4012 Background: Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. The POLAR trial demonstrated promising results combining pembrolizumab with olaparib as maintenance therapy in patients (pts) with homologous recombination deficiency (HRD) mutations. S2001 is a randomized phase II trial evaluating the addition of pembrolizumab to olaparib as maintenance therapy in patients with gBRCA1/2. Methods: Eligible pts had mPDA with gBRCA1/2 mutations and had received a minimum of 4 months of platinum-based chemotherapy without progression. Pts were randomized 1:1 to olaparib 300 mg twice per day plus pembrolizumab 200 mg every 3 weeks or olaparib alone. The primary endpoint was progression-free survival (PFS) with a target hazard ratio (HR) of 0.6 (median PFS 7.0 vs 11.7 months) with 1-sided alpha=0.1 and 80% power. Secondary outcomes were safety and tolerability, overall survival (OS), overall response rate (ORR), and disease control rate (DCR). The accrual goal was 88 pts to have 78 eligible for analysis. Differences in PFS by treatment arm were assessed via stratified log-rank test, with first line platinum-based chemotherapy, Zubrod PS, and disease status after first line treatment as stratification factors. Tissue and blood samples for correlative studies were banked. Results: The study enrolled 73 patients, with 68 eligible, and was closed for futility after a planned interim analysis showed that PFS was not improved in the pembrolizumab + olaparib arm (p=0.82), despite higher ORR (p=0.20) (Table). Treatment was well tolerated, with no grade 4-5 treatment-related adverse events and similar toxicity profiles across arms. Autoimmune toxicities on the experimental arm included adrenal insufficiency, hyperthyroidism, and hypothyroidism. Grade 3 adverse events in both arms included neutropenia, anemia, thrombocytopenia, gastrointestinal toxicity and fatigue. Conclusions: S2001 is the first randomized controlled trial evaluating the addition of pembrolizumab to olaparib in pancreas cancer. Despite doubling the ORR and improvement in DCR and PFS in the experimental arm, the high bar of improving PFS to 11.7 months was not met. Activity seen in the experimental arm of S2001 is comparable to the HRD cohort of the POLAR trial which demonstrated ORR 35%, DCR 90% and PFS of 8.2 months. Further follow-up for mature survival outcomes and translational analysis of DNA and RNA are planned. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819 with additional support from by Merck & Co, Inc. Clinical trial information: NCT04548752 . Pembrolizumab + Olaparib (n=34) Olaparib (n=34) Median PFS 8.2 months 6.4 months Median OS 20.0 months 22.1 months ORR 28.1% 14.3% DCR 84.4% 64.3%

PURPOSE ERBB2 overexpression/amplification in RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC; human epidermal growth factor receptor 2 [HER2]-positive mCRC) appears to be associated with limited benefit from anti-EGFR antibodies and promising responses to dual-HER2 inhibition; however, comparative efficacy has not been investigated. We conducted a randomized phase II trial to evaluate efficacy and safety of dual-HER2 inhibition against standard-of-care anti-EGFR antibody–based therapy as second/third-line treatment in HER2-positive mCRC. METHODS Patients with RAS/BRAF -WT mCRC after central confirmation of HER2 positivity (immunohistochemistry 3+ or 2+ and in situ hybridization amplified [HER2/CEP17 ratio >2.0]) were assigned (1:1) to either trastuzumab plus pertuzumab (TP; trastuzumab 6 mg/kg and pertuzumab 420 mg once every 3 weeks) or cetuximab plus irinotecan (CETIRI; cetuximab 500 mg/m 2 and irinotecan 180 mg/m 2 once every 2 weeks) until progression or unacceptable toxicity. Crossover to TP was allowed after progression on CETIRI. The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival, safety, and HER2 gene copy number (GCN ≥20/<20) as a predictive factor. RESULTS Between October 2017 and March 2022, 54 participants were assigned to TP (n = 26) and CETIRI (n = 28). Median PFS did not vary significantly by treatment: 4.7 (95% CI, 1.9 to 7.6) and 3.7 (95% CI, 1.6 to 6.7) months in the TP and CETIRI groups, respectively. Efficacy of TP versus CETIRI differed significantly by HER2 GCN (median PFS, GCN ≥20 [9.9 v 2.9 months] and GCN <20 [3.0 v 4.2 months], respectively; P interaction = .003). On TP, ORR was 34.6% (57.1% with GCN ≥20 v 9.1% with GCN <20) with median GCN of 29.7 versus 13.2 for responders and nonresponders, respectively ( P = .004). Grade ≥3 adverse events occurred in 23.1% and 46.1% of participants with TP and CETIRI, respectively. CONCLUSION TP appears to be a safe and effective cytotoxic chemotherapy-free option for patients with RAS/BRAF -WT, HER2-positive mCRC. Higher levels of HER2 amplification were associated with greater degree of clinical benefit from TP vis-à-vis CETIRI.

Background: Chemotherapy is required to improve the overall survival (OS) of patients with resectable pancreatic ductal adenocarcinoma (PDAC). Assessing the impact of chemotherapy dose density (DD) on survival is difficult as a result of confounding. The objective of this study was to determine the impact of chemotherapy DD on OS in patients with resectable PDAC. Methods: This was a secondary analysis of SWOG 1505, a randomized phase 2 trial of perioperative chemotherapy in resectable PDAC. DD was defined as the percentage of chemotherapy dose received of the total planned. Two landmark time points for OS were used: after surgery and at 40 weeks (which encompassed the entire treatment period). Results: Of the 102 eligible patients enrolled, 73 (71%) underwent surgery, and median preoperative chemotherapy DD was 89%. Patients with >= 85% DD had higher OS compared to those with <85% DD (median, 38.1 vs. 17.2 months; p = .039). Of the 82 patients who survived to 40 weeks postrandomization, 67 underwent surgery, and median DD for all perioperative chemotherapy was 67%. In this cohort, DD >= 70% was associated with better OS (median, 32.2 vs. 14.0 months; p = .017). Perioperative DD was not significantly associated with pathologic response, margin status, or lymph node negativity. Conclusions: This is the first study to identify a prognostic association of chemotherapy DD with OS in patients undergoing perioperative chemotherapy and surgery for resectable PDAC. Patients who received >= 85% DD preoperatively and/or >= 70% DD perioperatively survived longer than those receiving a smaller proportion of protocol therapy.

Table S3. Sensitivity analysis of the association between plasma 25-hydroxyvitamin level and disease-free survival, overall survival, and time to recurrence, excluding patients who recurred or died within three months of blood collection

Figure S2. Dose-response relationship and test of linearity for the hazard ratio (HR) of disease-free survival (A), overall survival (B), and time to recurrence (C) by continuous predicted vitamin D scores, with reference of plasma 25-hydroxyvitamin D set at 12 ng/ml

Table S4. Hazard ratio of disease-free survival, overall survival, time to recurrence by quartiles of predicted vitamin D score

TPS311 Background: Approximately 45% of dMMR/MSI-H metastatic colorectal cancer (mCRC) in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC patients (pts) may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF as well as between oxaliplatin/anti-PD-1 in murine CRC models, and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Within the AtezoTRIBE 8-pt dMMR CRC subgroup treated with FOLFOXIRI+bev+atezo, median PFS was not reached, with the first progression event at ~16 mos. Additionally, in other solid tumor malignancies, anti-PD-1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD-1 plus chemotherapy (i.e., gastroesophageal and lung cancers) combinations are standard first-line treatments. Methods: This two-arm prospective phase III open-label trial randomizes (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Key inclusion criteria have been simplified on recent amendments to better mirror clinical practice for pts receiving mFOLFOX6/bev+atezo: One cycle of FOLFOX or CAPOX, with or without bev (or biosimilar) prior to enrollment allowed, dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; pts with total bilirubin ≤4.0 x ULN; duration of therapy for up to two years for both arms; imaging frequency on post-treatment follow-up has been reduced; as has measurable disease per RECIST. Primary endpoint is PFS. Assuming the atezo monotherapy control arm has a 48% PFS at 24 mos as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include overall survival, objective response rate, safety profile, disease control rate, and duration of response. Archived tumor tissue and blood samples will be collected for correlative studies. Harmonization of translational analyses is planned between GI004 (COMMIT) and A021502 (ATOMIC). Sample size has been modified with the accrual goal of 120 pts randomized between the two immunotherapy arms needed for study completion. Enrollment actively continues at U.S. sites. Current accrual (as of 9-20-2024): 100/120. Clinical trial information: NCT02997228 .

Objective Assess the impact of a new website, MyMenoplan.org, on menopause knowledge, decision-making progress, treatment and coping intentions among people experiencing perimenopause and menopause. The website was designed to provide women and their clinicians with comprehensive, evidence-based information and decision-making tools about a broad range of symptoms and treatments, address common questions and facilitate conversations with clinicians when desired. Study design Women were recruited online and randomized to interact with the MyMenoplan.org website created by MsFLASH investigators (n = 200) or control websites (n = 210) for at least 20 min before completing an online survey. Women in the control arm could choose any website(s), including three suggested high-quality websites from governmental or non-profit organizations. Fraud-detection protocols were followed. Outcome differences by arm were estimated via adjusted linear regression models. Primary outcomes Behavioral change intentions, menopause knowledge, decision-making progress, and user website experience. Results 99 % of controls visited at least one recommended website. Compared with the control arm, the MyMenoplan.org arm reported significantly higher levels of intent to change treatment (3.87 vs. 3.61), knowledge of menopause symptoms and treatments (4.17 vs. 3.85), treatment decision-making progress (3.94 vs. 3.71), clarity about benefits and risks of treatments (4.04 vs. 3.81), perceived website quality (4.05 vs. 3.70), intentions to return to the website (4.40 vs. 3.97), and likelihood of recommending it to others (4.35 vs. 4.04; each p < 0.001). Conclusion MyMenoplan.org is the first NIH-funded website shown to be effective in helping women learn and make decisions about management of the menopause transition. The website serves as a model for providing much-needed, evidence-based information for health-care providers and women nearing or in perimenopause and menopause.Clinical Trial Registration Number: ClinicalTrials.gov ID NCT05299983

TPS793 Background: Olaparib was approved in 2019 as maintenance therapy for gBRCA1/2+ metastatic pancreatic cancer (mPDA) patients (pts). The POLO trial showed an improvement in median progression-free survival (mPFS) with olaparib compared to placebo (7.4 vs 3.8 months) for platinum sensitive gBRCA1/2+ mPDA pts. Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. Results of the phase 2 pembrolizumab and olaparib (POLAR) maintenance trial in patients with germline or somatic BRCA1/2 or PALB2 mutations responding to platinum-based chemotherapy for at least 4 months was presented at ESMO 2024. In 33 patients, a 35% overall response rate with 90% disease control rate at 6 months was observed. S2001 is an important randomized study to better define the impact of the combination. Methods: S2001 was developed in collaboration with the Alliance and was activated in SWOG in October 2020. Key eligibility criteria include: mPDA pts with gBRCA1/2 mutations identified with standard of care germline genetic testing and progression-free after receiving at least 4 months of platinum-based chemotherapy (FOLFIRINOX, FOLFOX or gemcitabine/cisplatin +/- nab-paclitaxel). One cycle of gemcitabine and nab-paclitaxel is allowed while waiting for germline testing. Zubrod performance status (PS) 0 or 1 pts are eligible. Pts are stratified according to first line chemotherapy, PS 0 vs 1, and disease status after 1st line treatment. The primary objective of this study is to evaluate the PFS of mPDA pts treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy. Based upon the POLO trial, we expect a mPFS of 7 months in the control arm. Targeting a mPFS of 11.7 months in the experimental arm (hazard ratio 0.6) and assuming 15 months follow-up, 80% power and a 1-sided alpha = 0.10, this design requires 78 evaluable pts with a total sample size of 88 pts. Prospective serial blood samples will be collected to bank DNA and RNA for future correlative studies. Support: NIH/NCI grants U10CA180888 and U10CA180819, U10CA180821 and U10CA180868. Clinical trial information: NCT04548752 .

Figure S1. Diagram for study cohort derivation

Table S2. Representativeness of study participants

Table S5. Hazard ratio of cancer-specific mortality by plasma 25-hydroxyvitamin D levels in plasma biomarker companion study and by predicted vitamin D scores in diet and lifestyle companion study

Figure S3. Multivariable hazard ratio and 95% confidence intervals for disease-free survival (A), overall survival (B), and time to recurrence (C), comparing plasma 25-hydroxyvitamin D ≥12 versus <12 ng/ml, across strata of potential effect modifiers

BackgroundSurvivors of rectal cancer experience persistent bowel dysfunction after treatments. Dietary interventions may be an effective approach for symptom management and posttreatment diet quality. SWOG S1820 was a pilot randomized trial of the Altering Intake, Managing Symptoms in Rectal Cancer (AIMS-RC) intervention for bowel dysfunction in survivors of rectal cancer.MethodsNinety-three posttreatment survivors were randomized to the AIMS-RC group (N = 47) or the Healthy Living Education attention control group (N = 46) after informed consent and completion of a prerandomization run-in. Outcome measures were completed at baseline and at 18 and 26 weeks postrandomization. The primary end point was total bowel function score, and exploratory end points included low anterior resection syndrome (LARS) score, quality of life, dietary quality, motivation, self-efficacy, and positive/negative affect.ResultsMost participants were White and college educated, with a mean age of 55.2 years and median time since surgery of 13.1 months. There were no statistically significant differences in total bowel function score by group, with the AIMS-RC group demonstrating statistically significant improvements in the exploratory end points of LARS (p = .01) and the frequency subscale of the bowel function index (p = .03). The AIMS-RC group reported significantly higher acceptability of the study.ConclusionsSWOG S1820 did not provide evidence of benefit from the AIMS-RC intervention relative to the attention control. Select secondary end points did demonstrate improvements. The study was highly feasible and acceptable for participants in the National Cancer Institute Community Oncology Research Program. Findings provide strong support for further refinement and effectiveness testing of the AIMS-RC intervention. In this feasibility and preliminary efficacy randomized trial, the Altering Intake, Managing Symptoms in Rectal Cancer (AIMS-RC) diet modification intervention did not significantly improve total bowel function among survivors of rectal cancer but demonstrated improvements in the frequency of bowel movements and low anterior resection syndrome. SWOG S1820 and the AIMS-RC intervention were highly feasible and acceptable for participants enrolled via the National Cancer Institute Community Oncology Research Program.

OBJECTIVE:In premenopausal individuals, vaginal microbiota diversity and lack of Lactobacillus dominance are associated with greater mucosal inflammation, which is linked to a higher risk of cervical dysplasia and infections. It is not known if the association between the vaginal microbiota and inflammation is present after menopause, when the vaginal microbiota is generally higher-diversity and fewer people have Lactobacillus dominance. METHODS:This is a post hoc analysis of a subset of postmenopausal individuals enrolled in a randomized trial for treatment of moderate-severe vulvovaginal discomfort that compared vaginal moisturizer, estradiol, or placebo. Vaginal fluid samples from 0, 4, and 12 weeks were characterized using 16S rRNA gene sequencing (microbiota) and MesoScale Discovery (vaginal fluid immune markers: IL-1b, IL-1a, IL-2, IL-6, IL-18, IL-10, IL-9, IL-13, IL-8, IP10, MIP1a, MIP1b, MIP3a). Global associations between cytokines and microbiota (assessed by relative abundance of individual taxa and Shannon index for alpha, or community, diversity) were explored, adjusting for treatment arm, using linear mixed models, principal component analysis, and Generalized Linear Mixed Model + Microbiome Regression-based Kernel Association Test (GLMM-MiRKAT). RESULTS:A total of 119 individuals with mean age of 61 years were included. At baseline, 29.5% of participants had a Lactobacillus -dominant vaginal microbiota. Across all timepoints, alpha diversity (Shannon index, P = 0.003) was highly associated with immune markers. Individual markers that were associated with Lactobacillus dominance were similar to those observed in premenopausal people: IL-10, IL-1b, IL-6, IL-8 (false discovery rate [FDR] < 0.01), IL-13 (FDR = 0.02), and IL-2 (FDR = 0.09). Over 12 weeks, change in alpha diversity was associated with change in cytokine concentration (Shannon, P = 0.018), with decreased proinflammatory cytokine concentrations observed with decreasing alpha diversity. CONCLUSIONS:In this cohort of postmenopausal individuals, Lactobacillus dominance and lower alpha diversity were associated with lower concentrations of inflammatory immune markers, as has been reported in premenopausal people. This suggests that after menopause lactobacilli continue to have beneficial effects on vaginal immune homeostasis, despite lower prevalence.

TPS430 Background: Anti-VEGFR2 antibody (ramucirumab) has efficacy in gastric cancer (GC), both as monotherapy & in combination with paclitaxel based on the REGARD & RAINBOW trials that led to its FDA approvals in the 2nd line setting. Preclinical data demonstrate significant tumor immune microenvironment modulatory effects from antiangiogenic agents, supporting the clinical study of dual VEGFR with immune checkpoint blockade. This has resulted in at least 7 FDA-approved combinations of anti-VEGF/VEGFR with anti-PD-1/PD-L1 agents in lung, renal, endometrial & liver cancers. Recent data showed encouraging activity with ramucirumab plus nivolumab & other trials with pembrolizumab and durvalumab in GC & esophageal adenocarcinoma. Notably, the addition of nivolumab to 2nd line ramucirumab plus paclitaxel was evaluated in a multi-center phase I/II trial. Study population consisted of 60% (26/43) harboring tumors positive for PD-L1 CPS ≥ 1. Results revealed encouraging efficacy (ORR 37.2%, 6-month PFS 46.5%) in the overall population. Median PFS and OS were found to be numerically higher in PD-L1 CPS ≥ 1 (6.4 months & 13.8 months respectively) compared to CPS-negative participants (5.1 months & 8.0 months), suggesting a predictive impact of PD-L1 CPS in this treatment setting. Methods: SWOG2303 is a national, randomized, open label, phase II/III trial to assess the efficacy and safety of nivolumab + paclitaxel + ramucirumab versus paclitaxel + ramucirumab in adult patients with advanced stage MSS/pMMR PD-L1 CPS ≥ 1 gastric and esophageal adenocarcinoma. Patients must have documented MSI and PD-L1 CPS status by standard of care tissue-based analysis, evaluable disease on imaging, and Zubrod performance status (PS) 0-1. They should also have clinical or radiographic progression or intolerance to frontline standard of care systemic therapy with PD-1 inhibitor containing fluoropyrimidine based chemotherapy regimen. Patients with HER2 positive disease are excluded as well as patients with prior significant immunotherapy related adverse events (iRAEs) that prompted permanent discontinuation of the PD-1 agent. Planned enrollment is 224. Participants will be randomized using a dynamic balancing algorithm with stratification based on Zubrod PS (0 vs 1), tumor location (gastric vs GEJ or esophageal) and PD-L1 CPS (≥5 vs <5). Primary endpoints are PFS for phase II and OS for phase III. Secondary endpoints include overall response rate, disease control rate, & safety. Baseline and pharmacodynamic changes in cellular and plasma angiogenic, inflammatory, and immune biomarkers will be explored & correlated with the efficacy. Other endpoints include health quality of life measured using the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga). Enrollment is ongoing.

Sub-micrometer size devices are strong candidates for future use as probes of quantum fluids. They can be reproducibly manufactured with resonant frequencies in the range of kilohertz to gigahertz and have low power consumption and dissipation. Here, we present doubly clamped aluminum nanobeams of lengths from 15 mu m up to 100 mu m operated in vacuum and the hydrodynamic regime of liquid He-4. We observe that in vacuum devices are described well using a simple harmonic motion with a constant Duffing coefficient, and in helium, we quantitatively model their behavior with the conventional hydrodynamic model.

With a median age at diagnosis of 70, lung cancer remains a significant public health challenge for older Americans. Surgery is a key component in treating most patients with non-metastatic lung cancer. These patients experience postoperative pain, fatigue, loss of respiratory capacity, and decreased physical function. Data on quality of life (QOL) in older adults undergoing lung cancer surgery is limited, and few interventions are designed to target the needs of older adults and their family caregivers (FCGs). The primary aim of this comparative effectiveness trial is to determine whether telephone-based physical activity coaching before and after surgery will be more beneficial than physical activity self-monitoring alone for older adults and their FCGs. In this multicenter comparative effectiveness trial, 382 older adults (≥ 65 years) with lung cancer and their FCGs will be recruited before surgery and randomized to either telephone-based physical activity coaching or physical activity self-monitoring alone. Participants allocated to the telephone-based coaching comparator will receive five telephone sessions with coaches (1 pre and 4 post surgery), an intervention resource manual, and a wristband pedometer. Participants in the self-monitoring only arm will receive American Society of Clinical Oncology (ASCO) physical activity information and wristband pedometers. All participants will be assessed at before surgery (baseline), at discharge, and at days 30, 60, and 180 post-discharge. The primary endpoint is the 6-minute walk test (6MWT) at 30 days post-discharge. Geriatric assessment, lower extremity function, self-reported physical function, self-efficacy, and QOL will also be assessed. The trial will determine whether this telephone-based physical activity coaching approach can enhance postoperative functional capacity and QOL outcomes for older adults with lung cancer and their FCGs. Trial results will provide critical findings to inform models of postoperative care for older adults with cancer and their FCGs. ClinicalTrials.gov Identifier: NCT06196008.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease characterized by a spatially heterogeneous tumor microenvironment. Within the PDA microenvironment, cells organize into communities where cell fate is influenced by neighboring cells of diverse ontogeny and function. However, it remains unclear how cell neighborhoods in the tumor microenvironment evolve with treatment and impact clinical outcomes. METHODS: Here, using automated chromogenic multiplex immunohistochemistry and unsupervised computational image analysis of human PDA tumors, we investigated cell neighborhoods in surgically resected tumors from patients with chemotherapy-na & iuml;ve PDA (n = 59) and neoadjuvant chemotherapy-treated PDA (n = 57). Single cells were defined fi ned by lineage markers (CD3, CD8, Foxp3, CD68, CK19), proliferation (Ki67), and neighboring cells. RESULTS: Distinct intratumoral immune and tumor cell subsets were defined fi ned by neighboring cells. Higher content of stromal-associated macrophages was seen in chemotherapy-na & iuml;ve tumors from long-term survivors (overall survival > 3 years) compared with short-term survivors (overall survival < 1 year), whereas immune-excluded tumor cells were higher in short-term survivors. Chemotherapy-treated vs-na & iuml;ve tumors showed lower content of tumor-associated T cells and macrophages but similar densities of stromal-associated immune cells. However, proliferating tumor cell subsets with immune-rich neighborhoods were higher in chemotherapy-treated tumors. In a blinded analysis of tumors from patients treated with neoadjuvant chemotherapy, a composite index comprising lower quantities of immune-excluded tumor cells and higher spatially distinct immune cell subsets was associated with prolonged survival. CONCLUSIONS: Together, these data provide new insights into discrete cell communities in PDA and show their clinical relevance.