Bardia, Aditya

ImportanceCytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.ObjectiveTo determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.ExposuresImmunosuppression due to therapy; systemic anticancer therapy (IO or non-IO).Main Outcomes and MeasuresThe primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm.ResultsThe median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79).Conclusions and RelevanceThis cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm.Trial RegistrationClinicalTrials.gov Identifier: NCT04354701

Abstract Background: Two PARP inhibitors are approved for germline BRCA1/2 mutant metastatic breast cancer (MBC), based on clinical trials demonstrating an improvement in patient outcomes and quality of life. However, germline BRCA1/2 mutations are identified in 5-10% of breast cancer, limiting their potential applicability. Our prior work demonstrated that somatic BRCA1/2 mutations can be detected in cell-free DNA (cfDNA) in a proportion of patients with MBC who are not germline BRCA1/2 carriers, and that a PARP inhibitor caused growth inhibition in a circulating tumor cell line generated from a patient with MBC and a pathogenic somatic BRCA1 mutation (Vidula, Dubash, CCR, 2020). Thus, we hypothesize that a PARP inhibitor may have efficacy in somatic BRCA1/2 mutant MBC identified by cfDNA. Trial Design: This phase II investigator initiated open label clinical trial is enrolling 30 patients who have pathogenic somatic BRCA1/2 mutations found in cfDNA. Patients must not be known germline BRCA1/2 carriers. Patients receive treatment with the PARP inhibitor, talazoparib, until disease progression. Serial imaging (CT chest, abdomen, pelvis, and bone scan) occurs every 3 months, and cfDNA is collected monthly to evaluate changes in the genomic environment. Patients will also have blood collected at baseline for the Cancer Risk B assay (CR-B), a novel flow variant assay to assess double strand break repair mutations in circulating blood cells (Syeda, Genetics, 2017). Eligibility criteria: Patients with MBC (TNBC with ≥ 1 prior chemotherapy or HR+/HER2- with ≥ 1 prior hormone therapy or ineligible for hormone therapy) with a somatic BRCA1/2 mutation identified in cfDNA (established pathogenic variant) are being enrolled. Patients should not be known germline BRCA1/2 carriers (genetic testing is not required but can be obtained per physician discretion) and may not have previously received a PARP inhibitor. There is no limit on the number of prior therapies, and a prior platinum chemotherapy is allowed in the absence of disease progression on the platinum. Patients must have adequate performance status and organ function. Specific Aims: The primary endpoint is progression-free survival (PFS) using RECIST 1.1. Secondary endpoints include objective response rate and toxicity (NCI CTCAE v 5.0). Exploratory objectives include evaluating serial changes in BRCA1/2 mutant allelic frequency in cfDNA, evaluating the impact of BRCA1/2 reversion mutations, comparing pre- and post-treatment cfDNA results to identify markers of resistance, evaluating the CR-B assay positivity rate, and ultimately correlating these analyses with treatment response. Statistical Methods: A two-stage design with 80% power to demonstrate that talazoparib is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha) is being used. Accrual: This study (NCT03990896) is currently open at Massachusetts General Hospital, where 4 patients are completing screening for enrollment. This study will be activated soon at the University of California San Francisco, MD Anderson, Mayo Clinic Rochester and Jacksonville, Northwestern, and Emory (7 academic centers). Funding: Support for this study is provided by a Pfizer ASPIRE award and Conquer Cancer Foundation of ASCO–Breast Cancer Research Foundation- Career Development Award. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu Citation Format: Neelima Vidula, Erica Blouch, Erin Basile, Nathan Royce Ruffle-Deignan, Nora Horick, Senthil Damodaran, Alvaro Moreno Aspitia, Manali Bhave, Ami Shah, Minetta C. Liu, Joseph Sparano, Harry Ostrer, Hope Rugo, Leif W. Ellisen, Aditya Bardia. Phase II study of a PARP inhibitor in metastatic breast cancer with somaticBRCA1/2mutations identified by cell-free DNA: Genotyping based clinical trial [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 OT2-24-03.

TPS1110 Background: PARP inhibitors are approved for the treatment of HER2 negative metastatic breast cancer (MBC) with germline BRCA1/2 mutations, based on phase III studies demonstrating an improvement in progression-free survival (PFS) compared to chemotherapy in this population and better patient reported outcomes (Robson, NEJM, 2017; Litton, NEJM, 2018). However, germline BRCA1/2 mutations account for only 5-10% of breast cancer, limiting the current clinical applicability of PARP inhibitors. Somatic BRCA1/2 mutations are detectable in circulating cell-free DNA (cfDNA) in ̃13.5% of patients with MBC; in pre-clinical models, pathogenic somatic BRCA1/2 mutations have been shown to respond to PARP inhibition (Vidula, CCR, 2020). The purpose of this study is to evaluate the efficacy of talazoparib, a PARP inhibitor, in patients with MBC who have somatic BRCA1/2 mutations detectable in cfDNA, in the absence of a germline BRCA1/2 mutation, which we hypothesize will be effective in this setting. This study may help expand the population of patients with MBC who benefit from PARP inhibitors. Methods: This is an investigator initiated multicenter, single arm, phase II clinical trial studying the efficacy of talazoparib in 30 patients with MBC who have pathogenic somatic BRCA1/2 mutations detected in cfDNA. Patients with MBC who are found to have pathogenic somatic BRCA1/2 mutations detected in cfDNA in the absence of a germline BRCA1/2 mutation are eligible. Patients may have triple negative (with ≥ 1 prior chemotherapy), or hormone receptor positive/HER2 negative breast cancer (with ≥ 1 prior hormone therapy). Patients may have received any number of prior lines of chemotherapy, including a prior platinum (in the absence of progression). They must have adequate organ function and ECOG performance status ≤2, and should not have previously received a PARP inhibitor. Patients are treated with talazoparib 1 mg daily until disease progression or intolerability, with serial imaging using CT chest/abdomen/pelvis and bone scan performed at baseline and every 12 weeks, and cfDNA collection every 4 weeks. Primary endpoint is PFS by RECIST 1.1. Patients are being enrolled in a two-stage design with 80% power to demonstrate that the treatment is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha). Secondary endpoints include objective response rate and safety (NCI CTCAE v 5.0). Exploratory analyses include studying serial changes in cfDNA BRCA1/2 mutant allelic frequency and comparing pre-and post-treatment cfDNA for the emergence of BRCA1/2 reversion and resistance mutations. This study is activated and open at Massachusetts General Hospital, where 2 patients are completing screening. It is also opening soon at 6 other academic centers (NCT03990896). Grant support includes a Pfizer ASPIRE award and 2020 Conquer Cancer Foundation of ASCO – Breast Cancer Research Foundation – Career Development Award. Clinical trial information: NCT03990896 .

4044 Background: To aid in decisions regarding adjuvant therapy (AT) for resected high-risk CC, two prog models are in common use: the Mayo Clinic NUM calculator developed from a pooled data analysis of 7 randomized 5FU-based AT trials, and ADJ! developed using SEER data. This study examines the accuracy of NUM and ADJ! utilizing a cohort of patients (pts) referred to the BC Cancer Agency (BCCA). Methods: Demographic, disease and treatment data for pts with stage II/III CC referred to the BCCA from 1995–1996 + 1999–2003 were collected. Observed (obs) 5-year relapse free survival (RFS) and overall survival (OS) were compared to predicted estimates (pred) using NUM and ADJ!, both overall and for all prog subgroups with ≥ 10pts, as stratified by T stage, N stage, tumor grade and age. Data are presented in a descriptive manner and using confidence intervals. Results: Median follow-up was 5.6 yrs for 2,033 pts - 53% male, median age 68y, 40% N0. The mean percentages of 5 year pred outcomes for each of the two models and the actual Kaplan Meier mean survivals are presented in the table . The percentage correct predictions of 5 y status is also presented, with correctness deemed accurate if the pt was alive and predicted to be alive by ≥ 50% as determined by each model or dead while the respective tool predicted < 50% possibility of being alive. For surgery alone pts, ADJ!pred were more often closer to what was observed, as compared to NUMpred, in the prog subgroups (for RFS 56%, OS 88%). For surgery + 5-FU pts, within these subgroups, NUMpred were more often closer to what was observed, as compared to ADJ!pred, for RFS (62%) and for OS (55%). Conclusions: In this independent population-based validation, NUM and ADJ! have acceptable and similar reliability with modest over-estimations of 5y RFS and OS. Both models thus appear to be useful adjuvant decision-aids. [Table: see text] No significant financial relationships to disclose.

e15031 Background: Two web based prognostic calculators, Adjuvant! and Numeracy (JCO 22:1797–1806, 2004) are widely used to provide individual patient outcome predictions to aid decisions regarding adjuvant therapy for colon cancer. The comparability of these tools has not been studied yet. The aim of this project was to assess whether the Numeracy and Adjuvant! Colon cancer prognostic tools produced similar results for patients with resected stage II and III colon cancer based on a set of hypothetical patients. Methods: All possible hypothetical scenarios were formulated for the Numeracy calculator based on all potential combinations of age, lymph nodes status, tumor stage, and grade of tumor. These were applied to three post- surgical therapy choices: observation, 5-FU (5-fluorouracil), or FOLFOX (5-FU, leucovorin and oxaliplatin). Predictions for these hypothetical scenarios (N= 192 for males and 192 for females) were also entered into the Adjuvant! Program. Predicted relapse free survival (RFS) and overall survival (OS) were obtained using both calculators. Wilcoxon signed rank tests were used to compare the numerical predictions between the calculators for each outcome. Results: In the majority of the 384 hypothetical patient scenarios, predictions for RFS and OS from Adjuvant! were statistically significantly higher than from Numeracy (p value < 0.05), except for age≥70 for FOLFOX, and the number of positive nodes of 0 and 1–4 using FOLFOX, among males. The net estimate of benefit for RFS and OS for 5-FU over surgery, obtained from Adjuvant! and Numeracy, were similar (for both males and females), but the benefit in RFS and OS for FOLFOX over 5-FU obtained from Adjuvant! was significantly lower than the estimate obtained from Numeracy (p value < 0.05). Conclusions: Based on a hypothetical set of patients with resected stage II and III colon cancer, the estimated benefit in RFS and OS of FOLFOX over 5-FU based chemotherapy is lower in Adjuvant! than in the Numeracy tool (but benefit for 5-FU over surgery alone is similar). Further studies are needed to clarify the discrepancy and to assess which of these tools most accurately reflects actual patient outcome. No significant financial relationships to disclose.

1002 Background: Physical activity is a modifiable breast cancer risk factor, perhaps mediating risk reduction through regulation of estrogen metabolism. Evidence regarding effect of physical activity is conflicting partly because breast cancer is a heterogenous constellation of different tumor subtypes with differing etiologies. No prospective study has examined the relationship between physical activity and breast cancer incidence based on ER/PR status or histological subtype. Objective: Examine effect of physical activity on breast cancer incidence based on ER/PR status and histological subtypes of breast cancer. Methods: The Iowa Women’s Health Study is a prospective cohort study of postmenopausal women (N=41,837). Physical activity was self-reported on baseline questionnaire, and three levels (high, medium and low) were defined. Breast cancer incidence, histologic subtype and ER/PR status, through 18 years of follow-up, were ascertained by linkage with the Iowa SEER Cancer Registry. Cox proportional hazards models were used to estimate multivariate relative risks (RRs) and 95% confidence intervals (CIs) of breast cancer, adjusting for other breast cancer risk factors. Results: During 554,819 person-years of follow-up, 2548 incident cases of breast cancer were observed. High physical activity was associated with decreased risk for breast cancer (RR 0.91, 95 % CI 0.81–1.01) compared to low activity. The protective effect was most marked in ER+/PR− (RR 0.66, CI 0.46–0.94), intermediate in ER−/PR− (RR 0.80, CI 0.56–1.15), weakest in ER+/PR+ (RR 0.94, CI 0.81–1.08), and elevated in ER-/PR+ (RR 1.42, CI 0.67–3.01) tumors. Higher physical activity was also associated with a decreased risk of invasive ductal/lobular carcinoma (RR 0.90, CI 0.80–1.02), but not with invasive breast cancer with a favorable histology (RR 1.19, CI 0.78–1.81). Conclusions: Higher physical activity was associated with a 10% decreased risk of breast cancer. Unexpectedly, risk reduction was most marked in PR- tumors, particularly ER+/PR-, and the more aggressive histologic forms. Further studies are needed to confirm these findings, and also evaluate other risk factors based on ER/PR status and histological subtypes. No significant financial relationships to disclose.

Abstract Background: Obesity has been associated with risk of non-Hodgkin lymphoma (NHL) in several recent studies. However, the effect of weight gain during adulthood, a potentially modifiable risk factor, on the incidence of NHL is not clear. We therefore examined the association of weight gain since age 18 years with the risk of NHL among older women. Methods: We examined this association in the Iowa Women’s Health Study, a prospective study of 37,762 Iowa women aged 55 to 69 years at enrollment in 1986. Lifestyle and other risk factors, including weight at age 18 and at enrollment, were self-reported on a mailed questionnaire. We defined stable weight as no increase in weight or up to a 10% weight loss from age 18 to enrollment, while percent weight gain was divided into tertiles based on the distribution observed in the cohort. NHL incidence through 18 years of follow-up was ascertained by linkage with the Iowa SEER Cancer Registry. Cox proportional hazards models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) of percent weight gain with NHL incidence, adjusting for age (Age-adjusted model) and age, marital status, farm residence, transfusion history, diabetes, use of hormone replacement therapy, alcohol use, smoking, and intake of red meat and fruits (Multivariate model). Results: The mean age of the women in the cohort in 1986 was 62.1 years. During 593,474 person-years of follow-up, 379 incident cases of NHL were observed. The mean age at diagnosis was 72.6 years (range 58–87 years). The main results are reported in the table. Similar results were found for absolute weight gain. Stratification of these results on body mass index at age 18 (using a cutpoint of 21 kg/m2) showed similar results, with the exception of >10% weight loss for women with a BMI of <21 at age 18 where we could not estimate a RR (no cases observed). Conclusions: Weight gain or large weight loss (>10% of body weight) during adulthood were both associated with increased risk of NHL, although the RRs for percent weight gain were not statistically significant and there was no dose-response. This study suggests another potential benefit of avoiding adult weight gain, although further studies are needed to confirm these novel findings. Association of percent weight change during adulthood (age 18 to age 55–69 years) and risk of NHL % Weight Change NHL Cases Person-years Age-Adjusted RR(95% CI) Multivariate RR (95% CI) >10% weight loss 15 17053 2.06 (1.05–4.02) 2.02 (1.03–3.95) Stable 20 45973 1 (reference) 1 (reference) 0–18.2% gain 115 175883 1.50 (0.94–2.42) 1.50 (0.93–2.41) 18.3–34.8% gain 119 176258 1.54 (0.96–2.47) 1.53 (0.95–2.47) >34.8% gain 110 178308 1.40 (0.87–2.25) 1.32 (0.82–2.14).