxicities and does not appear to be an effective treatment option for TNBC.

Strategies for the prevention or reversal of PARP inhibitor resistance.

INTRODUCTION: Advances in our understanding of tumor biology shed light on hallmarks of cancer development and progression that include dysregulated DNA damage repair (DDR) machinery. Leveraging the underlying tumor genomic instability and tumor-specific defects in DDR, Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) induced DNA damage emerges as a novel non-chemotherapy therapeutic opportunity. PARPis are currently approved in multiple tumor types, with the largest benefit seen in tumors with homologous recombination repair (HRR) deficiency, including germline and somatic mutations in BRCA1/2 genes (BRCA) and other pathway members such as PALB2 and Rad51c. AREAS COVERED: This review article summarizes the current approval landscape and known and proposed mechanisms of resistance to PARPi. Further, therapeutic strategies to overcome PARPi resistance are discussed, including ongoing clinical trials. EXPERT OPINION: PARPi have proven to be a safe and effective therapy and represents a cornerstone treatment across multiple solid tumor types. Elucidating innate and acquired mechanisms of resistance, coupled with the emergence of novel therapeutic options to capitalize on the activity of PARPi and prevent or reverse the acquisition of resistance, provides an opportunity to further expand the role of PARPi in cancer therapy.

Association between Gut Microbiota and Breast Cancer: Diet as a Potential Modulating Factor.

Breast cancer (BCa) has many well-known risk factors, including age, genetics, lifestyle, and diet; however, the influence of the gut microbiome on BCa remains an emerging area of investigation. This study explores the connection between the gut microbiome, dietary habits, and BCa risk. We enrolled newly diagnosed BCa patients and age-matched cancer-free controls in a case-control study. Comprehensive patient data was collected, including dietary habits assessed through the National Cancer Institute Diet History Questionnaire (DHQ). 16S rRNA amplicon sequencing was used to analyze gut microbiome composition and assess alpha and beta diversity. Microbiome analysis revealed differences in the gut microbiome composition between cases and controls, with reduced microbial diversity in BCa patients. The abundance of three specific microbial genera-Acidaminococus, Tyzzerella, and Hungatella-was enriched in the fecal samples taken from BCa patients. These genera were associated with distinct dietary patterns, revealing significant associations between the presence of these genera in the microbiome and specific HEI2015 components, such as vegetables and dairy for Hungatella, and whole fruits for Acidaminococus. Demographic characteristics were well-balanced between groups, with a significantly higher body mass index and lower physical activity observed in cases, underscoring the role of weight management in BCa risk. Associations between significant microbial genera identified from BCa cases and dietary intakes were identified, which highlights the potential of the gut microbiome as a source of biomarkers for BCa risk assessment. This study calls attention to the complex interplay between the gut microbiome, lifestyle factors including diet, and BCa risk.

Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib.

Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2- breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation.

Impact of TP53 mutations in Triple Negative Breast Cancer.

Identifying triple negative breast cancer (TNBC) patients expected to have poor outcomes provides an opportunity to enhance clinical management. We applied an Evolutionary Action Score to functionally characterize TP53 mutations (EAp53) in 96 TNBC patients and observed that EAp53 stratification may identify TP53 mutations associated with worse outcomes. These findings merit further exploration in larger TNBC cohorts and in patients treated with neoadjuvant chemotherapy regimens.

A randomized-controlled trial comparing supervised aerobic training to resistance training followed by unsupervised exercise on physical functioning in older breast cancer survivors.

INTRODUCTION: This study compared the relative efficacy of aerobic training to resistance training on physical functioning in older breast cancer survivors and determined whether benefits could be maintained by transitioning to unsupervised home-based training. MATERIALS AND METHODS: Early-stage, post-treatment, older (≥65 years) breast cancer survivors (n = 114; mean age 72 years) were randomized to 12 months of supervised aerobic (n = 37), resistance (n = 39) or stretching (active control; n = 38) training followed by 6 months of unsupervised home-based training. Outcomes included aerobic capacity by 6-min walk distance (6MWD; m), maximal upper and lower body strength (1-repetition maximum; kg); physical function by short physical performance battery (SPPB), SF-36 and Late Life Function and Disability Instruments. RESULTS: Over 12-months of supervised exercise, all groups improved in muscle strength and SPPB scores, but resistance trained women also improved 6MWD. Improvements in upper and lower body strength in the resistance group were significantly greater than those in the stretching control (+2.5 kg vs. +1.8 kg; p = 0.05) and aerobic groups (+8.3 kg vs +2.7 kg; p = 0.047), respectively, with trends for greater improvements in 6MWD (+57.9 m vs. +22.5 m; p = 0.057) and self-report physical function (+4.8 vs. -4.4; 0.066) in resistance trained women versus controls. Compared to values at 12 months, there were no changes during unsupervised training in any measure within or between groups, except for self-reported advanced lower extremity function which improved in the resistance group and fell in the aerobic group (+1.3 vs. -3.1; p = 0.043). DISCUSSION: Supervised exercise can improve strength and physical functioning among older breast cancer survivors. Resistance training may lead to better improvements compared to aerobic or flexibility training, whether in a supervised or unsupervised setting. Clinicaltrials.govNCT00662103.

An omic and multidimensional spatial atlas from serial biopsies of an evolving metastatic breast cancer.

Mechanisms of therapeutic resistance and vulnerability evolve in metastatic cancers as tumor cells and extrinsic microenvironmental influences change during treatment. To support the development of methods for identifying these mechanisms in individual people, here we present an omic and multidimensional spatial (OMS) atlas generated from four serial biopsies of an individual with metastatic breast cancer during 3.5 years of therapy. This resource links detailed, longitudinal clinical metadata that includes treatment times and doses, anatomic imaging, and blood-based response measurements to clinical and exploratory analyses, which includes comprehensive DNA, RNA, and protein profiles; images of multiplexed immunostaining; and 2- and 3-dimensional scanning electron micrographs. These data report aspects of heterogeneity and evolution of the cancer genome, signaling pathways, immune microenvironment, cellular composition and organization, and ultrastructure. We present illustrative examples of how integrative analyses of these data reveal potential mechanisms of response and resistance and suggest novel therapeutic vulnerabilities.

Study protocol for the Exercising Together© trial: a randomized, controlled trial of partnered exercise for couples coping with cancer.

BACKGROUND: Most cancer survivors are married, and cancer strains the physical and mental health of each partner and their intimate relationship. We created a partnered strength training program, Exercising Together©, where the survivor and his/her partner exercise as a team in order to improve physical and mental health of both members of the couple as well as the quality of their relationship. We have not yet determined if Exercising Together© is similarly effective in couples coping with different types of cancer nor if training as a team has unique and added benefits over those derived from supervised group training and/or shared behavior change. The purpose of this study is to determine the unique benefits of Exercising Together© on physical, mental, and relational health in couples coping with breast, prostate, or colorectal cancer. METHODS: Survivors of prostate, breast and colorectal cancer (N = 294, 98 per cancer site) and their intimate, co-residing partners are recruited to participate in a single-blind, parallel group, randomized trial comparing three exercise groups that train twice per week for 6 months. Couples are randomized to one of three groups: (1) Exercising Together© where partners train as a team in a supervised group setting; (2) separate supervised group exercise classes for survivors or partners, respectively; (3) unsupervised home exercise program provided to each partner. The primary outcome is relationship quality (dyadic coping by the Dyadic Coping scale, emotional intimacy by the Dyadic Adjustment Scale, physical intimacy by the Physical Intimacy Behavior Scale, and symptom incongruence). Secondary outcomes are physical health (% body fat by DXA, serum fasting lipids (triglycerides, HDL, and LDL cholesterol), insulin resistance (HOMA-IR), resting blood pressure, C-reactive protein, TNF alpha, and physical functioning by the short Physical Performance Battery and SF-36) and mental health (depressive symptoms, anxiety, fear of recurrence) of each partner. Outcomes are collected at baseline, mid (3 months), post-intervention (6 months), and follow-up (12 months). DISCUSSION: Exercising Together© could shift the paradigm of survivorship care toward novel couple-based approaches that could optimize outcomes for each partner because their health is interdependent on each other and their relationship. TRIAL REGISTRATION: ClinicalTrials.gov NCT03630354 . Registered August 14, 2018.

Characterizing advanced breast cancer heterogeneity and treatment resistance through serial biopsies and comprehensive analytics.

Molecular heterogeneity in metastatic breast cancer presents multiple clinical challenges in accurately characterizing and treating the disease. Current diagnostic approaches offer limited ability to assess heterogeneity that exists among multiple metastatic lesions throughout the treatment course. We developed a precision oncology platform that combines serial biopsies, multi-omic analysis, longitudinal patient monitoring, and molecular tumor boards, with the goal of improving cancer management through enhanced understanding of the entire cancer ecosystem within each patient. We describe this integrative approach using comprehensive analytics generated from serial-biopsied lesions in a metastatic breast cancer patient. The serial biopsies identified remarkable heterogeneity among metastatic lesions that presented clinically as discordance in receptor status and genomic alterations with mixed treatment response. Based on our study, we highlight clinical scenarios, such as rapid progression or mixed response, that indicate consideration for repeat biopsies to evaluate intermetastatic heterogeneity (IMH), with the objective of refining targeted therapy. We present a framework for understanding the clinical significance of heterogeneity in breast cancer between metastatic lesions utilizing multi-omic analyses of serial biopsies and its implication for effective personalized treatment.

Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies.

In a pilot study, we evaluated the feasibility of real-time deep analysis of serial tumor samples from triple negative breast cancer patients to identify mechanisms of resistance and treatment opportunities as they emerge under therapeutic stress engendered by poly-ADP-ribose polymerase (PARP) inhibitors (PARPi). In a BRCA-mutant basal breast cancer exceptional long-term survivor, a striking tumor destruction was accompanied by a marked infiltration of immune cells containing CD8 effector cells, consistent with pre-clinical evidence for association between STING mediated immune activation and benefit from PARPi and immunotherapy. Tumor cells in the exceptional responder underwent extensive protein network rewiring in response to PARP inhibition. In contrast, there were minimal changes in the ecosystem of a luminal androgen receptor rapid progressor, likely due to indifference to the effects of PARP inhibition. Together, identification of PARPi-induced emergent changes could be used to select patient specific combination therapies, based on tumor and immune state changes.