Whether sex and co-mutations impact prognosis of patients with SMARCA4-mutated (mutSMARCA4) malignancies is not clear.
This cohort included patients from Northern California Kaiser Permanente with ...next-generation sequencing (NGS) performed from August 2020 to October 2022. We used Cox regression modeling to examine the association between sex and overall survival (OS), adjusting for demographics, performance status, Charlson comorbidity index, receipt of treatment, tumor mutation burden (TMB), and
,
,
,
, and
co-mutations.
Out of 9221 cases with NGS performed, 125 cases (1.4%) had a mutSMARCA4. The most common malignancies with a mutSMARCA4 were non-small cell lung cancer (NSCLC, 35.2%), esophageal and stomach adenocarcinoma (12.8%), and cancer of unknown primary (11.2%). The most common co-mutations were
(mutp53, 59.2%),
(mutKRAS, 28.8%),
(mutCDKN2A, 31.2%),
(mutSTK11, 12.8%), and
(mutKeap1, 8.8%) mutations. Male patients had substantially worse OS than female patients both among the entire mutSMARCA4 cohort (HR = 1.71, 95% CI 0.92-3.18) with a median OS of 3.0 versus 43.3 months (
< 0.001), and among the NSCLC subgroup (HR = 14.2, 95% CI 2.76-73.4) with a median OS of 2.75 months versus un-estimable (
= 0.02). Among all patients with mutSMARCA4, mutp53 versus wtp53 (HR = 2.12, 95% CI 1.04-4.29) and mutSTK11 versus wtSTK11 (HR = 2.59, 95% CI 0.87-7.73) were associated with worse OS. Among the NSCLC subgroup, mutp53 versus wtp53 (HR = 0.35, 0.06-1.97) and mutKRAS versus wtKRAS (HR = 0.04, 0.003-.45) were associated with better OS, while mutCDKN2A versus wtCDKN2A (HR = 5.04, 1.12-22.32), mutSTK11 versus wtSTK11 (HR = 13.10, 95% CI 1.16-148.26), and mutKeap1 versus wtKeap1 (HR = 5.06, 95% CI 0.89-26.61}) were associated with worse OS.
In our cohort of patients with mutSMARCA4, males had substantially worse prognosis than females, while mutTP53, mutKRAS, mutCDKN2A, mutSTK11 and mutKeap1were differentially associated with prognosis among all patients and among the NSCLC subgroup. Our results, if confirmed, could suggest potentially unidentified mechanisms that underly this sex and co-mutation-dependent prognostic disparity among patients whose tumor bears a mutSMARCA4.
Activating epidermal growth factor receptor (EGFR) mutations in metastatic non-small cell lung cancer (NSCLC) are associated with a high response rate to EGFR tyrosine kinase inhibitor (TKI). The ...current guidelines recommend routine EGFR mutational analysis prior to initiating first line systemic therapy. The clinical characteristics including smoking status, histologic type, sex and ethnicity are known to be associated with the incidence of EGFR mutations. We retrospectively analyzed 277 patients with metastatic NSCLC within Kaiser Permanente Northern California (KPNC); among these patients, 83 were positive for EGFR mutations. We performed both univariate and multivariable logistic regressions to identify predictors of EGFR mutations. We found that histologic grade was significantly associated with the incidence of EGFR mutation, regardless of ethnicity, sex and smoking status. In grade I (well differentiated) and II (moderately differentiated), histology was associated with significantly higher incidence of EGFR mutations compared to grade II-III (moderate-to-poorly differentiated) and III (poorly differentiated). Ever-smokers with grade III lung adenocarcinoma had 1.8% incidence of EGFR mutations. This study indicates that histologic grade is a predictive factor for the incidence of EGFR mutations and suggests that for patients with grade II-III or III lung adenocarcinoma, prompt initiation of first-line chemotherapy or immunotherapy is appropriate while awaiting results of EGFR mutational analysis, particularly for patients with history of smoking.
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Background: Whether sex and co-mutations impact prognosis of patients with SMARCA4-mutated (mutSMARCA4) malignancies is not clear. Methods: This cohort included patients from Northern ...California Kaiser Permanente with next-generation sequencing (NGS) performed from August 2020 to October 2022. We used Cox regression modeling to examine the association between sex and overall survival (OS), adjusting for demographics, performance status, Charlson comorbidity index, receipt of treatment, tumor mutation burden (TMB), and TP53, KRAS, CDKN2A and STK11 co-mutations. Results: Out of 9221 cases with NGS performed, 125 cases (1.3%) had a mut SMARCA4. The most common malignancies with a mutSMARCA4 were non-small cell lung cancer (NSCLC, 35.2%), esophageal and stomach adenocarcinoma (12.8%), and cancer of unknown primary (11.2%). The most common co-mutations were p53 (mutp53, 59.2%), KRAS (mutKRAS, 28.8%), CDKN2A (mutCDKN2A, 31.2%) and STK11 (12.8%) mutations. Male patients had substantially worse OS than female patients both among the entire cohort (HR = 1.76, 95% CI .94-3.30) with a median OS of 3.0 versus 43.3 months ( P < .001), and among NSCLC cohort (HR = 9.72, 95% CI 2.19-43.19) with a median OS of 2.75 months versus un-estimable ( P = .02). Among the entire cohort, mutp53 versus wtp53 (HR = 2.16, 95% CI 1.06-4.41) and mutSTJ11 versus wtSTK11 (HR = 3.09, 95% CI 1.10-8.68) were associated with worse OS. Among NSCLC cohort, mutp53 versus wtp53 (HR = .20, .03-1.31) and mutKRAS versus wtKRAS (HR = .13, .01-1.03) were associated with better OS, while mutCDKN2A versus wtCDKN2A (HR = 4.38, 1.13-16.9) and mutSTK11 versus wtSTK11 (HR = 18.1, 95% CI 1.30-251) were associated with worse OS. Conclusions: Male patients had substantially worse prognosis than female patients, while MutTP53, mutKRAS, mutCDKN2A and mutSTK11 were differentially associated with prognosis among the entire cohort and among NSCLC cohort. Our results, if confirmed, could suggest potentially unidentified mechanisms that underly this sex and co-mutation-dependent prognostic disparity among patients whose tumor bears a mutSMARCA4.
To examine the association of gain-of-function (GOF) and non-gain-of-function (non-GOF)
mutations with prognosis of metastatic right-sided (RCC) versus left-sided colorectal cancer (LCC).
This cohort ...study included patients with metastatic colorectal cancer (CRC) who had next-generation sequencing performed from November 2017 to January 2021. We defined R175H, R248W, R248Q, R249S, R273H, R273L, and R282W as GOF and all other mutp53 as non-GOF. We used Cox regression modeling to examine the association between GOF and non-GOF mutp53 and overall survival (OS), adjusting for age, sex, ethnicity, performance status, Charlson comorbidity index and receipt of chemotherapy.
Of total 1,043 patients, 735 had tumors with mutp53 and 308 had wild-type p53 (wtp53). GOF was associated with worse OS than non-GOF mutp53 only in LCC (hazard ratio HR = 1.66 95% CI, 1.20 to 2.29), but not in RCC (HR = 0.79 95% CI, 0.49 to 1.26). Importantly, RCC was associated with worse OS than LCC only in the subset of patients whose CRC carried non-GOF (HR = 1.76 95% CI, 1.30 to 2.39), but not GOF mutp53 (HR = 0.92 95% CI, 0.55 to 1.53) or wtp53 (HR = 0.88 95% CI, 0.60 to 1.28). These associations were largely unchanged after also adjusting for RAS, BRAF, and PIK3CA mutations, and microsatellite instability-high.
Poorer survival of patients with metastatic RCC versus LCC appeared to be restricted to the subset with non-GOF mutp53, whereas GOF versus non-GOF mutp53 was associated with poorer survival only among patients with LCC. This approach of collectively classifying mutp53 into GOF and non-GOF provides new insight for prognostic stratification and for understanding the mechanism of sidedness-dependent prognosis. If confirmed, future CRC clinical trials may benefit from incorporating this approach.
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Background: Androgen deprivation therapy (ADT) plus either Abiraterone, Docetaxel or Enzalutamide (ADE) improves overall survival (OS) of men with metastatic M1 castrate-sensitive prostate cancer ...(mCSPC), compared to ADT alone and is currently standard of care. Men with mCSPC with a point mutation of the speckle-type pox virus and zinc finger mutation (mutSPOP) derive superior response to ADT compared to wild type SPOP. The additive benefit of ADE to ADT in this subclass of CSPC is unclear. We sought to evaluate the benefit of therapy in patients with mutSPOP in a real-world setting. Methods: Between November 2017 and July 2022, 1002, patients in the Kaiser Permanente Northern California (KPNC) health system with advanced prostate cancer had tumor specimens examined by next generation sequencing (NGS). Of these patients, we retrospectively identified 70 mCSPC patients with mutSPOP. Patient records were reviewed to determine baseline characteristics, therapy for CSPC, subsequent therapy for Castrate Resistant Prostate Cancer (CRPC), and clinical outcome. The primary outcome was progression-free survival (PFS) for patients who received ADT alone or ADT plus ADE. PFS was defined as time to either PSA progression by PCWG2 criteria, clinical progression, or time to next line of therapy. Results: Median age for the 70 patients with mutSPOP was 75 years (range 50-91). Thirty-six (51%) were non-Hispanic white; 11 (16%) were African American; and 13 (19%) were Asian. F133 was the most frequently mutated allele (64%), TP53 was the most common co-mutated gene (27%), and mutations in MSH2, MSH6 and BRCA1 were identified in one patient each. Two patients had concurrent ERG fusion. Thirty-six patients (51%) had a Gleason score 8-10 and 48 (69%) were diagnosed with de-novo metastatic disease. Twenty-seven patients (39%) received ADT alone, 41 (59%) received ADT + ADE, 2 patients elected observation only. PFS was 28.1 months (mos) for ADT alone vs 35 for ADT+ADE (p=0.08). Twenty-nine patients (41%) received 2nd line therapy at CRPC; among them 24 received ADT plus Abiraterone or Enzalutamide. Median PFS for all the CRPC patients who received 2nd line treatment was 15mos. Median PFS for CRPC patients who received 2nd line treatment with Abiraterone, or Enzalutamide was 15.3 mos. Median overall survival for the entire group was 173 mos (95% CI 135-NR). Conclusions: In this real-world study within KPNC, we confirmed the durable benefit of ADT based therapy in patients with mutSPOP. Patients with mutSPOP derived similar benefit regardless of 1st line therapy (ADT vs ADT + ADE). We also noted durable responses to abiraterone or enzalutamide for CRPC after initial treatment with ADE for CSPC. Confirmation of these findings from an another large NGS database is ongoing and will be reported later.
Abstract
Background
Financial toxicity is a growing problem in oncology, but no prior studies have prospectively measured the financial impact of cancer treatment in a diverse national cohort of ...newly diagnosed cancer patients. S1417CD was the first cooperative group-led multicenter prospective cohort study to evaluate financial hardship in metastatic colorectal cancer (mCRC) patients.
Methods
Patients aged 18 years or older within 120 days of mCRC diagnosis completed quarterly questionnaires for 12 months. We estimated the cumulative incidence of major financial hardship (MFH), defined as 1 or more of increased debt, new loans from family and/or friends, selling or refinancing home, or 20% or more income decline. We evaluated the association between patient characteristics and MFH using multivariate cox regression and the association between MFH and quality of life using linear regression.
Results
A total of 380 patients (median age = 59.9 years) were enrolled; 77.7% were White, 98.0% insured, and 56.5% had annual income of $50 000 or less. Cumulative incidence of MFH at 12 months was 71.3% (95% confidence interval = 65.7% to 76.1%). Age, race, marital status, and income (split at $50 000 per year) were not statistically significantly associated with MFH. However, income less than $100 000 and total assets less than $100 000 were both associated with greater MFH. MFH at 3 months was associated with decreased social functioning and quality of life at 6 months.
Conclusions
Nearly 3 out of 4 mCRC patients experienced MFH despite access to health insurance. These findings underscore the need for clinic and policy solutions that protect cancer patients from financial harm.
3140 Background: Several ADCs are FDA-approved for patients with advanced solid tumors; dozens more are in trials. Predictive biomarkers are lacking, with ADC target expression alone performing ...poorly across ADCs/tumor types. We previously described the development of ADC Treatment Response Scores (ADC-TRS)—a tissue-based multivariate gene-expression test combining individual ADC target expression with proliferation and adhesion—with high correlation of per-ADC/tumor type biomarker frequency (TRS-High) with corresponding clinical trial ORRs for 9 ADCs (PO1-14-04; SABCS 2023). Here we evaluated ADC-TRS in two cohorts of patients treated with approved ADCs. Methods: Adults with advanced solid tumors from an observational trial (NCT03061305) treated with an ADC with TRS results from FFPE tissue (collected prior to 1 st ADC treatment) were eligible; HER2+ patients previously treated with trastuzumab or with hormonal therapy treatment between sample collection/first ADC treatment were excluded. Kaiser Permanente Northern California (KPNC; limited to breast BR and bladder BL cancer) patients and non-KPNC patient (pan-solid tumor) cohorts were analyzed separately. We evaluated whether treatment-matched ADC-TRS status (High or Low) was significantly associated with overall survival (OS) after ADC treatment initiation by Cox proportional hazards models (adjusting for age, indication, and years since tissue collection). Additional analyses in the non-KPNC cohort evaluated whether proliferation/adhesion-related gene expression provided information on outcomes beyond ADC target expression only and predictive/prognostic effect. Results: Patients treated with an approved ADC were included in the non-KPNC (n=72; 5 ADCs/9 tumor types); most frequent sacituzumab govitecan/BR 43%) and KPNC (n=127; 3 ADCs/two tumor types; most frequent enfortumab vedotin/BL50%) cohorts, respectively. In both cohorts, ADC TRS status was significantly associated with OS (High vs. Low, median OS 22.8 vs. 8.7 months mo., aHR 0.15, p=0.005, and median OS 15.3 vs. 8.3 mo., aHR 0.58, p=0.011, respectively). In the non-KP cohort, ADC-TRS significantly improved model fit for OS beyond target gene expression alone (likelihood ratio test LRT p=0.0008). A predictive biomarker effect was confirmed by lack of ADC-TRS status association with OS from systemic chemotherapy start in indication-matched patients not treated with an ADC (n=126, aHR 0.43-2.79, p=0.11-1.0 for the 9 individual TRS). In a 15,108 patient pan-tumor cohort (regardless of treatment), 26.7% were ADC-TRS High for at least 1 approved ADC outside approved indications. Conclusions: Results support ADC-TRS as a multivariate gene-expression-based biomarker that predicts ADC OS across tumor types and targets. More than 25% of all patients with advanced solid tumors have a greater likelihood of being responsive to one or more approved ADCs outside of approved indications.
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Background: Developmentally pancreas head derives from ventral bud while pancreas neck, body and tail derive from dorsal bud. Pancreatic ductal adenocarcinoma (PDAC) frequently harbors ...multiple mutations including KRAS, TP53, CDKN2A, and others. It is unknown how TP53 gain-of-function (GOF) and non-gain-of-function (non-GOF) mutations affect the prognosis. Methods: We retrospectively examined a cohort of 741 Kaiser Permanente (KP) patients with locally advanced/metastatic PDAC who had NGS performed to determine the association of KRAS (mutKRAS), TP53 (mutp53) and CDKN2A (mutCDKN2A) mutations (individually and in combination) with overall survival (OS). We used Cox modeling to estimate hazard ratios (HR) adjusted for age, sex, ethnicity, performance status, Charlston Comorbidity Index, chemotherapy received, anatomic location and co-mutations. We also analyzed the TCGA PDAC dataset to examine the association of OS with these same mutations. Results: In the KP cohort, patient ages ranged from 36 to 94 years and approximately 50% were female. In 384 patients PDAC was on the head, and 357 patients had PDAC on a non-head location (neck, body, and tail). Those with head PDAC had modestly better OS compared to non-head PDAC (HR = 0.87), and this appeared to be driven by the subsets of patients with wtp53 (HR = 0.68), with wtKRAS (HR = .74) and with wtCDKN2A (HR = .78). Approximately 67.5% of patients had mutp53, 89.2% had mutKRAS and 44.8% had mutCDKN2A. Among all KP patients, OS was similar for patients with mutp53 vs. wtp53 (HR = 1.05); worse for patients with mutKRAS vs. wtKRAS (HR = 1.26), and worse for patients with mutCDKN2 vs. wtCDKN2A (HR = 1.51). Interestingly, among patients with a GOF mutp53, those with mutCDKN2A had substantially worse OS vs patients with wtCDKN2A (HR = 2.56, 95% CI 1.46-4.50). In contrast, among patients with a non-GOF mutp53, patients with mutCDKN2A had only moderately worse OS compared to patients with wtCDKN2A (HR = 1.37, 95% CI 1.06-1.79). Analysis of the TCGA PDAC dataset showed that the number of mutations (0, 1, 2, or 3, of p53, KRAS and CDKN2A) was associated with incrementally worse OS ( p < .001). Conclusions: Better OS of head vs. non-head PDAC was primarily driven by patients with wtp53, wtKRAS, and wtCDKN2A. The adverse effect of mutCDKN2A on OS appears to be most pronounced in patients with GOF mutp53. Our TCGA analysis suggests interactions among TP53, KRAS and CDKN2A mutations in affecting PDAC survival.
9060
Background: Inactivating STK11 genomic alterations are prevalent in non-squamous (nsq) NSCLC and define a patient (pt) subgroup with poor prognosis and inferior response to immune checkpoint ...inhibitors (CPIs). PARP inhibitors (PARPi) can potentiate response to CPIs in preclinical models. We conducted a single arm Phase II study within Lung-MAP to evaluate the efficacy and safety of talazoparib in combination with avelumab in patients (pts) with previously treated nsq NSCLC harboring pathogenic STK11 genomic alterations. Methods: Eligibility: STK11 pathogenic somatic mutation or bi-allelic loss on tumor identified via LUNGMAP screening; stage IV or recurrent nsq NSCLC, receipt of one prior line of anti-PD-1/anti-PD-L1 therapy and platinum-based chemotherapy for stage IV or recurrent disease (sequentially or in combination) and disease progression > 42 days following treatment initiation, a ECOG PS of 0-1, adequate organ function and no previous PARPi exposure. Pts received talazoparib (1000 mg PO daily) plus avelumab (800 mg IV Q2W). Co-primary objectives were to evaluate the best objective response rate (ORR) and disease control rate at 12 weeks (DCR12) after study registration, assessed by RECISTv1.1. Rejection of an ORR of 10% required ≥ 8 responses or rejection of a DCR12 of 30% required ≥18 w/ disease control at 12 weeks and ≥4 responses. Results: 47 pts enrolled from January 16 - November 16, 2020; 42 pts met eligibility (50% male, 50% female). 54% of pts had PD-L1 TPS < 1%. The median TMB was 8.83 Mut/Mb and 45% of pts had KRAS mutations. 52% of the pts had received ≥2 prior lines of treatment for stage IV disease. As of the November 24, 2021 data cutoff, 3 pts remain on treatment, the ORR was 2% (n = 1) and the DCR12 was 40% (n = 17). 26 pts (62%) had SD as best objective response. One responding pt remained on treatment for > 14 mo. The median progression-free survival (39 events) was 2.7 mo (95% CI, 1.6-3.9 mo) and the median overall survival (30 events) was 7.6 mo (95% CI, 6.3-12.2 mo). There were no reported grade 5 treatment toxicities and most grade 3-4 toxicities were hematologic. Additional biomarker analysis to assess effects of key co-mutations on clinical outcomes will be presented. Conclusions: Treatment with talazoparib and avelumab did not meet the pre-specified threshold for efficacy in previously treated STK11-mutant NSCLC in this biomarker-driven Phase II study, though durable disease stabilization was observed. Further studies are required to determine optimal therapeutic approaches for this challenging subset of NSCLC pts. Funding: NIH/NCI grants U10CA180888, U10CA180819. Talazoparib was provided by Pfizer. Avelumab was provided by Pfizer, as part of an alliance between Pfizer and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100004755). Clinical trial information: NCT04173507.
6597
Background: We prospectively assessed financial burden (FB) due to treatment costs among patients with colorectal cancer (CRC) recruited by NCI Community Oncology Research Program (NCORP) sites. ...Methods: Patients with newly diagnosed CRC treated with curative intent enrolled through NCORP sites and completed the FACIT Comprehensive Score for Financial Toxicity (COST) instrument at 0-, 3, 6, and 12 months. Higher COST score (range 0-44) indicates greater financial well-being. Effects of demographic, clinical, self-efficacy and safety net affiliation on FB were assessed using linear mixed modeling with compound symmetry covariance structure to account for measurement correlation from the same subject. Results: In 450 patients (mean age 61, 47% female, 84% white, 64% colon, 31% rectal) attrition was comparable across demographics, clinical variables and baseline FB. Higher COST score was linearly correlated with time. Increasing age, income less than $60,000 (vs. less than $29,999), higher self-efficacy, and higher neighborhood socioeconomic status (nSES) predicted a higher COST score; these effects were not moderated by time. Chemotherapy receipt, insurance type, and treatment at a safety net hospital did not predict COST score. Conclusions: Among those with CRC treated with curative intent in community settings, FB improves over the 12 months post diagnosis. Individual and neighborhood level social determinants of health are protective from financial fragility.Table: see text
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