Jeremy Force

PURPOSE: To examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAT). PATIENTS AND METHODS: We identified responders (RCB-0/1) and matched non-responders (RCB-2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel vs. cisplatin in TNBC. We collected plasma samples at baseline, three weeks, and twelve weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence. RESULTS: Of 139 patients, 68 had complete samples and no additional NAT. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3, and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10 -4 (range: 7.9 × 10 -7 to 4.9 × 10 -1 ). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10/11 patients with RCB-0, 3/8 with RCB-1, 4/15 with RCB-2, and 0/4 with RCB-3. Among 6 patients with known recurrence five had persistent ctDNA at week 12. CONCLUSION: NAT for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine if ctDNA-guided approaches can improve outcomes.

Therapeutic cancer vaccines, designed to activate immune effectors against tumor antigens, utilize a number of different platforms for antigen delivery. Among these are messenger RNAs (mRNA), successfully deployed in some prophylactic SARS-CoV2 vaccines. To enhance the immunogenicity of mRNA-delivered epitopes, self-replicating RNAs (srRNA) that markedly increase epitope expression have been developed. These vectors are derived from positive-strand RNA viruses in which the structural protein genes have been replaced with heterologous genes of interest, and the structural proteins are provided in trans to create single cycle viral replicon particles (VRPs). Clinical stage srRNA vectors have been derived from alphaviruses, including Venezuelan Equine Encephalitis (VEE), Sindbis, and Semliki Forest virus (SFV) and have encoded the tumor antigens carcinoembryonic antigen (CEA), human epidermal growth factor receptor 2 (HER2), prostate specific membrane antigen (PSMA), and human papilloma virus (HPV) antigens E6 and E7. Adverse events have mainly been grade 1 toxicities and minimal injection site reactions. We review here the clinical experience with these vaccines and our recent safety data from a study combining a VRP encoding HER2 plus an anti-PD1 monoclonal antibody (pembrolizumab). This experience with VRP-based srRNA supports recent development of fully synthetic srRNA technologies, where the viral structural proteins are replaced with protective lipid nanoparticles (LNP), cationic nanoemulsions or polymers.

Atezolizumab with chemotherapy has shown improved progression-free and overall survival in patients with metastatic PD-L1 positive triple negative breast cancer (TNBC). Atezolizumab with anthracycline- and taxane-based neoadjuvant chemotherapy has also shown increased pathological complete response (pCR) rates in early TNBC. This trial evaluated neoadjuvant carboplatin and paclitaxel with or without atezolizumab in patients with clinical stages II-III TNBC. The co-primary objectives were to evaluate if chemotherapy and atezolizumab increase pCR rate and tumor infiltrating lymphocyte (TIL) percentage compared to chemotherapy alone in the mITT population. Sixty-seven patients (ages 25-78 years; median, 52 years) were randomly assigned - 22 patients to Arm A, and 45 to Arm B. Median follow up was 6.6 months. In the modified intent to treat population (all patients evaluable for the primary endpoints who received at least one dose of combination therapy), the pCR rate was 18.8% (95% CI 4.0-45.6%) in Arm A, and 55.6% (95% CI 40.0-70.4%) in Arm B (estimated treatment difference: 36.8%, 95% CI 8.5-56.6%; p = 0.018). Grade 3 or higher treatment-related adverse events occurred in 62.5% of patients in Arm A, and 57.8% of patients in Arm B. One patient in Arm B died from recurrent disease during the follow-up period. TIL percentage increased slightly from baseline to cycle 1 in both Arm A (mean ± SD: 0.6% ± 21.0%) and Arm B (5.7% ± 15.8%) (p = 0.36). Patients with pCR had higher median TIL percentages (24.8%) than those with non-pCR (14.2%) (p = 0.02). Although subgroup analyses were limited by the small sample size, PD-L1-positive patients treated with chemotherapy and atezolizumab had a pCR rate of 75% (12/16). The addition of atezolizumab to neoadjuvant carboplatin and paclitaxel resulted in a statistically significant and clinically relevant increased pCR rate in patients with clinical stages II and III TNBC. (Funded by National Cancer Institute).

PURPOSE: SOLAR-1 investigated alpelisib-fulvestrant (ALP + FLV) in patients with HR + /HER2-, PIK3CA-mutated advanced breast cancer and demonstrated a clinically significant increase in all-grade and grade (G) 3-4 hyperglycemia (HG) compared to placebo-fulvestrant. Given high rates of HG, a preventative protocol and identification of associated risk factors was implemented. METHODS: This single-center, retrospective study included patients receiving ALP + FLV. One week before ALP initiation, patients started an insulin-sensitizer. Patients had fasting plasma glucose (FPG) levels drawn day 8, 15, 28, then monthly. Primary outcome was incidence of G2-4 HG by day 28. Risk factors assessed included age, BMI, FPG, and HbA1c. Number of risk factors were compared between patients with and without HG. RESULTS: Sixteen women were included with median age of 59 years. The cohort was 69% White, 25% Black, 75% with BMI ≥ 25 kg/m2, and 50% with history of diabetes. By day 28, 9 patients (56%) had G2-4 HG, with only 3 (19%) G3 and zero G4. Patients with G2-4 HG had a median of 2 risk factors compared to only 1 if no HG (p = 0.03). 5 patients (31%) required a temporary hold of ALP and 3 (19%) required dose reduction due to HG. 13 patients permanently discontinued ALP-9 due to disease progression and 4 from an adverse event (only 1 HG). CONCLUSION: Implementation of a HG prophylaxis protocol with ALP in a single-center study demonstrated fewer G3-4 HG events compared to that seen in SOLAR-1 (19% vs 36.6%). An increase in HG-associated risk factors correlated with a higher incidence of G2-4 HG.

<jats:title>Abstract</jats:title> <jats:p>Background: During the COVID pandemic, we designed and implemented a program, called BQual-D, to maintain high quality care for patients with HR+, HER2 negative MBC who were taking oral anti-cancer therapy and needed to shelter at home. This program augmented available clinical resources with (1) trained nurse coaches to manage side effects, improve adherence, monitor for cancer progression and screen for psychological distress via telehealth, and (2) a care coordinator to arrange blood testing at local labs to facilitate timely medication dose adjustments. BQual-D served patients from August, 2020 through April of 2021. Here, we describe survey results assessing provider satisfaction with BQual-D. Methods: Surveys assessing provider satisfaction were distributed in December, 2020 (Survey#1) and in April, 2021 (Survey#2). Provider demographics were collected with Survey#1. Eight questions assessed satisfaction with different aspects of the BQual-D program, including content of the nurse coach notes, communication with the program, timeliness of communication, frequency of notes, ease of reading the notes, ease of referring patients, and turnaround time for labs, which were rated on a Likert scale of 1 (strongly dissatisfied) to 10 (strongly satisfied), with an additional response choice of 0 (unable to assess). Providers were also asked if BQual-D led to changes in patient management (yes/no), the degree to which BQual-D supported the medical management of the patient (from 1=not at all to 7=significantly), the influence of BQual-D on patient wellbeing (positive effects, no change, negative effects), and the overall quality of care delivered by the program (from 1=excellent to 4=poor). Finally, we asked providers if they would continue to recommend their patients to BQual-D (yes, in the same way as the program has been deployed; yes but with improvements; or no). Results are described by frequencies and means. Results: Nineteen providers responded to Survey#1. Providers were physicians (31.6%), advanced practice providers (31.6%), nurses (31.6%) and a clinical pharmacist (5.3%). Respondents were 89.5% female, 94.7% White, and had a mean age of 44 years and mean 11 years in practice. Providers rated the quality of care provided by the BQual-D program as excellent (44%) or good (57%), all providers surveyed indicated that they would continue to recommend the program to patients, and 95% of providers indicated that the program had a positive effect on patients’ well-being. Half of the respondents indicated that BQual-D resulted in changes in or addition to patient management and 90% indicated that BQual-D significantly supported medical management. Providers were strongly satisfied (scores of 8-10 on the Likert scale) with overall communication with the BQual-D team (74%) and timeliness of communications (79%). Providers were also strongly satisfied with the content (68.4%), frequency (74%), and ease of reading (68%) program notes. Seven providers completed Survey#2, in which providers rated the overall quality of the program as excellent (57%) or good (43%); 86% indicated that they would continue to recommend the program to patients, and 86% indicated that the program had a positive effect on patients’ well-being. Conclusions: During the COVID pandemic, when sheltering at home was encouraged, provider satisfaction with BQual-D, which provided additional health resources (nurse coaches, care coordinator) to support patients on oral therapy for HR+ MBC, was high. Resources needed to implement BQual-D should be explored as a way of providing additional support for patients and providers in order to minimize the requirement for in-person visits. Funding: Supported by a grant from Pfizer.</jats:p> <jats:p>Citation Format: Gretchen Kimmick, Smrithi Davakaran, Heather Moore, Cynthia Rose, Pamela Gentry, Michael Willis, Susan Dent, Sarah Sammons, Jeremy Force, Kelly Westbrook, Carey Anders, Rebecca Shelby. Best quality care from a distance (BQual-D): Maintaining high quality care for hormone receptor positive (HR+) metastatic breast cancer (MBC) during the COVID pandemic, description of the program and provider satisfaction [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-06.</jats:p>