Pilot study of a decision aid on BRCA1/2 genetic testing among Orthodox Jewish women.

INTRODUCTION: Orthodox Jewish women face unique social, cultural, and religious factors that may influence uptake of BRCA1/2 genetic testing. We examined the impact of a web-based decision aid (DA) on BRCA1/2 genetic testing intention/completion among Orthodox Jewish women. We conducted a single-arm pilot study among 50 Orthodox Jewish women who were given access to a web-based DA entitled RealRisks and administered serial surveys at baseline and 1 and 6 months after exposure to the DA. Descriptive statistics were conducted for baseline characteristics and study measures. Comparisons were made to assess changes in study measures over time. Fifty Orthodox Jewish women enrolled in the study with a mean age of 43.9 years (standard deviation [SD] 14.6), 70% Modern Orthodox, 2% with personal history of breast cancer, and 68% and 16% with a family history of breast or ovarian cancer, respectively. At baseline, 27 (54%) participants intended to complete genetic testing. Forty-three participants (86%) completed RealRisks and the 1-month survey and 38 (76%) completed the 6-month survey. There was a significant improvement in BRCA1/2 genetic testing knowledge and decrease in decisional conflict after exposure to the DA. At 1 month, only 20 (46.5%) completed or intended to complete genetic testing (p = 0.473 compared to baseline). While the DA improved genetic testing knowledge and reduced decisional conflict, genetic testing intention/completion did not increase over time. Future interventions should directly address barriers to BRCA1/2 genetic testing uptake and include input from leaders in the Orthodox Jewish community. GOV ID: NCT03624088 (8/7/18).

Understanding Social, Cultural, and Religious Factors Influencing Medical Decision-Making on BRCA1/2 Genetic Testing in the Orthodox Jewish Community.

INTRODUCTION: Although the prevalence of a pathogenic variant in the BRCA1 and BRCA2 genes is about 1:400 (0.25%) in the general population, the prevalence is as high as 1:40 (2.5%) among the Ashkenazi Jewish population. Despite cost-effective preventive measures for mutation carriers, Orthodox Jews constitute a cultural and religious group that requires different approaches to BRCA1 and BRCA2 genetic testing relative to other groups. This study analyzed a dialog of key stakeholders and community members to explore factors that influence decision-making about BRCA1 and BRCA2 genetic testing in the New York Orthodox Jewish community. METHODS: Qualitative research methods, based on Grounded Theory and Narrative Research, were utilized to analyze the narrative data collected from 49 key stakeholders and community members. A content analysis was conducted to identify themes; inter-rater reliability was 71%. RESULTS: Facilitators of genetic testing were a desire for preventive interventions and education, while barriers to genetic testing included negative emotions, feared impact on family/romantic relationships, cost, and stigma. Views differed on the role of religious leaders and healthcare professionals in medical decision-making. Education, health, and community were discussed as influential factors, and concerns were expressed about disclosure, implementation, and information needs. CONCLUSION: This study elicited the opinions of Orthodox Jewish women (decision-makers) and key stakeholders (influencers) who play critical roles in the medical decision-making process. The findings have broad implications for engaging community stakeholders within faith-based or culturally distinct groups to ensure better utilization of healthcare services for cancer screening and prevention designed to improve population health.

Randomized adaptive selection trial of cryotherapy, compression therapy, and placebo to prevent taxane-induced peripheral neuropathy in patients with breast cancer.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating adverse effect of taxane therapy. Small non-randomized studies in patients with early-stage breast cancer (ESBC) suggest both cryotherapy and compression therapy may prevent CIPN. It is unknown which is more effective. METHODS: We conducted a randomized phase IIB adaptive sequential selection trial of cryotherapy vs. compression therapy vs. placebo ("loose" gloves/socks) during taxane chemotherapy. Participants were randomized in triplets. Garments were worn for 90-120 min, beginning 15 min prior and continuing for 15 min following the infusion. The primary goal was to select the best intervention based on a Levin-Robbins-Leu sequential selection procedure. The primary endpoint was a < 5-point decrease in the Functional Assessment of Cancer Therapy Neurotoxicity (FACT-NTX) at 12 weeks. An arm was eliminated if it had four or more fewer successes than the currently leading arm. Secondary endpoints included intervention adherence and patient-reported comfort/satisfaction. RESULTS: Between April 2019 and April 2021, 63 patients were randomized (cryotherapy (20); compression (22); placebo (21)). Most patients (60.3%) were treated with docetaxel. The stopping criterion was met after the 17th triplet (n = 51) was evaluated; success at 12 weeks occurred in 11 (64.7%) on compression therapy, 7 (41.1%) on cryotherapy, and 7 (41.1%) on placebo. Adherence to the intervention was lowest with cryotherapy (35.0%) compared to compression (72.7%) and placebo (76.2%). CONCLUSION: Compression therapy was the most effective intervention in this phase IIB selection trial to prevent CIPN and was well tolerated. Compression therapy for the prevention of CIPN should be evaluated in a phase III study. CLINICAL TRIAL REGISTRATION: ClinicaTrials.gov Identifier: NCT03873272.

Outcomes of Telestroke Inter-Hospital Transfers Among Intervention and Non-Intervention Patients.

Background: Telestroke is an established telemedicine method of delivering emergency stroke care. However, not all neurological patients utilizing telestroke service require emergency interventions or transfer to a comprehensive stroke center. To develop an understanding of the appropriateness of inter-hospital neurological transfers utilizing the telemedicine, our study aimed to assess the differences in outcomes of inter-hospital transfers utilizing the service in relation to the need for neurological interventions. Methods: The pragmatic, retrospective analysis included 181 consecutive patients, who were emergently transferred from telestroke-affiliated regional medical centers between October 3, 2021, and May 3, 2022. In this exploratory study investigating the outcomes of telestroke-referred patients, patients receiving interventions were compared to those that did not following transfer to our tertiary center. Neurological interventions included mechanical thrombectomy (MT) and/or tissue plasminogen activator (tPA), craniectomy, electroencephalography (EEG), or external ventricular drain (EVD). Transfer mortality rate, discharge functional status defined by modified Rankin scale (mRS), neurological status defined by National Institutes of Health Stroke Scale (NIHSS), 30-day unpreventable readmission rate, 90-day clinical major adverse cardiovascular events (MACE), and 90-day mRS, and NIHSS were studied. We used χ2 or Fisher exact tests to evaluate the association between the intervention and categorical or dichotomous variables. Continuous or ordinal measures were compared using Wilcoxon rank-sum tests. All tests of statistical significance were considered to be significant at P < 0.05. Results: Among the 181 transferred patients, 114 (63%) received neuro-intervention and 67 (37%) did not. The death rate during the index admission was not statistically significant between the intervention and non-intervention groups (P = 0.196). The discharge NIHSS and mRS were worse in the intervention compared to the non-intervention (P < 0.05 each, respectively). The 90-day mortality and cardiovascular event rates were similar between intervention and non-intervention groups (P > 0.05 each, respectively). The 30-day readmission rates were also similar between the two groups (14% intervention vs. 13.4% non-intervention, P = 0.910). The 90-day mRS were not significantly different between intervention and non-intervention groups (median 3 (IQR: 1 - 6) vs. 2 (IQR: 0 - 6), P = 0.109). However, 90-day NIHSS was worse in the intervention compared to non-intervention group (median 2 (IQR: 0 - 11) vs. 0 (IQR: 0 - 3), P = 0.004). Conclusions: Telestroke is a valuable resource that expedites emergent neurological care via referral to a stroke center. However, not all transferred patients benefit from the transfer process. Future multicenter studies are warranted to study the effects or appropriateness of telestroke networks, and to better understand the patient characteristics, resources allocation, and transferring institutions to improve telestroke care.

Randomized Phase II Trial of Endocrine Therapy With or Without Ribociclib After Progression on Cyclin-Dependent Kinase 4/6 Inhibition in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: MAINTAIN Trial.

PURPOSE: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) improves progression-free survival (PFS) and overall survival (OS) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Although preclinical and clinical data demonstrate a benefit in changing ET and continuing a CDK4/6i at progression, no randomized prospective trials have evaluated this approach. METHODS: In this investigator-initiated, phase II, double-blind placebo-controlled trial in patients with HR+/HER2- MBC whose cancer progressed during ET and CDK4/6i, participants switched ET (fulvestrant or exemestane) from ET used pre-random assignment and randomly assigned 1:1 to the CDK4/6i ribociclib versus placebo. PFS was the primary end point, defined as time from random assignment to disease progression or death. Assuming a median PFS of 3.8 months with placebo, we had 80% power to detect a hazard ratio (HR) of 0.58 (corresponding to a median PFS of at least 6.5 months with ribociclib) with 120 patients randomly assigned using a one-sided log-rank test and significance level set at 2.5%. RESULTS: Of the 119 randomly assigned participants, 103 (86.5%) previously received palbociclib and 14 participants received ribociclib (11.7%). There was a statistically significant PFS improvement for patients randomly assigned to switched ET plus ribociclib (median, 5.29 months; 95% CI, 3.02 to 8.12 months) versus switched ET plus placebo (median, 2.76 months; 95% CI, 2.66 to 3.25 months) HR, 0.57 (95% CI, 0.39 to 0.85); P = .006. At 6 and 12 months, the PFS rate was 41.2% and 24.6% with ribociclib, respectively, compared with 23.9% and 7.4% with placebo. CONCLUSION: In this randomized trial, there was a significant PFS benefit for patients with HR+/HER2- MBC who switched ET and received ribociclib compared with placebo after previous CDK4/6i and different ET.

Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer.

Inhibiting individual histone deacetylase (HDAC) is emerging as well-tolerated anticancer strategy compared with pan-HDAC inhibitors. Through preclinical studies, we demonstrated that the sensitivity to the leading HDAC6 inhibitor (HDAC6i) ricolinstat can be predicted by a computational network-based algorithm (HDAC6 score). Analysis of ~3,000 human breast cancers (BCs) showed that ~30% of them could benefice from HDAC6i therapy. Thus, we designed a phase 1b dose-escalation clinical trial to evaluate the activity of ricolinostat plus nab-paclitaxel in patients with metastatic BC (MBC) (NCT02632071). Study results showed that the two agents can be safely combined, that clinical activity is identified in patients with HR+/HER2- disease and that the HDAC6 score has potential as predictive biomarker. Analysis of other tumor types also identified multiple cohorts with predicted sensitivity to HDAC6i's. Mechanistically, we have linked the anticancer activity of HDAC6i's to their ability to induce c-Myc hyperacetylation (ac-K148) promoting its proteasome-mediated degradation in sensitive cancer cells.

New steps on an old path: Novel estrogen receptor inhibitors in breast cancer.

Estrogen receptor (ER) signaling represents the main driver of tumor growth and survival in hormone receptor positive (HR+) breast cancer (BC). Thus, endocrine therapy (ET) alone or in combination with targeted agents constitutes the mainstay of the treatment for this BC subtype. Despite its efficacy, intrinsic or acquired resistance to ET occurs in a large proportion of cases, mainly due to aberrant activation of ER signaling (i.e. through ligand-independent ER activation, in the presence of estrogen receptor 1 (ESR1) gene aberration or ER protein phosphorylation) and/or the upregulation of escape pathways, such as the PI3K/AKT/mTOR pathway. Therefore, the development of new ER pathway targeting agents remains essential to delay and overcome ET resistance, enhance treatment efficacy and tolerability, and ultimately prolong patient survival and improve their quality of life. Several novel ER targeting agents are currently under investigation. Among these, the oral selective ER degraders (SERDs) represent the pharmacological class at the most advanced stage of development and promise to enrich the therapeutic armamentarium of HR+ BC in the next few years, as they showed promising results in several clinical trials, either as single ET agents or in combination with targeted therapies. In this manuscript, we aim to provide a comprehensive overview on the clinical development of novel ER targeting agents, reporting the most up-to-date evidence on oral SERDs and other compounds, including new selective ER modulators (SERMs), ER proteolysis targeting chimera (PROTACs), selective ER covalent antagonists (SERCAs), complete ER antagonists (CERANs), selective human ER partial agonists (ShERPAs). Furthermore, we discuss the potential implications of introducing these novel treatment strategies in the evolving and complex therapeutic scenario of HR+ BC.

Qualitative analysis of shared decision-making for chemoprevention in the primary care setting: provider-related barriers.

BACKGROUND: Chemoprevention with anti-estrogens, such as tamoxifen, raloxifene or aromatase inhibitors, have been shown to reduce breast cancer risk in randomized controlled trials; however, uptake among women at high-risk for developing breast cancer remains low. The aim of this study is to identify provider-related barriers to shared decision-making (SDM) for chemoprevention in the primary care setting. METHODS: Primary care providers (PCPs) and high-risk women eligible for chemoprevention were enrolled in a pilot study and a randomized clinical trial of web-based decision support tools to increase chemoprevention uptake. PCPs included internists, family practitioners, and gynecologists, whereas patients were high-risk women, age 35-75 years, who had a 5-year invasive breast cancer risk ≥ 1.67%, according to the Gail model. Seven clinical encounters of high-risk women and their PCPs who were given access to these decision support tools were included in this study. Audio-recordings of the clinical encounters were transcribed verbatim and analyzed using grounded theory methodology. RESULTS: Six primary care providers, of which four were males (mean age 36 [SD 6.5]) and two were females (mean age 39, [SD 11.5]) and seven racially/ethnically diverse high-risk female patients participated in this study. Qualitative analysis revealed three themes: (1) Competing demands during clinical encounters; (2) lack of knowledge among providers about chemoprevention; and (3) limited risk communication during clinical encounters. CONCLUSIONS: Critical barriers to SDM about chemoprevention were identified among PCPs. Providers need education and resources through decision support tools to engage in risk communication and SDM with their high-risk patients, and to gain confidence in prescribing chemoprevention in the primary care setting.

Lessons from the Failure to Complete a Trial of Denosumab in Women With a Pathogenic BRCA1/2 Variant Scheduling Risk-Reducing Salpingo-Oophorectomy.

Female carriers of pathogenic/likely pathogenic (P/LP) BRCA1/2 variants are at increased risk of developing breast and ovarian cancer. Currently, the only effective strategy for ovarian cancer risk reduction is risk-reducing bilateral salpingo-oophorectomy (RR-BSO), which carries adverse effects related to early menopause. There is ongoing investigation of inhibition of the RANK ligand (RANKL) with denosumab as a means of chemoprevention for breast cancer in carriers of BRCA1 P/LP variants. Through the NCI Division of Cancer Prevention (DCP) Early Phase Clinical Trials Prevention Consortia, a presurgical pilot study of denosumab was developed in premenopausal carriers of P/LP BRCA1/2 variants scheduled for RR-BSO with the goal of collecting valuable data on the biologic effects of denosumab on gynecologic tissue. The study was terminated early due to the inability to accrue participants. Challenges which impacted the conduct of this study included a study design with highly selective eligibility criteria and requirements and the COVID-19 pandemic. It is critical to reflect on these issues to enhance the successful completion of future prevention studies in individuals with hereditary cancer syndromes.

Patient and Clinician Decision Support to Increase Genetic Counseling for Hereditary Breast and Ovarian Cancer Syndrome in Primary Care: A Cluster Randomized Clinical Trial.

Importance: To promote the identification of women carrying BRCA1/2 variants, the US Preventive Services Task Force recommends that primary care clinicians screen asymptomatic women for an increased risk of carrying a BRCA1/2 variant risk. Objective: To examine the effects of patient and clinician decision support about BRCA1/2 genetic testing compared with standard education alone. Design, Setting, and Participants: This clustered randomized clinical trial was conducted at an academic medical center including 67 clinicians (unit of randomization) and 187 patients. Patient eligibility criteria included women aged 21 to 75 years with no history of breast or ovarian cancer, no prior genetic counseling or testing for hereditary breast and ovarian cancer syndrome (HBOC), and meeting family history criteria for BRCA1/2 genetic testing. Interventions: RealRisks decision aid for patients and the Breast Cancer Risk Navigation Tool decision support for clinicians. Patients scheduled a visit with their clinician within 6 months of enrollment. Main Outcomes and Measures: The primary end point was genetic counseling uptake at 6 months. Secondary outcomes were genetic testing uptake at 6 and 24 months, decision-making measures (perceived breast cancer risk, breast cancer worry, genetic testing knowledge, decision conflict) based upon patient surveys administered at baseline, 1 month, postclinic visit, and 6 months. Results: From December 2018 to February 2020, 187 evaluable patients (101 in the intervention group, 86 in the control group) were enrolled (mean [SD] age: 40.7 [13.2] years; 88 Hispanic patients [46.6%]; 15 non-Hispanic Black patients [8.1%]; 72 non-Hispanic White patients [38.9%]; 35 patients [18.9%] with high school education or less) and 164 (87.8%) completed the trial. There was no significant difference in genetic counseling uptake at 6 months between the intervention group (20 patients [19.8%]) and control group (10 patients [11.6%]; difference, 8.2 percentage points; OR, 1.88 [95% CI, 0.82-4.30]; P = .14). Genetic testing uptake within 6 months was also statistically nonsignificant (13 patients [12.9%] in the intervention group vs 7 patients [8.1%] in the control group; P = .31). At 24 months, genetic testing uptake was 31 patients (30.7%) in intervention vs 18 patients (20.9%) in control (P = .14). Comparing decision-making measures between groups at baseline to 6 months, there were significant decreases in perceived breast cancer risk and in breast cancer worry (standard mean differences = -0.48 and -0.40, respectively). Conclusions and Relevance: This randomized clinical trial did not find a significant increase in genetic counseling uptake among patients who received patient and clinician decision support vs those who received standard education, although more than one-third of the ethnically diverse women enrolled in the intervention underwent genetic counseling. These findings suggest that the main advantage for these high-risk women is the ability to opt for screening and preventive services to decrease their cancer risk. Trial Registration: ClinicalTrials.gov Identifier: NCT03470402.

Use of a convolutional neural network-based mammographic evaluation to predict breast cancer recurrence among women with hormone receptor-positive operable breast cancer.

PURPOSE: We evaluated whether a novel, fully automated convolutional neural network (CNN)-based mammographic evaluation can predict breast cancer relapse among women with operable hormone receptor (HR)-positive breast cancer. METHODS: We conducted a retrospective cohort study among women with stage I-III, HR-positive unilateral breast cancer diagnosed at Columbia University Medical Center from 2007 to 2017, who received adjuvant endocrine therapy and had at least two mammograms (baseline, annual follow-up) of the contralateral unaffected breast for CNN analysis. We extracted demographics, clinicopathologic characteristics, breast cancer treatments, and relapse status from the electronic health record. Our primary endpoint was change in CNN risk score (range, 0-1). We used two-sample t-tests to assess for difference in mean CNN scores between patients who relapsed vs. remained in remission, and conducted Cox regression analyses to assess for association between change in CNN score and breast cancer-free interval (BCFI), adjusting for known prognostic factors. RESULTS: Among 848 women followed for a median of 59 months, there were 67 (7.9%) breast cancer relapses (36 distant, 25 local, 6 new primaries). There was a significant difference in mean absolute change in CNN risk score from baseline to 1-year follow-up between those who relapsed vs. remained in remission (0.001 vs. - 0.022, p = 0.030). After adjustment for prognostic factors, a 0.01 absolute increase in CNN score at 1-year was significantly associated with BCFI, hazard ratio = 1.05 (95% Confidence Interval 1.01-1.09, p = 0.011). CONCLUSION: Short-term change in the CNN-based breast cancer risk model on adjuvant endocrine therapy predicts breast cancer relapse, and warrants further evaluation in prospective studies.

Making National Cancer Institute-Designated Comprehensive Cancer Center Knowledge Accessible to Community Oncologists via an Online Tumor Board: Longitudinal Observational Study.

BACKGROUND: Expert knowledge is often shared among multidisciplinary academic teams at tumor boards (TBs) across the country, but these conversations exist in silos and do not reach the wider oncology community. OBJECTIVE: Using an oncologist-only question and answer (Q&A) website, we sought to document expert insights from TBs at National Cancer Institute-designated Comprehensive Cancer Centers (NCI-CCCs) to provide educational benefits to the oncology community. METHODS: We designed a process with the NCI-CCCs to document and share discussions from the TBs focused on areas of practice variation on theMednet, an interactive Q&A website of over 13,000 US oncologists. The faculty translated the TB discussions into concise, non-case-based Q&As on theMednet. Answers were peer reviewed and disseminated in email newsletters to registered oncologists. Reach and engagement were measured. Following each Q&A, a survey question asked how the TB Q&As impacted the readers' practice. RESULTS: A total of 23 breast, thoracic, gastrointestinal, and genitourinary programs from 16 NCI-CCC sites participated. Between December 2016 and July 2021, the faculty highlighted 368 questions from their TBs. Q&As were viewed 147,661 times by 7381 oncologists at 3515 institutions from all 50 states. A total of 277 (75%) Q&As were viewed every month. Of the 1063 responses to a survey question on how the Q&A affected clinicians' practices, 646 (61%) reported that it confirmed their current practice, 163 (20%) indicated that a Q&A would change their future practice, and 214 (15%) reported learning something new. CONCLUSIONS: Through an online Q&A platform, academics at the NCI-CCCs share knowledge outside the walls of academia with oncologists across the United States. Access to up-to-date expert knowledge can reassure clinicians' practices, significantly impact patient care in community practices, and be a source of new knowledge and education.

Association Between Genetic Testing for Hereditary Breast Cancer and Contralateral Prophylactic Mastectomy Among Multiethnic Women Diagnosed With Early-Stage Breast Cancer.

PURPOSE: Increasing usage of multigene panel testing has identified more patients with pathogenic or likely pathogenic (P or LP) variants in low-moderate penetrance genes or variants of uncertain significance (VUS). Our study evaluates the association between genetic test results and contralateral prophylactic mastectomy (CPM) among patients with breast cancer. METHODS: We conducted a retrospective cohort study among women diagnosed with unilateral stage 0-III breast cancer between 2013 and 2020 who underwent genetic testing. We examined whether genetic test results were associated with CPM using multivariable logistic regression models. RESULTS: Among 707 racially or ethnically diverse women, most had benign or likely benign (B or LB) variants, whereas 12.5% had P or LP and 17.9% had VUS. Racial or ethnic minorities were twice as likely to receive VUS. Patients with P or LP variants had higher CPM rates than VUS or B or LB (64.8% v 25.8% v 25.9%), and highest among women with P or LP variants in high-penetrance genes (74.6%). On multivariable analysis, P or LP compared with B or LB variants were significantly associated with CPM (odds ratio = 4.24; 95% CI, 2.48 to 7.26). CONCLUSION: Women with P or LP variants on genetic testing were over four times more likely to undergo CPM than B or LB. Those with VUS had similar CPM rates as B or LB. Our findings suggest appropriate genetic counseling and communication of cancer risk to multiethnic breast cancer survivors.

Diagnosis of Leptomeningeal Metastasis in Women With Breast Cancer Through Identification of Tumor Cells in Cerebrospinal Fluid Using the CNSide™ Assay.

INTRODUCTION: Diagnosis of LM is limited by low sensitivity of cerebrospinal fluid (CSF) cytopathology. Detecting tumor cells in CSF (CSF-TCs) might be more sensitive. We evaluated if CNSide (CNSide), a novel assay for tumor cell detection in CSF, can detect CSF-TCs better than conventional CSF cytology. METHODS: We enrolled adults with metastatic breast cancer and clinical suspicion for LM to undergo lumbar puncture (LP) for CSF cytopathology and CNSide. CNSide captured CSF-TCs using a primary 10-antibody mixture, streptavidin-coated microfluidic channel, and biotinylated secondary antibodies. CSF-TCs were assessed for estrogen receptor (ER) expression by fluorescent antibody and HER2 amplification by fluorescent in situ hybridization (FISH). CSF cell-free DNA (cfDNA) was extracted for next-generation sequencing (NGS). Leptomeningeal disease was defined as positive CSF cytology and/or unequivocal MRI findings. We calculated sensitivity and specificity of CSF cytology and CNSide for the diagnosis of LM. RESULTS: Ten patients, median age 51 years (range, 37-64), underwent diagnostic LP with CSF evaluation by cytology and CNSide. CNSide had sensitivity of 100% (95% Confidence Interval [CI], 40%-100%) and specificity of 83% (95% CI, 36%-100%) for LM. Among these patients, concordance of ER and HER2 status between CSF-TCs and metastatic biopsy were 60% and 75%, respectively. NGS of CSF cfDNA identified somatic mutations in three patients, including one with PIK3CA p.H1047L in blood and CSF. CONCLUSIONS: CNSide may be a viable platform to detect CSF-TCs, with potential use as a diagnostic tool for LM in patients with metastatic breast cancer. Additional, larger studies are warranted.

Serial single-cell genomics reveals convergent subclonal evolution of resistance as early-stage breast cancer patients progress on endocrine plus CDK4/6 therapy.

Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for metastatic estrogen receptor positive (ER+) breast cancer patients but its value in earlier stage patients is unclear. We examined evolutionary trajectories of early-stage breast cancer tumors, using single cell RNA sequencing (scRNAseq) of serial biopsies from the FELINE clinical trial (#NCT02712723) of endocrine therapy (letrozole) alone or combined with the CDK inhibitor ribociclib. Despite differences in subclonal diversity evolution across patients and treatments, common resistance phenotypes emerged. Resistant tumors treated with combination therapy showed accelerated loss of estrogen signaling with convergent up-regulation of JNK signaling through growth factor receptors. In contrast, cancer cells maintaining estrogen signaling during mono- or combination therapy showed potentiation of CDK4/6 activation and ERK upregulation through ERBB4 signaling. These results indicate that combination therapy in early-stage ER+ breast cancer leads to emergence of resistance through a shift from estrogen to alternative growth signal-mediated proliferation.

Diffuse optical tomography breast imaging measurements are modifiable with pre-surgical targeted and endocrine therapies among women with early stage breast cancer.

PURPOSE: Diffuse optical tomography breast imaging system (DOTBIS) non-invasively measures tissue concentration of hemoglobin, which is a potential biomarker of short-term response to neoadjuvant chemotherapy. We evaluated whether DOTBIS-derived measurements are modifiable with targeted therapies, including AKT inhibition and endocrine therapy. METHODS: We conducted a proof of principle study in seven postmenopausal women with stage I-III breast cancer who were enrolled in pre-surgical studies of the AKT inhibitor MK-2206 (n = 4) or the aromatase inhibitors exemestane (n = 2) and letrozole (n = 1). We performed DOTBIS at baseline (before initiation of therapy) and post-therapy in the affected breast (tumor volume) and contralateral, unaffected breast, and measured tissue concentrations (in µM) of total hemoglobin (ctTHb), oxyhemoglobin (ctO2Hb), and deoxyhemoglobin (ctHHb), as well as water fraction (%). RESULTS: We found consistent decreases in DOTBIS-measured hemoglobin concentrations in tumor volume, with median percent changes for ctTHb, ctHHb, ctO2Hb, and water fraction for the entire cohort of - 27.1% (interquartile range [IQR] 37.5%), - 49.8% (IQR 29.3%), - 33.5% (IQR 47.4%), and - 3.6% (IQR 10.6%), respectively. In the contralateral breast, median percent changes for ctTHb, ctHHb, ctO2Hb, and water fraction were + 1.8% (IQR 26.7%), - 8.6% (IQR 29.3%), + 6.2% (IQR 29.5%), and + 1.9% (IQR 30.7%), respectively. CONCLUSION: We demonstrated that DOTBIS-derived measurements are modifiable with pre-surgical AKT inhibition and endocrine therapy, supporting further investigation of DOTBIS as a potential imaging assessment of response to neoadjuvant targeted therapies in early stage breast cancer.

Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer.

PURPOSE: Preclinical data demonstrate STAT3 as an important regulator in HER2+ tumors, and disruption of the IL6-JAK2-STAT-S100A8/S100A9 signaling cascade reduces HER2+ cell viability. Ruxolitinib is an FDA approved inhibitor of JAK1 and JAK2. We performed a phase I/II trial investigating the safety and efficacy of the combination of trastuzumab and ruxolitinib in patients with trastuzumab-resistant metastatic HER2+ breast cancer. METHODS: Patients with metastatic HER2+ breast cancer progressing on at least 2 lines of HER2-directed therapy were eligible. The phase I portion determined the tolerable dose of ruxolitinib in combination with trastuzumab. The primary objective of the phase II was to assess the progression free survival (PFS) of the combination of ruxolitinib plus trastuzumab compared to historical control. RESULTS: Twenty-eight patients were enrolled, with a median number of prior therapies of 4.5. Ruxolitinib 25 mg twice daily was the recommended phase II dose with no dose limiting toxicities (DLTs). Of 26 evaluable patients in phase II, the median PFS was 8.3 weeks (95% CI 7.1, 13.9). Among the 14 patients with measurable disease, 1 patient had a partial response and 4 patients had stable disease. Most of the adverse events were hematologic. CONCLUSION: While well tolerated with a strong preclinical rationale, the combination of ruxolitinib and trastuzumab did not lead to an improvement in PFS compared to historical control in patients with trastuzumab-resistant metastatic HER2+ breast cancer.

Patient Knowledge and Expectations About Return of Genomic Results in a Biomarker-Driven Master Protocol Trial (SWOG S1400GEN).

PURPOSE: Biomarker-driven master protocols represent a new paradigm in oncology clinical trials, but their complex designs and wide-ranging genomic results returned can be difficult to communicate to participants. The objective of this pilot study was to evaluate patient knowledge and expectations related to return of genomic results in the Lung Cancer Master Protocol (Lung-MAP). METHODS: Eligible participants with previously treated advanced non-small-cell lung cancer were recruited from patients enrolled in Lung-MAP. Participants completed a 38-item telephone survey ≤ 30 days from Lung-MAP consent. The survey assessed understanding about the benefits and risks of Lung-MAP participation and knowledge of the potential uses of somatic testing results returned. Descriptive statistics and odds ratios for associations between demographic factors and correct responses to survey items were assessed. RESULTS: From August 1, 2017, to June 30, 2019, we recruited 207 participants with a median age of 67, 57.3% male, and 94.2% White. Most participants "strongly/somewhat agreed" with statements that they "received enough information to understand" Lung-MAP benefits (82.6%) and risks (69.5%). In items asking about potential uses of Lung-MAP genomic results, 87.0% correctly indicated that the results help to select cancer treatment, but < 20% correctly indicated that the results are not used to confirm cancer diagnosis, would not reveal risk of developing diseases besides cancer, and would not indicate if family members had increased cancer risk. There were no associations between sociodemographic factors and proportions providing correct responses. CONCLUSION: In a large National Clinical Trials Network biomarker-driven master protocol, most participants demonstrated incorrect knowledge and expectations about the uses of genomic results provided in the study despite most indicating that they had enough information to understand benefits and risks.

Phase II study of propranolol feasibility with neoadjuvant chemotherapy in patients with newly diagnosed breast cancer.

PURPOSE: Propranolol regulates angiogenesis in pre-clinical models and reduces distant breast cancer (BC) metastases in observational studies. We assessed the feasibility of combining propranolol with neoadjuvant chemotherapy (NAC) in patients with BC. METHODS: Women with clinical stage II-III BC undergoing NAC [weekly paclitaxel × 12, followed by dose-dense adriamycin/cyclophosphamide (AC) × 4] started propranolol 20 mg PO BID with paclitaxel #1, and increased to 80 mg extended release (ER) PO daily, as tolerated. The primary endpoint was to assess feasibility, defined as at least 75% of patients having at least 80% adherence to propranolol as prescribed. Secondary endpoints included identifying safety, rate of dose holds and modification, and rate of reaching 80 mg ER daily. The proposed sample size was 20 patients. RESULTS: From November 2012 to September 2015, ten patients were enrolled. Median age was 50.5 years (range, 44-67). All patients had hormone receptor-positive/HER2-negative breast cancer. Three women had grade I bradycardia that resulted in a 1-week delay in increasing the propranolol dose. Ninety percent of women reached the target propranolol dosing of 80 mg ER daily, and 70% took the target propranolol dose until the night before surgery. Of the 4 women who dose-reduced propranolol, 1 increased to the target propranolol dose. Mean adherence to propranolol dosing was 96% (range: 91-100%). All patients went to surgery. CONCLUSION: Our results support the feasibility of combining propranolol (up to 80 mg ER) with neoadjuvant taxane/anthracycline-based chemotherapy.