Ou, Fang-Shu

Metastatic colorectal cancer (mCRC) is a heterogeneous disease that can evoke discordant responses to therapy among different lesions in individual patients. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria do not take into consideration response heterogeneity. We explored and developed lesion-based measurement response criteria to evaluate their prognostic effect on overall survival (OS). Patients and Methods: Patients enrolled in 17 first-line clinical trials, who had mCRC with ≥ 2 lesions at baseline, and a restaging scan by 12 weeks were included. For each patient, lesions were categorized as a progressing lesion (PL: > 20% increase in the longest diameter (LD)), responding lesion (RL: > 30% decrease in LD), or stable lesion (SL: neither PL nor RL) based on the 12-week scan. Lesion-based response criteria were defined for each patient as follows: PL only, SL only, RL only, and varied responses (mixture of RL, SL, and PL). Lesion-based response criteria and OS were correlated using stratified multivariable Cox models. The concordance between OS and classifications was measured using the C statistic. Results: Among 10,551 patients with mCRC from 17 first-line studies, varied responses were noted in 51.6% of patients, among whom, 3.3% had RL/PL at 12 weeks. Among patients with RL/SL, 52% had stable disease (SD) by RECIST 1.1, and they had a longer OS (median OS (mOS) = 19.9 months) than those with SL only (mOS = 16.8 months, HR (95% CI) = 0.81 (0.76, 0.85), p < 0.001), although a shorter OS than those with RL only (mOS = 25.8 months, HR (95% CI) = 1.42 (1.32, 1.53), p < 0.001). Among patients with SL/PL, 74% had SD by RECIST 1.1, and they had a longer OS (mOS = 9.0 months) than those with PL only (mOS = 8.0 months, HR (95% CI) = 0.75 (0.57, 0.98), p = 0.040), yet a shorter OS than those with SL only (mOS = 16.8 months, HR (95% CI) = 1.98 (1.80, 2.18), p < 0.001). These associations were consistent across treatment regimen subgroups. The lesion-based response criteria showed slightly higher concordance than RECIST 1.1, although it was not statistically significant. Conclusion: Varied responses at first restaging are common among patients receiving first-line therapy for mCRC. Our lesion-based measurement criteria allowed for better mortality discrimination, which could potentially be informative for treatment decision-making and influence patient outcomes.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co‐primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Acquired genomic alterations (Acq-GAs), specifically RAS, BRAF, and EGFR-ectodomain mutations and ERBB2 and MET amplifications, are recognized as major mechanisms of resistance to later-line anti–EGFR-antibody therapy in metastatic colorectal cancer (mCRC). However, data regarding emergence of these Acq-GAs under the selective pressure of first-line anti–EGFR-chemotherapy are lacking. We performed next-generation sequencing (Guardant360) on circulating tumor DNA obtained from paired plasma samples (pretreatment and postprogression) from the CALGB/SWOG-80405 trial, which randomly assigned patients with mCRC between first-line chemotherapy with cetuximab (anti–EGFR-chemotherapy) or bevacizumab (anti–VEGF-chemotherapy). The primary objective was to determine the prevalence of Acq-GAs on anti–EGFR-chemotherapy and compare this to the prevalence with anti–VEGF-chemotherapy on trial and pooled estimates (N = 292) seen with later-line anti–EGFR-antibody therapy as reported in the literature. Among the 61 patients on anti–EGFR-chemotherapy, only four (6.6%) developed ≥ 1 Acq-GAs of interest compared with 10.1% (7) on anti–VEGF-chemotherapy (odds ratio, 0.62; 95% CI, 0.20 to 2.11) and 62.0% on anti–EGFR-antibody therapy in later lines (odds ratio, 0.09; 95% CI, 0.03 to 0.23). Acq-GAs, classically associated with anti–EGFR-antibody resistance in later lines ( RAS, BRAF, and EGFR-ectodomain mutations; ERBB2 and MET amplifications), were rare with up-front use of anti–EGFR-chemotherapy indicating divergent resistance mechanisms. These findings have critical translational relevance to timing and value of circulating tumor DNA–guided anti-EGFR rechallenge in patients with mCRC, especially those treated with anti-EGFR therapy upfront.

Abstract Purpose: CALGB/SWOG 80405 was a randomized phase III trial in first-line patients with metastatic colorectal cancer treated with bevacizumab, cetuximab, or both, plus chemotherapy. We tested the effect of tumor immune features on overall survival (OS). Experimental Design: Primary tumors (N = 554) were profiled by RNA sequencing. Immune signatures of macrophages, lymphocytes, TGFβ, IFNγ, wound healing, and cytotoxicity were measured. CIBERSORTx scores of naive and memory B cells, plasma cells, CD8+ T cells, resting and activated memory CD4+ T cells, M0 and M2 macrophages, and activated mast cells were measured. Results: Increased M2 macrophage score [HR, 6.30; 95% confidence interval (CI), 3.0–12.15] and TGFβ signature expression (HR, 1.35; 95% CI, 1.05–1.77) were associated with shorter OS. Increased scores of plasma cells (HR, 0.55; 95% CI, 0.38–0.87) and activated memory CD4+ T cells (HR, 0.34; 95% CI, 0.16–0.65) were associated with longer OS. Using optimal cutoffs from these four features, patients were categorized as having either 4, 3, 2, or 0–1 beneficial features associated with longer OS, and the median (95% CI) OS decreased from 42.5 (35.8–47.8) to 31.0 (28.8–34.4), 25.2 (20.6–27.9), and 17.7 (13.5–20.4) months respectively (P = 3.48e–11). Conclusions: New immune features can be further evaluated to improve patient response. They provide the rationale for more effective immunotherapy strategies.

Abstract Background Limited and conflicting findings have been reported regarding the association between social support and colorectal cancer (CRC) outcomes. We sought to assess the influences of marital status and living arrangement on survival outcomes among patients with stage III colon cancer. Patients and Methods We conducted a secondary analysis of 1082 patients with stage III colon cancer prospectively followed in the CALGB 89803 randomized adjuvant chemotherapy trial. Marital status and living arrangement were both self-reported at the time of enrollment as, respectively, married, divorced, separated, widowed, or never-married, and living alone, with a spouse or partner, with other family, in a nursing home, or other. Results Over a median follow-up of 7.6 years, divorced/separated/widowed patients experienced worse outcomes relative to those married regarding disease free-survival (DFS) (hazards ratio (HR), 1.44 (95% CI, 1.14-1.81); P =.002), recurrence-free survival (RFS) (HR, 1.35 (95% CI, 1.05-1.73); P = .02), and overall survival (OS) (HR, 1.40 (95% CI, 1.08-1.82); P =.01); outcomes were not significantly different for never-married patients. Compared to patients living with a spouse/partner, those living with other family experienced a DFS of 1.47 (95% CI, 1.02-2.11; P = .04), RFS of 1.34 (95% CI, 0.91-1.98; P = .14), and OS of 1.50 (95% CI, 1.00-2.25; P =.05); patients living alone did not experience significantly different outcomes. Conclusion Among patients with stage III colon cancer who received uniform treatment and follow-up within a nationwide randomized clinical trial, being divorced/separated/widowed and living with other family were significantly associated with greater colon cancer mortality. Interventions enhancing social support services may be clinically relevant for this patient population. Trial Registration ClinicalTrials.gov Identifier: NCT00003835

PURPOSECurrent tools in predicting survival outcomes for patients with colon cancer predominantly rely on clinical and pathologic characteristics, but increasing evidence suggests that diet and lifestyle habits are associated with patient outcomes and should be considered to enhance model accuracy.METHODSUsing an adjuvant chemotherapy trial for stage III colon cancer (CALGB 89803), we developed prediction models of disease-free survival (DFS) and overall survival by additionally incorporating self-reported nine diet and lifestyle factors. Both models were assessed by multivariable Cox proportional hazards regression and externally validated using another trial for stage III colon cancer (CALGB/SWOG 80702), and visual nomograms of prediction models were constructed accordingly. We also proposed three hypothetical scenarios for patients with (1) good-risk, (2) average-risk, and (3) poor-risk clinical and pathologic features, and estimated their predictive survival by considering clinical and pathologic features with or without adding self-reported diet and lifestyle factors.RESULTSAmong 1,024 patients (median age 60.0 years, 43.8% female), we observed 394 DFS events and 311 deaths after median follow-up of 7.3 years. Adding self-reported diet and lifestyle factors to clinical and pathologic characteristics meaningfully improved performance of prediction models (c-index from 0.64 [95% CI, 0.62 to 0.67] to 0.69 [95% CI, 0.67 to 0.72] for DFS, and from 0.67 [95% CI, 0.64 to 0.70] to 0.71 [95% CI, 0.69 to 0.75] for overall survival). External validation also indicated good performance of discrimination and calibration. Adding most self-reported favorable diet and lifestyle exposures to multivariate modeling improved 5-year DFS of all patients and by 6.3% for good-risk, 21.4% for average-risk, and 42.6% for poor-risk clinical and pathologic features.CONCLUSIONDiet and lifestyle factors further inform current recurrence and survival prediction models for patients with stage III colon cancer.

Abstract Background Combination irinotecan and cetuximab is approved for irinotecan-refractory metastatic colorectal cancer (mCRC). It is unknown if adding bevacizumab improves outcomes. Patients and Methods In this multicenter, randomized, double-blind, placebo-controlled phase II trial, patients with irinotecan-refractory RAS-wildtype mCRC and no prior anti-EGFR therapy were randomized to cetuximab 500 mg/m2, bevacizumab 5 mg/kg, and irinotecan 180 mg/m2 (or previously tolerated dose) (CBI) versus cetuximab, irinotecan, and placebo (CI) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results The study closed early after the accrual of 36 out of a planned 120 patients due to changes in funding. Nineteen patients were randomized to CBI and 17 to CI. Baseline characteristics were similar between arms. Median PFS was 9.7 versus 5.5 months for CBI and CI, respectively (1-sided log-rank P = .38; adjusted hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.25-1.66). Median OS was 19.7 versus 10.2 months for CBI and CI (1-sided log-rank P = .02; adjusted HR = 0.41; 95% CI, 0.15-1.09). ORR was 36.8% for CBI versus 11.8% for CI (P = .13). Grade 3 or higher AEs occurred in 47% of patients receiving CBI versus 35% for CI (P = .46). Conclusion In this prematurely discontinued trial, there was no significant difference in the primary endpoint of PFS between CBI and CI. There was a statistically significant improvement in OS in favor of CBI compared with CI. Further investigation of CBI for the treatment of irinotecan-refractory mCRC is warranted. Clinical Trial Registration: NCT02292758

Abstract Background The incidence of young-onset colorectal cancer (yoCRC) is increasing. It is unknown if there are survival differences between young and older patients with metastatic colorectal cancer (mCRC). Methods We studied the association of age with survival in 2326 mCRC patients enrolled in the Cancer and Leukemia Group B and SWOG 80405 trial, a multicenter, randomized trial of first-line chemotherapy plus biologics. The primary and secondary outcomes of this study were overall survival (OS) and progression-free survival (PFS), respectively, which were assessed by Kaplan-Meier method and compared among younger vs older patients with the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated based on Cox proportional hazards modeling, adjusting for known prognostic variables. All statistical tests were 2-sided. Results Of 2326 eligible subjects, 514 (22.1%) were younger than age 50 years at study entry (yoCRC cohort). The median age of yoCRC patients was 44.3 vs 62.5 years in patients aged 50 years and older. There was no statistically significant difference in OS between yoCRC vs older-onset patients (median = 27.07 vs 26.12 months; adjusted HR = 0.98, 95% CI = 0.88 to 1.10; P = .78). The median PFS was also similar in yoCRC vs older patients (10.87 vs 10.55 months) with an adjusted hazard ratio of 1.02 (95% CI = 0.92 to 1.13; P = .67). Patients younger than age 35 years had the shortest OS with median OS of 21.95 vs 26.12 months in older-onset patients with an adjusted hazard ratio of 1.08 (95% CI = 0.81 to 1.44; Ptrend = .93). Conclusion In this large study of mCRC patients, there were no statistically significant differences in survival between patients with yoCRC and CRC patients aged 50 years and older.

There are no biomarkers predictive of resistance to docetaxel or cabazitaxel validated for patients with metastatic castration-resistant prostate cancer (mCRPC). We assessed the association between ABCB1 amplification and primary resistance to docetaxel or cabazitaxel for patients with mCRPC, using circulating cell-free DNA (cfDNA). Patients with ≥1 plasma sample drawn within 12 months before starting docetaxel (cohort A) or cabazitaxel (cohort B) for mCRPC were identified from the Dana–Farber Cancer Institute IRB approved database. Sparse whole genome sequencing was performed on the selected cfDNA samples and tumor fractions were estimated using the computational tool ichorCNA. We evaluated the association between ABCB1 amplification or other copy number alterations and primary resistance to docetaxel or cabazitaxel. Of the selected 176 patients, 45 samples in cohort A and 21 samples in cohort B had sufficient tumor content. No significant association was found between ABCB1 amplification and primary resistance to docetaxel (p = 0.58; odds ratio (OR) = 1.49) or cabazitaxel (p = 0.97; OR = 1.06). No significant association was found between exploratory biomarkers and primary resistance to docetaxel or cabazitaxel. In this study, ABCB1 amplification did not predict primary resistance to docetaxel or cabazitaxel for mCRPC. Future studies including ABCB1 amplification in a suite of putative biomarkers and a larger cohort may aid in drawing definitive conclusions.

PURPOSECholangiocarcinomas (CCA) are a group of heterogeneous tumors arising from the biliary epithelia. Significant sequencing efforts have provided further insights into the molecular mechanisms of this disease including fibroblast growth factor receptor ( FGFR) alterations, which occurs in approximately 15%-20% of intrahepatic CCAs. Herein, we describe the FGFR inhibitor (FGFRi)-associated treatment toxicity and cancer-specific outcomes from a multicenter single-institution cohort.METHODSThis is a retrospective study of patients with CCA and known FGFR alterations treated with FGFRi. We describe the toxicity and efficacy in patients treated at Mayo Clinic between January 2010 and December 2020.RESULTSOur group identified 61 patients with advanced or metastatic CCA, 19 males (31%) and 42 females (69%), harboring FGFR alterations who received FGFRi. The most common grade 1 or higher adverse events for all patients included fatigue (92%), AST elevations (78%), anemia (80%), decreased platelet count (63%), and hyperphosphatemia (74%). Median progression-free survival on FGFRi was 5.8 months for all patients (95% CI, 4.9 to 9.0). Females had significantly longer progression-free survival at 6.9 months (95% CI, 5.2 to 11.8) on FGFRi compared with males at 4.9 months (95% CI, 2.8 to not estimable; P = .038).CONCLUSIONFGFRi are well tolerated with clinical efficacy. With the recent approval of FGFRi by the US Food and Drug Administration and ongoing clinical trials for new FGFRi, understanding outcomes and toxicity associated with these medications is important for precision oncology.

PURPOSE To evaluate the use of early assessment of chemotherapy responsiveness by positron emission tomography (PET) imaging to tailor therapy in patients with esophageal and esophagogastric junction adenocarcinoma. METHODS After baseline PET, patients were randomly assigned to an induction chemotherapy regimen: modified oxaliplatin, leucovorin, and fluorouracil (FOLFOX) or carboplatin-paclitaxel (CP). Repeat PET was performed after induction; change in maximum standardized uptake value (SUV) from baseline was assessed. PET nonresponders (< 35% decrease in SUV) crossed over to the alternative chemotherapy during chemoradiation (50.4 Gy/28 fractions). PET responders (≥ 35% decrease in SUV) continued on the same chemotherapy during chemoradiation. Patients underwent surgery at 6 weeks postchemoradiation. Primary end point was pathologic complete response (pCR) rate in nonresponders after switching chemotherapy. RESULTS Two hundred forty-one eligible patients received Protocol treatment, of whom 225 had an evaluable repeat PET. The pCR rates for PET nonresponders after induction FOLFOX who crossed over to CP (n = 39) or after induction CP who changed to FOLFOX (n = 50) was 18.0% (95% CI, 7.5 to 33.5) and 20% (95% CI, 10 to 33.7), respectively. The pCR rate in responders who received induction FOLFOX was 40.3% (95% CI, 28.9 to 52.5) and 14.1% (95% CI, 6.6 to 25.0) in responders to CP. With a median follow-up of 5.2 years, median overall survival was 48.8 months (95% CI, 33.2 months to not estimable) for PET responders and 27.4 months (95% CI, 19.4 months to not estimable) for nonresponders. For induction FOLFOX patients who were PET responders, median survival was not reached. CONCLUSION Early response assessment using PET imaging as a biomarker to individualize therapy for patients with esophageal and esophagogastric junction adenocarcinoma was effective, improving pCR rates in PET nonresponders. PET responders to induction FOLFOX who continued on FOLFOX during chemoradiation achieved a promising 5-year overall survival of 53%.