Targeting BRCA and PALB2 in Pancreatic Cancer.

OPINION STATEMENT: An important subgroup of pancreatic ductal adenocarcinomas (PDACs) harbor pathogenic variants in BRCA1, BRCA2, or PALB2. These tumors are exquisitely sensitive to platinum-based chemotherapy and patients may experience deep and durable responses to this treatment. PARP inhibitors offer potential respite from the cumulative toxicities of chemotherapy as they significantly extend progression-free survival compared to a chemotherapy holiday. Given the lack of proven survival benefit, the decision to use a maintenance PARP inhibitor rather than continue chemotherapy should be individualized. Interestingly, in both published clinical trials of maintenance PARP inhibitors, there is a striking range of interpatient benefit: Even in the platinum-sensitive setting, roughly 25% of tumors appear to be PARP inhibitor refractory (progressive disease within 2 months of starting treatment), 50% sustain moderate benefit (up to 2 years), and 25% are hyper-responsive (more than 2 years of benefit). This finding highlights the need to refine our understanding of which patients will respond to maintenance PARP inhibitors, both by being able to identify biallelic loss and by deepening our knowledge of resistance mechanisms and who develops them. Recent data supports that reversion mutations are common in PARP inhibitor refractory patients, but we have little understanding of the mechanisms that drive delayed resistance and long-term responses. Identifying which patients are more prone to certain mechanisms of resistance and tackling them with specific treatment strategies are areas of active investigation. Additionally, given that PARP inhibitors have limited overall efficacy for most patients, upfront combination strategies are an important future strategy.

Analysis of BRCA1- and BRCA2-Related Pancreatic Cancer and Survival.

This cohort study compares the outcomes of patients with BRCA1 and BRCA-related pancreatic cancers using 2 large data sets.

Tumor Differentiation as a Prognostic Marker in Clinically Staged T1bN0 Esophageal Adenocarcinoma.

Current guidelines recommend that clinically staged T1N0 esophageal cancers are to be referred to surgery or endoscopic resection. Using the National Cancer Database, we identified 733 individuals with clinically staged T1N0 esophageal carcinoma, who underwent upfront surgery and did not receive any prior treatment. We assessed upstaging, which was defined as ≥ T2 disease or positive lymph nodes. Poorly differentiated adenocarcinomas were associated with upstaging, whereas squamous cell carcinomas were not. Specifically, the percentage of upstaging among individuals with clinically staged T1b and poorly differentiated tumor was 33.8%. Therefore, clinically staged T1bN0 poorly differentiated esophageal adenocarcinomas are at high risk for upstaging following surgery.

Biallelic BRCA Loss and Homologous Recombination Deficiency in Nonbreast/Ovarian Tumors in Germline BRCA1/2 Carriers.

PURPOSE: Breast and ovarian tumors in germline BRCA1/2 carriers undergo allele-specific loss of heterozygosity, resulting in homologous recombination deficiency (HRD) and sensitivity to poly-ADP-ribose polymerase (PARP) inhibitors. This study investigated whether biallelic loss and HRD also occur in primary nonbreast/ovarian tumors that arise in germline BRCA1/2 carriers. METHODS: A clinically ascertained cohort of BRCA1/2 carriers with a primary nonbreast/ovarian cancer was identified, including canonical (prostate and pancreatic cancers) and noncanonical (all other) tumor types. Whole-exome sequencing or clinical sequencing results (n = 45) were analyzed. A pan-cancer analysis of nonbreast/ovarian primary tumors from germline BRCA1/2 carriers from The Cancer Genome Atlas (TCGA, n = 73) was used as a validation cohort. RESULTS: Ages of nonbreast/ovarian cancer diagnosis in germline BRCA1/2 carriers were similar to controls for the majority of cancer types. Nine of 45 (20%) primary nonbreast/ovarian tumors from germline BRCA1/2 carriers had biallelic loss of BRCA1/2 in the clinical cohort, and 23 of 73 (32%) in the TCGA cohort. In the combined cohort, 35% and 27% of primary canonical and noncanonical BRCA tumor types, respectively, had biallelic loss. High HRD scores (HRDex > 42) were detected in 81% of tumors with biallelic BRCA loss compared with 22% (P < .001) of tumors without biallelic BRCA loss. No differences in genomic profile, including mutational signatures, mutation spectrum, tumor mutational burden, or microsatellite instability, were found in primary nonbreast/ovarian tumors with or without biallelic BRCA1/2 loss. CONCLUSION: A proportion of noncanonical primary tumors have biallelic loss and evidence of HRD. Our data suggest that assessment of biallelic loss and HRD could supplement identification of germline BRCA1/2 mutations in selection of patients for platinum or PARP inhibitor therapy.

The Clinical Implications of Reversions in Patients with Advanced Pancreatic Cancer and Pathogenic Variants in BRCA1, BRCA2, or PALB2 after Progression on Rucaparib.

PURPOSE: PARP inhibitors (PARPi) provide an effective maintenance option for patients with BRCA- or PALB2-mutated pancreatic cancer. However, mechanisms of PARPi resistance and optimal post-PARPi therapeutic strategies are poorly characterized. EXPERIMENTAL DESIGN: We collected paired cell-free DNA samples and post-PARPi clinical data on 42 patients with advanced, platinum-sensitive pancreatic cancer who were treated with maintenance rucaparib on NCT03140670, of whom 32 developed progressive disease. RESULTS: Peripherally detected, acquired BRCA or PALB2 reversion variants were uncommon (5/30; 16.6%) in patients who progressed on rucaparib. Reversions were significantly associated with rapid resistance to PARPi treatment (median PFS, 3.7 vs. 12.5 months; P = 0.001) and poor overall survival (median OS, 6.2 vs. 23.0 months; P < 0.0001). All patients with reversions received rechallenge with platinum-based chemotherapy following PARPi progression and experienced faster progression on this therapy than those without reversion variants (real-world time-to-treatment discontinuation, 2.4 vs. 5.8 months; P = 0.004). Of the patients who progressed on PARPi and received further chemotherapy, the OS from initiation of second-line therapy was significantly lower in those with reversion variants than in those without (5.5 vs. 12.0 months, P = 0.002). Finally, high levels of tumor shedding were independently associated with poor outcomes in patients who received rucaparib. CONCLUSIONS: Acquired reversion variants were uncommon but detrimental in a population of patients with advanced BRCA- or PALB2-related pancreatic ductal adenocarcinoma who received maintenance rucaparib. Reversion variants led to rapid progression on PARPi, rapid failure of subsequent platinum-based treatment, and poor OS of patients. The identification of such variants in the blood may have both predictive and prognostic value. See related commentary by Tsang and Gallinger, p. 5005.

Advancements in Systemic Therapy for Pancreatic Cancer.

Outcomes for patients with advanced pancreatic cancer have improved in the past 12 years, mainly because of progress made in systemic therapies. New treatment strategies for advanced pancreatic cancer include switch maintenance with cytotoxic therapies, induction maintenance, and the utilization of targeted agents for patients with actionable variants, as well as ongoing development of cytotoxic regimens, such as NALIRIFOX. The activity of immunotherapy has been disappointing to date, but novel combinations and identifying appropriate patient populations may further unlock its potential.

A randomized, phase II trial of oral azacitidine (CC-486) in patients with resected pancreatic adenocarcinoma at high risk for recurrence.

BACKGROUND: Of the only 20% of patients with resectable pancreatic ductal adenocarcinoma (rPDA), cancer recurs in 80% of cases. Epigenetic dysregulation is an early hallmark of cancer cells acquiring metastatic potential, and epigenetic modulators may reactivate tumor suppressor genes, delay recurrence, and sensitize PDA to future chemotherapy. METHODS: This was a randomized phase II study (NCT01845805) of CC-486 (oral DNA methyltransferase inhibitor azacitidine) vs. observation (OBS) in rPDA patients harboring high-risk features (stage pN1-2, R1 margins, or elevated CA 19-9 level) with no evidence of disease following standard adjuvant therapy. Patients were randomized to oral CC-486 treatment (300 mg daily on days 1-21 on a 28-day cycle) or OBS for up to 12 cycles or until disease relapse/unacceptable toxicities. Following recurrence, records of next-line therapies, imaging, and survival were obtained. The primary endpoint was progression-free survival (PFS)-time from randomization to recurrence (imaging/biopsy confirmed or death). Secondary endpoints included OS and PFS and ORR and metastatic PFS with subsequent next-line systemic therapy in metastatic setting. RESULTS: Forty-nine patients (24 in CC-486 arm, 25 in OBS arm) were randomized: median age 66 (range 36-81), 53% male, 73% node positive, 49% elevated CA 19-9, 20% R1 resection, 63% and 100% received perioperative concurrent chemoradiation and chemotherapy, respectively. Median time from surgery to randomization was 9.6 mo (range 2.9-36.8). For the CC-486 arm, median treatment duration was 5.6 mo (range 1.3 to 12.8) with 14 treatment-related grade 3 or 4 AEs among 5 patients (22%) resulting in dose-reduction. Four patients (17%) discontinued therapy due to AEs. With median follow-up of 20.3mo (IQR 12.8, 41.4), 38 (79%) of evaluable patients recurred (34 imaging-confirmed, 4 clinically). Median PFS in imagining-confirmed cases was 9.2 and 8.9mo (HR 0.94, 95% CI 0.46-1.87, p = 0.85) for CC-486 and OBS patients, respectively. Median OS (2-yr OS%) was 33.8 (50%) and 26.4 mo (61%) in CC-486 and OBS patients, respectively. (HR 0.98, 95% CI 0.46-2.05, p = 0.96). ORR with subsequent chemotherapy in the metastatic setting was minimal in both arms. CONCLUSIONS: Treatment with CC-486 following adjuvant therapy did not prolong time-to-relapse in patients with high-risk rPDA or improve disease response on 1st-line metastatic therapy.

PARPis and Other Novel, Targeted Therapeutics in Pancreatic Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a mere ∼10% of patients in the United States surviving 5 years from the time of diagnosis. Until recently, the treatment for advanced PDAC differed little based on patient or tumor characteristics. However, recent breakthroughs have identified subgroups of patients who benefit from novel, biomarker-driven therapies. We review the data and role for PARP inhibitors and for other biomarker-directed therapies, including for patients with NTRK fusions, NRG1 fusions, mismatch repair deficiency, and KRAS p.G12C mutations.

Multianalyte Prognostic Signature Including Circulating Tumor DNA and Circulating Tumor Cells in Patients With Advanced Pancreatic Adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis. Multianalyte signatures, including liquid biopsy and traditional clinical variables, have shown promise for improving prognostication in other solid tumors but have not yet been rigorously assessed for PDAC. MATERIALS AND METHODS: We performed a prospective cohort study of patients with newly diagnosed locally advanced pancreatic cancer (LAPC) or metastatic PDAC (mPDAC) who were planned to undergo systemic therapy. We collected peripheral blood before systemic therapy and assessed circulating tumor cells (CTCs), cell-free DNA concentration (cfDNA), and circulating tumor KRAS (ctKRAS)-variant allele fraction (VAF). Association of variables with overall survival (OS) was assessed in univariate and multivariate survival analysis, and comparisons were made between models containing liquid biopsy variables combined with traditional clinical prognostic variables versus models containing traditional clinical prognostic variables alone. RESULTS: One hundred four patients, 40 with LAPC and 64 with mPDAC, were enrolled. CTCs, cfDNA concentration, and ctKRAS VAF were all significantly higher in patients with mPDAC than patients with LAPC. ctKRAS VAF (cube root; 0.05 unit increments; hazard ratio, 1.11; 95% CI, 1.03 to 1.21; P = .01), and CTCs ≥ 1/mL (hazard ratio, 2.22; 95% CI, 1.34 to 3.69; P = .002) were significantly associated with worse OS in multivariate analysis while cfDNA concentration was not. A model selected by backward selection containing traditional clinical variables plus liquid biopsy variables had better discrimination of OS compared with a model containing traditional clinical variables alone (optimism-corrected Harrell's C-statistic 0.725 v 0.681). CONCLUSION: A multianalyte prognostic signature containing CTCs, ctKRAS, and cfDNA concentration outperformed a model containing traditional clinical variables alone suggesting that CTCs, ctKRAS, and cfDNA provide prognostic information complementary to traditional clinical variables in advanced PDAC.

Niraparib plus nivolumab or niraparib plus ipilimumab in patients with platinum-sensitive advanced pancreatic cancer: a randomised, phase 1b/2 trial.

BACKGROUND: Establishing alternatives to lifelong chemotherapy for patients with advanced pancreatic cancer has been proposed to address chemotherapy resistance and cumulative toxicity. Poly(ADP-ribose) polymerase (PARP) inhibitors have shown efficacy in this setting, and concurrent immune checkpoint blockade could offer synergistic tumour control. The aim of this study was to test the safety and antitumour activity of maintenance with PARP inhibition combined with immune checkpoint blockade in patients with advanced pancreatic cancer who had a stable response to platinum-based chemotherapy. METHODS: We conducted an open-label, randomised, phase 1b/2 study of niraparib plus anti-PD-1 (nivolumab) or anti-CTLA-4 (ipilimumab) therapy for patients with advanced pancreatic cancer whose cancer had not progressed after at least 16 weeks of platinum-based therapy. Patients were randomly assigned (1:1) via permuted block randomisation (block sizes 2 and 4) to niraparib 200 mg orally per day plus either nivolumab 240 mg intravenously every 2 weeks (later changed to 480 mg intravenously every 4 weeks based on manufacturer update) or ipilimumab 3 mg/kg intravenously every 4 weeks for four doses. The primary endpoints were safety and progression-free survival at 6 months. Treatment groups were not compared for activity, which was assessed in each group against a clinically meaningful progression-free survival at 6 months of 44% (null hypothesis). Superiority of a treatment regimen could be declared if 6-month progression-free survival was 60%, and inferiority if 6-month progression-free survival was 27%. All patients who received at least one dose of study treatment and had at least one post-treatment assessment of response according to Response Evaluation Criteria in Solid Tumours version 1.1 were included in the efficacy population. The safety population consisted of all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03404960, and enrolment is completed and follow-up is ongoing. FINDINGS: 91 patients were enrolled between Feb 7, 2018, and Oct 5, 2021 and were randomly assigned to niraparib plus nivolumab (n=46) or niraparib plus ipilimumab (n=45). Of these patients, 84 were evaluable for the progression-free survival endpoint (niraparib plus nivolumab=44; niraparib plus ipilimumab=40). Median follow-up was 23·0 months (IQR 15·0-31·5). 6-month progression-free survival was 20·6% (95% CI 8·3-32·9; p=0·0002 vs the null hypothesis of 44%) in the niraparib plus nivolumab group; and 59·6% (44·3-74·9; p=0·045) in the niraparib plus ipilimumab group. Ten (22%) of 46 patients in the niraparib plus nivolumab group and 23 (50%) of 45 patients in the niraparib plus ipilimumab group had a grade 3 or worse treatment-related adverse event. The most common grade 3 or worse adverse events in the niraparib plus nivolumab group were hypertension (in four [8%] patients), anaemia (two [4%]), and thrombocytopenia (two [4%]) whereas in the niraparib plus ipilimumab group these were fatigue (in six [14%]), anaemia (five [11%]), and hypertension (four [9%]). There were no treatment-related deaths. INTERPRETATION: The primary endpoint of 6-month progression-free survival was met in the niraparib plus ipilimumab maintenance group, whereas niraparib plus nivolumab yielded inferior progression-free survival. These findings highlight the potential for non-cytotoxic maintenance therapies in patients with advanced pancreatic cancer. FUNDING: Bristol Myers Squibb, GlaxoSmithKline, the Basser Center Young Leadership Council, The Konner Foundation, The Pearl and Philip Basser Innovation Research Award, the Anonymous Foundation, and the US National Institutes of Health.

Phase I Trial of Regorafenib, Hydroxychloroquine, and Entinostat in Metastatic Colorectal Cancer.

BACKGROUND: The antiangiogenic tyrosine kinase inhibitor regorafenib provides a survival benefit in patients with previously treated metastatic colorectal cancer (CRC). Antiangiogenic therapy causes hypoxic stress within tumor cells, which activates autophagy as a survival mechanism. The histone deacetylase inhibitor (HDAC) entinostat increases dependence on autophagy through epigenetic mechanisms. Hydroxychloroquine (HCQ) blocks autophagy by blunting lysosomal acidification. We hypothesized that HCQ and entinostat would be tolerable with regorafenib and potentiate the antitumor response. METHODS: This was a 3+3 phase I trial of HCQ and entinostat with regorafenib in patients with metastatic CRC. The primary objective was safety, and the secondary objective was clinical efficacy. RESULTS: Twenty patients received study therapy. Six evaluable patients were enrolled at each of the three planned dose levels, one patient at an intermediate dose level, and one additional patient withdrew consent after 4 days to receive treatment closer to home. One dose-limiting toxicity was noted in the study at dose level 2 (grade 3 fatigue). Seven patients discontinued therapy due to related toxicities; rapid weight loss was near universal, with a median weight loss of 4.4 kg (range 1.5-12.2 kg) in the first 2 weeks of treatment. No objective responses were observed. CONCLUSION: The combination of regorafenib, HCQ, and entinostat was poorly tolerated without evident activity in metastatic CRC. CLINICALTRIALS.GOV IDENTIFIER: NCT03215264.

Benefit for single-agent adjuvant chemotherapy in elderly patients with locally advanced gastric adenocarcinoma.

BACKGROUND: Current NCCN guidelines exclude the possibility of using single-agent adjuvant chemotherapy in locally advanced gastric adenocarcinoma, while allowing doublet chemotherapy. However, single-agent adjuvant chemotherapy is a valid treatment option in other gastrointestinal malignancies, preferred for elderly and/or frail patients. The current study used a nationwide oncology database to assess the benefit of single-agent adjuvant chemotherapy, specifically in the elderly population. METHODS: Using the National Cancer Database (2004-2016) we identified 1953 individuals with non-metastatic gastric adenocarcinoma who underwent upfront D2 gastrectomy with pathologic stage ≥ T3 or Npos and free surgical margins, and had not received either preoperative chemotherapy or pre-/postoperative radiotherapy. We used IPTW analysis to compare overall survival between individuals receiving either single- or multi-agent adjuvant chemotherapy, or referred to observation alone. RESULTS: Individuals receiving single-agent chemotherapy had an overall survival benefit compared with observation alone, with an HR of 0.70 (95% CI 0.55-0.88, p < 0.001). Individuals over the age of 65 had an OS benefit with an HR of 0.61 (95% CI 0.46-0.82, p < 0.001). Comparing individuals over the age of 65 receiving single- vs. multi-agent chemotherapy, there was no overall survival difference with an HR of 0.87 (95% CI 0.64-1.18, p = 0.38). CONCLUSIONS: Single-agent adjuvant chemotherapy with a fluoropyrimidine in locally advanced gastric adenocarcinoma following D2 gastrectomy can improve overall survival in elderly patients. Clinicians may consider using either capecitabine or 5-FU as a treatment option in the adjuvant setting for this age group.

Cost-Effectiveness of a Risk-Tailored Pancreatic Cancer Early Detection Strategy Among Patients With New-Onset Diabetes.

BACKGROUND & AIMS: Screening for pancreatic ductal adenocarcinoma (PDAC) in asymptomatic adults is not recommended, however, patients with new-onset diabetes (NoD) have an 8 times higher risk of PDAC than expected. A novel risk-tailored early detection strategy targeting high-risk NoD patients might improve PDAC prognosis. We sought to evaluate the cost effectiveness of this strategy. METHODS: We compared PDAC early detection strategies targeting NoD individuals age 50 years and older at various minimal predicted PDAC risk thresholds vs standard of care in a Markov state-transition decision model under the health care sector perspective using a lifetime horizon. RESULTS: At a willingness to pay (WTP) threshold of $150,000 per quality-adjusted life-year, the early detection strategy targeting patients with a minimum predicted 3-year PDAC risk of 1% was cost effective (incremental cost-effectiveness ratio, $116,911). At a WTP threshold of $100,000 per quality-adjusted life-year, the early detection strategy at the 2% risk threshold was cost effective (incremental cost-effectiveness ratio, $63,045). The proportion of PDACs detected at local stage, costs of treatment for metastatic PDAC, utilities of local and regional cancers, and sensitivity of screening were the most influential parameters. Probabilistic sensitivity analysis confirmed that at a WTP threshold of $150,000, early detection at the 1.0% risk threshold was favored (30.6%), followed by the 0.5% risk threshold (20.4%) vs standard of care (1.7%). At a WTP threshold of $100,000, early detection at the 1.0% risk threshold was favored (27.3%) followed by the 2.0% risk threshold (22.8%) vs standard of care (2.0%). CONCLUSIONS: A risk-tailored PDAC early detection strategy targeting NoD patients with a minimum predicted 3-year PDAC risk of 1.0% to 2.0% may be cost effective.

PARP Inhibitors in Pancreatic Cancer.

ABSTRACT: Despite representing only 5% of all annual cancer diagnoses in the United States, pancreatic cancer is projected to become the second leading cause of cancer-related death within the next 10 years. Progress in the treatment of advanced pancreatic cancer has been slow. Systemic therapies rely on combination cytotoxic agents, with limited options at progression. Recently, poly(ADP-ribose) polymerase inhibitors have demonstrated clinical activity in patients with advanced pancreatic cancer and pathogenic variants in BRCA1, BRCA2, and PALB2. In this review, we discuss the development of poly(ADP-ribose) polymerase inhibitors in pancreatic cancer, relevant clinical trials, and future directions.

THSB2 as a prognostic biomarker for patients diagnosed with metastatic pancreatic ductal adenocarcinoma.

Patients newly diagnosed with metastatic pancreatic ductal adenocarcinoma generally have poor survival, with heterogeneous rates of progression. Biomarkers that could predict progression and/or survival would help inform patients and providers as they make care decisions. In a previous retrospective study, we discovered that circulating thrombospondin-2 (THBS2) could, in combination with CA19-9, better distinguish patients with PDAC versus healthy controls. Here we evaluated whether THBS2 levels, previously not known to be prognostic, were associated with outcome in 68 patients at time of diagnosis of metastatic PDAC. Specifically, we interrogated the association of THBS2 level, alone or in combination with CA19-9, with progression by 90 days and/or survival to 180 days. The results indicate that elevated THBS2 levels alone, at the time of a metastatic PDAC diagnosis, can identify patients with a shorter time to death and thus help patients and providers when planning treatment.

Determinants of Homologous Recombination Deficiency in Pancreatic Cancer.

Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique tumor responsiveness to HR-dependent DNA damage triggered by certain treatments (platinum chemotherapy and PARP inhibitors). While pathogenic mutations in HR genes are a major driver of this sensitivity, another layer of diverse tumor intrinsic and extrinsic factors regulate the HR deficiency (HRD) phenotype. Defining the mechanisms that drive HRD may guide the development of novel strategies and therapeutics to induce treatment sensitivity in non-HRD tumors. Here, we discuss the complexity underlying HRD in pancreatic cancer and highlight implications for identifying and treating this distinct subset of patients.

Uptake and acceptability of a mainstreaming model of hereditary cancer multigene panel testing among patients with ovarian, pancreatic, and prostate cancer.

PURPOSE: To address demands for timely germline information to guide treatments, we evaluated experiences of patients with ovarian, pancreatic, and prostate cancer with a mainstreaming genetic testing model wherein multigene panel testing was ordered by oncologists with standardized pretest patient education, and genetic counselors delivered results and post-test genetic counseling via telephone. METHODS: Among 1,203 eligible patients, we conducted a prospective single-arm study to examine patient uptake and acceptability (via self-report surveys at baseline and three weeks and three months following result return) of this mainstreaming model. RESULTS: Only 10% of eligible patients declined participation. Among 1,054 tested participants, 10% had pathogenic variants (PV), 16% had variants of uncertain significance (VUS), and 74% had no variant identified (NV). Participants reported high initial acceptability, including high satisfaction with their testing decision. Variability over time in several outcomes existed for participants with PV or NV: those with NV experienced a temporary increase in depression (pTime < 0.001; pTime2 < 0.001), and those with PV experienced a small increase in genetic testing distress (p = 0.03). Findings suggested that result type, sex, and cancer type were also associated with outcomes including clinical depression and uncertainty. CONCLUSION: This mainstreaming model may offer a feasible approach for extending access to germline genetic information.