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PURPOSE Prospective data on the efficacy of a watch-and-wait strategy to achieve organ preservation in patients with locally advanced rectal cancer treated with total neoadjuvant therapy are limited. METHODS In this prospective, randomized phase II trial, we assessed the outcomes of 324 patients with stage II or III rectal adenocarcinoma treated with induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) and either total mesorectal excision (TME) or watch-and-wait on the basis of tumor response. Patients in both groups received 4 months of infusional fluorouracil-leucovorin-oxaliplatin or capecitabine-oxaliplatin and 5,000 to 5,600 cGy of radiation combined with either continuous infusion fluorouracil or capecitabine during radiotherapy. The trial was designed as two stand-alone studies with disease-free survival (DFS) as the primary end point for both groups, with a comparison to a null hypothesis on the basis of historical data. The secondary end point was TME-free survival. RESULTS Median follow-up was 3 years. Three-year DFS was 76% (95% CI, 69 to 84) for the INCT-CRT group and 76% (95% CI, 69 to 83) for the CRT-CNCT group, in line with the 3-year DFS rate (75%) observed historically. Three-year TME-free survival was 41% (95% CI, 33 to 50) in the INCT-CRT group and 53% (95% CI, 45 to 62) in the CRT-CNCT group. No differences were found between groups in local recurrence-free survival, distant metastasis-free survival, or overall survival. Patients who underwent TME after restaging and patients who underwent TME after regrowth had similar DFS rates. CONCLUSION Organ preservation is achievable in half of the patients with rectal cancer treated with total neoadjuvant therapy, without an apparent detriment in survival, compared with historical controls treated with chemoradiotherapy, TME, and postoperative chemotherapy.

PURPOSE Current 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. METHODS Using 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. RESULTS Among 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. CONCLUSION Diet and lifestyle factors further inform current recurrence and survival prediction models for patients with stage III colon cancer.

Purpose: BRAF-mutant metastatic colorectal cancer (mCRC) forms an aggressive subset of colorectal cancer with minimal response to selective RAF inhibitors. Preclinical data show that reactivation of EGFR signaling occurs in colorectal tumor cells treated with RAF inhibitors and that the addition of an EGFR inhibitor enhances antitumor activity. These data suggest that combined therapy with RAF and EGFR inhibitors could be an effective strategy for treating BRAF V600E mCRC.Experimental Design: We undertook a pilot trial to assess the response rate and safety of the BRAF inhibitor vemurafenib combined with anti-EGFR antibody panitumumab in patients with BRAF-mutant mCRC. Patients received standard approved doses of panitumumab and vemurafenib.Results: Fifteen patients were treated. Performance status was Eastern Cooperative Oncology Group (ECOG) 0 in 4 patients (27%) and ECOG 1 in 11 patients (73%). All patients had progressed through at least one standard treatment regimen, and 8 (53%) had received previous fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy. Treatment was well tolerated, with less cutaneous toxicity than would be expected with either agent, and no cases of keratoacanthomas/squamous cell carcinomas. Tumor regressions were seen in 10 of 12 evaluable patients with partial responses in 2 patients (100% and 64% regression lasting 40 and 24 weeks, respectively), and stable disease lasting over 6 months in 2 patients.Conclusions: Combined RAF and EGFR inhibition is well tolerated, with less cutaneous toxicity than would be expected with either agent, and results in modest clinical activity in this highly aggressive and chemoresistant subset of CRC. Clin Cancer Res; 21(6); 1313–20. ©2015 AACR.

Supplemental Table 1: Clinical Characteristics, Treatment, and Recurrence Rates of of Patients with Stage II SBA Supplemental Table 2. Germline variants among SBA patients

Flow dot plots

Supplementary Information - PDF file 170K, methods for sequencing of TP53; ii) Table S1 giving the clinical and pathologic features of all patients enrolled in CALGB 89803 and the subset of patients in the current study as a function of TP53 genotype; iii) Table S2 giving the results of an exploratory analysis of DFS and OS as a function of treatment arm, TP53 genotype and gender; iv) Table S3 showing results of a multivariable analysis for DFS and OS with the following variables retained from a univariate analysis: sex,TP53 genotype, sex by TP53 genotype interaction, as well as pathologic variables; v) Supplementary Figure Legends

Supplemental table 1. Genes included in custom next-generation sequencing assay.

Purpose:Evaluate response of mismatch repair–deficient (dMMR) rectal cancer to neoadjuvant chemotherapy.Experimental Design:dMMR rectal tumors at Memorial Sloan Kettering Cancer Center (New York, NY) were retrospectively reviewed for characteristics, treatment, and outcomes. Fifty patients with dMMR rectal cancer were identified by IHC and/or microsatellite instability analysis, with initial treatment response compared with a matched MMR-proficient (pMMR) rectal cancer cohort. Germline and somatic mutation analyses were evaluated. Patient-derived dMMR rectal tumoroids were assessed for chemotherapy sensitivity.Results:Of 21 patients receiving neoadjuvant chemotherapy (fluorouracil/oxaliplatin), six (29%) had progression of disease. In comparison, no progression was noted in 63 pMMR rectal tumors (P = 0.0001). Rectal cancer dMMR tumoroids reflected this resistance to chemotherapy. No genomic predictors of chemotherapy response were identified. Of 16 patients receiving chemoradiation, 13 (93%) experienced tumor downstaging; one patient had stable disease, comparable with 48 pMMR rectal cancers. Of 13 patients undergoing surgery, 12 (92%) had early-stage disease. Forty-two (84%) of the 50 patients tested positive for Lynch syndrome with enrichment of germline MSH2 and MSH6 mutations when compared with 193 patients with Lynch syndrome–associated colon cancer (MSH2, 57% vs 36%; MSH6, 17% vs 9%; P < 0.003).Conclusions:Over one-fourth of dMMR rectal tumors treated with neoadjuvant chemotherapy exhibited disease progression. Conversely, dMMR rectal tumors were sensitive to chemoradiation. MMR status should be performed upfront in all locally advanced rectal tumors with careful monitoring for response on neoadjuvant chemotherapy and genetic testing for Lynch syndrome in patients with dMMR rectal cancer.

Purpose: Alterations in the RAS-RAF-MAP2K (MEK)-MAPK signaling pathway are major drivers in colorectal carcinogenesis. In colorectal cancer, BRAF mutation is associated with microsatellite instability (MSI), and typically predicts inferior prognosis. We examined the effect of BRAF mutation on survival and treatment efficacy in patients with stage III colon cancer.Methods: We assessed status of BRAF c.1799T>A (p.V600E) mutation and MSI in 506 stage III colon cancer patients enrolled in a randomized adjuvant chemotherapy trial [5-fluorouracil and leucovorin (FU/LV) vs. irinotecan (CPT11), FU and LV (IFL); CALGB 89803]. Cox proportional hazards model was used to assess the prognostic role of BRAF mutation, adjusting for clinical features, adjuvant chemotherapy arm, and MSI status.Results: Compared with 431 BRAF wild-type patients, 75 BRAF-mutated patients experienced significantly worse overall survival [OS; log-rank P = 0.015; multivariate HR = 1.66; 95% CI: 1.05–2.63]. By assessing combined status of BRAF and MSI, it seemed that BRAF-mutated MSS (microsatellite stable) tumor was an unfavorable subtype, whereas BRAF wild-type MSI-high tumor was a favorable subtype, and BRAF-mutated MSI-high tumor and BRAF wild-type MSS tumor were intermediate subtypes. Among patients with BRAF-mutated tumors, a nonsignificant trend toward improved OS was observed for IFL versus FU/LV arm (multivariate HR = 0.52; 95% CI: 0.25–1.10). Among patients with BRAF wild-type cancer, IFL conferred no suggestion of benefit beyond FU/LV alone (multivariate HR = 1.02; 95% CI: 0.72–1.46).Conclusions:BRAF mutation is associated with inferior survival in stage III colon cancer. Additional studies are necessary to assess whether there is any predictive role of BRAF mutation for irinotecan-based therapy. Clin Cancer Res; 18(3); 890–900. ©2011 AACR.

Purpose: The TP53 tumor suppressor is frequently mutated in colon cancer, but the influence of such mutations on survival remains controversial. We investigated whether mutations in the DNA-binding domain of TP53 are associated with survival in stage III colon cancer.Experimental Design: The impact of TP53 genotype was prospectively evaluated in Cancer and Leukemia Group B 89803, a trial that randomized stage III colon cancer patients to receive adjuvant 5-fluorouracil/leucovorin (5FU/LV) or 5FU/LV with irinotecan (IFL).Results:TP53 mutations were identified in 274 of 607 cases. The presence of any TP53 mutation did not predict disease-free survival (DFS) or overall survival with either adjuvant regimen when men and women were considered together or as separate groups. However, outcome differences among women became apparent when tumor TP53 genotype was stratified as wild-type versus zinc- or non-zinc-binding mutations in the TP53 DNA-binding domain. DFS at 5 years was 0.59, 0.52, and 0.78 for women with TP53 wild-type tumors, and tumors with zinc- or non-zinc-binding mutations, respectively. Survival at 5 years for these same women was 0.72, 0.59, and 0.90, respectively. No differences in survival by TP53 genotype were observed in men.Conclusions: The presence of any TP53 mutation within the DNA-binding domain did not predict survival in stage III colon cancer. However, TP53 genotype was predictive of survival in women following adjuvant therapy. Future colon cancer therapeutic trials, with inclusion of correlative molecular markers, should be designed to permit evaluation of survival and/or response to treatment in women separately from men. Clin Cancer Res; 19(20); 5777–87. ©2013 AACR.

Molecular predictors of progression free survival in patients treated with cytotoxic chemotherapy

Supplementary Figures - PDF file 341K, Figure S1. CALGB 89803 Consolidated Standards of Reporting Trials (CONSORT) diagram. Cancer and Leukemia Group B (CALGB) 89803 conducted a randomized trial of adjuvant therapy in patients with stage III colorectal cancers. The trial included prospective determination of the relationship between tumor TP53 mutational status, gender, and treatment outcome as a secondary study end point. CPT-11, irinotecan; FU, fluorouracil; LV, leucovorin. Figure S2. Kaplan-Meier estimates of disease-free survival related to TP53 status for men and women in CALGB 89803. A. DFS in the presence or absence of any TP53 mutation showed no differences among women (P = 0.16). B. Similarly, DFS in the presence or absence of any TP53 mutation showed no differences among men (P = 0.16). WT = wild type TP53; Mutant = any TP53 mutation in exons 5-8). Corresponding 5 year survival estimates are in Table 2, Rows 5 and 6. Figure S3. Kaplan-Meier estimates of disease-free survival related to TP53 status among men in CALGB 89803. Men whose tumors harbored wild-type (WT) TP53, or tumors with mutations in the zinc-binding (ZB) or non-zinc binding (NZB) domains of TP53 were treated with 5FU/LV (Figure S3A) or IFL (Figure S3B). No differences in survival according to TP53 genotype were observed among men treated with 5FU/LV (P = 0.65) or IFL, P = 0.14. Corresponding 5 year survival estimates are in Table 2, Rows 16-17. Figure S4. Kaplan-Meier estimates of disease-free survival related to TP53 status among women in CALGB 89803. Women whose tumors harbored wild-type TP53, or tumors with mutations in the zinc-binding (ZB) or non-zinc binding (NZB) domains of TP53 were treated with 5FU/LV or IFL. (A) Women with TP53 WT tumors experienced a statistically similar outcome on either treatment arm (P = 0.35. (B) Women whose tumors harbored ZB mutations may have benefited marginally from IFL as compared to 5FU/LV (P = 0.10). (C) Women whose tumors harbored NZB mutations experienced a trend toward better survival with 5FU/LV compared to IFL (P = 0.08)

Supplementary Methods and Supplementary Table 1

Overall survival from diagnosis with advanced disease by KRAS, ERBB2 and CDKN2A/B status

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Purpose:Immune checkpoint inhibition (ICI) alone is not active in mismatch repair–proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models.Patients and Methods:In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles.Results:We enrolled 24 patients, and report outcomes after a median follow-up of 21.8 (range: 15.9–26.3) months. The ORR was 8.3% (2 patients) [95% confidence interval (CI), 1.0–27.0]. The median progression-free survival was 1.8 (95% CI, 1.7–1.9) months, median overall survival was 11.4 (95% CI, 10.1–17.4) months. Twenty five percent of patients (n = 6) had treatment-related grade 3–4 adverse events. We observed increased circulating CD8+ T lymphocyte activation, differentiation, and proliferation in patients with objective response.Conclusions:This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.

PDF file - 50K, aplan-Meier analyses of stage III colon cancer patients according to treatment arm and MSI status. DFS, disease-free survival; FU/LV, 5-fluorouracil and leucovorin; IFL, irinotecan, 5-fluorouracil and leucovorin; MSI, microsatellite instability; MSS, microsatellite stable; OS, overall survival; RFS, recurrence-free survival.

Supplementary Methods, References, and Figures

Study design

Genomic and clinical information of MSKCC validation cohort (n=935) with corresponding data dictionary

Purpose:This two-part phase Ib trial determined the maximum tolerated dose (MTD) of the combination of trifluridine/tipiracil (FTD/TPI) and irinotecan in patients with advanced gastrointestinal tumors, and evaluated the safety, pharmacokinetics, and antitumor activity of the FTD/TPI, irinotecan, and bevacizumab triplet combination in previously treated metastatic colorectal cancer (mCRC).Patients and Methods:Dose escalation (3+3 design) in advanced gastrointestinal tumors was followed by expansion in mCRC. During dose escalation, patients received FTD/TPI (20–35 mg/m2 twice daily; days 1–5 of a 14-day cycle) and irinotecan (120–180 mg/m2; day 1). During expansion, the MTD of FTD/TPI and irinotecan plus bevacizumab (5 mg/kg; day 1) was administered.Results:Fifty patients (26 across six dose-escalation cohorts and 24 in the expansion phase) were enrolled. Two dose-limiting toxicities (fatigue and neutropenia) were observed in the dose-escalation phase, and MTD was defined as FTD/TPI 25 mg/m2 twice daily plus irinotecan 180 mg/m2. In the expansion phase, 83% (20/24) experienced any-cause grade ≥3 adverse events (AEs) with the triplet combination, most frequently neutropenia (42%), leukopenia (25%), and diarrhea (12%). AEs of any-cause led to dosing interruptions, modifications, and discontinuations in 29%, 17%, and 4% of patients, respectively. No treatment-related deaths occurred. Three patients (12%) experienced partial responses and 16 (67%) patients had stable disease lasting >4 months. The median progression-free survival was 7.9 months (95% confidence interval, 5.1–13.4 months).Conclusions:Tolerability and activity observed in this phase I trial support further investigation of the FTD/TPI–irinotecan–bevacizumab combination in previously treated mCRC.

PDF file - 42K, Distribution of stage III colon cancer according to MSI, KRAS and BRAF status.

Supplementary methods, supplementary results and Supplementary Tables S1 and S2

Purpose:The prevalence and clinical characteristics of small bowel adenocarcinomas (SBA) in the setting of Lynch syndrome have not been well studied. We characterized SBA according to DNA mismatch repair and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes.Experimental Design:A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via IHC staining. Germline DNA was analyzed for mutations in known cancer predisposition genes, including MMR (MLH1, MSH2, MSH6, PMS2, and EPCAM). Clinical variables were correlated with MMR/MSI status.Results:Twenty-six percent (26/100; 95% confidence interval, 18.4–35.4) of SBAs exhibited MMR deficiency (MMR-D). Lynch syndrome prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-Lynch syndrome MMR-D versus MMR-proficient (MMR-P) SBAs (65 vs. 61; P = 0.75), but significantly younger in Lynch syndrome (47.5 vs. 61; P = 0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P versus 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in Lynch syndrome (P = 0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared with 23.1% (6/26) in the MMR-D group (P = 0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared with 18.2% (2/11) in the MMR-D group (P = 0.0002).Conclusions:When compared with MMR-P SBA, MMR-D SBA was associated with earlier stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline Lynch syndrome testing in MMR-D SBA is warranted.

Radiation treatment summary

Supplementary Table 1: List of genes used for PGx modeling Supplementary Table 2: Correlation of PGx model prediction in tumor tissue to CTICs, soft tissue sarcoma. Supplementary Table 3. Normalized Enrichment Scores for chemotherapeutic agents modeled in three pancreatic cancer derived xenografts, referenced in (Figure 2). Supplementary Figure 1. Correlation of PGx model prediction in tumor tissue to CTICs, soft tissue sarcoma. Supplementary Figure 2. Correlation of Treatment Score to (A) PFS and (B) OS.

Gene mutations in responder patients

Purpose:We aimed to investigate genomic correlates underlying extremes of survivorship in metastatic colorectal cancer and their applicability in informing survival in distinct subsets of patients with metastatic colorectal cancer.Experimental Design:We examined differences in oncogenic somatic alterations between metastatic colorectal cancer cohorts demonstrating extremes of survivorship following complete metastasectomy: ≤2-year (n = 17) and ≥10-year (n = 18) survivors. Relevant genomic findings, and their association with overall survival (OS), were validated in two independent datasets of 935 stage IV and 443 resected stage I–IV patients.Results:In the extremes-of-survivorship cohort, significant co-occurrence of KRAS hotspot mutations and TP53 alterations was observed in ≤2-year survivors (P < 0.001). When validating these findings in the independent cohort of 935 stage IV patients, incorporation of the cumulative effect of any oncogenic Ras/B-raf (i.e., either KRAS, NRAS, or BRAF) and TP53 alteration generated three prognostic clusters: (i) TP53-altered alone (median OS, 132 months); (ii) Ras/B-raf–altered alone (65 months) or Ras/B-raf- and TP53 pan-wild-type (60 months); and (iii) coaltered Ras/B-raf–TP53 (40 months; P < 0.0001). Coaltered Ras/B-raf–TP53 was independently associated with mortality (HR, 2.47; 95% confidence interval, 1.91–3.21; P < 0.001). This molecular profile predicted survival in the second independent cohort of 443 resected stage I–IV patients. Coaltered Ras/B-raf–TP53 was associated with worse OS in patients with liver (n = 490) and lung (n = 172) but not peritoneal surface (n = 149) metastases. Moreover, coaltered Ras/B-raf–TP53 tumors were significantly more likely to involve extrahepatic metastatic sites with limited salvage options.Conclusions:Genomic analysis of extremes of survivorship following colorectal cancer metastasectomy identifies a prognostic role for coaltered Ras/B-raf–TP53 and its association with distinct patterns of colorectal cancer metastasis.

Purpose: Various genetic driver aberrations have been identified among distinct anatomic and clinical subtypes of intrahepatic and extrahepatic cholangiocarcinoma, and these molecular alterations may be prognostic biomarkers and/or predictive of drug response.Experimental Design: Tumor samples from patients with cholangiocarcinoma who consented prospectively were analyzed using the MSK-IMPACT platform, a targeted next-generation sequencing assay that analyzes all exons and selected introns of 410 cancer-associated genes. Fisher exact tests were performed to identify associations between clinical characteristics and genetic alterations.Results: A total of 195 patients were studied: 78% intrahepatic and 22% extrahepatic cholangiocarcinoma. The most commonly altered genes in intrahepatic cholangiocarcinoma were IDH1 (30%), ARID1A (23%), BAP1 (20%), TP53 (20%), and FGFR2 gene fusions (14%). A tendency toward mutual exclusivity was seen between multiple genes in intrahepatic cholangiocarcinoma including TP53:IDH1, IDH1:KRAS, TP53:BAP1, and IDH1:FGFR2. Alterations in CDKN2A/B and ERBB2 were associated with reduced survival and time to progression on chemotherapy in patients with locally advanced or metastatic disease. Genetic alterations with potential therapeutic implications were identified in 47% of patients, leading to biomarker-directed therapy or clinical trial enrollment in 16% of patients.Conclusions: Cholangiocarcinoma is a genetically diverse cancer. Alterations in CDKN2A/B and ERBB2 are associated with negative prognostic implications in patients with advanced disease. Somatic alterations with therapeutic implications were identified in almost half of patients. These prospective data provide a contemporary benchmark for guiding the development of targeted therapies in molecularly profiled cholangiocarcinoma, and support to the use of molecular profiling to guide therapy selection in patients with advanced biliary cancers. Clin Cancer Res; 24(17); 4154–61. ©2018 AACR.

Supplementary table 2. Tumor genetic mutations identified with next generation sequencing

Flow cytometry result summary

Purpose: Despite a challenging prognosis, modern cytotoxic therapy can induce tumor responses and extend life in pancreatic adenocarcinoma (PDAC). Pharmacogenomic (PGx) modeling of tumor tissue can predict the efficacy of chemotherapeutic agents in preclinical cancer models. We hypothesized that PGx profiling of circulating tumor and invasive cells (CTIC) isolated from peripheral blood could predict tumor response, progression, and resistance.Experimental Design: A PGx model was created and validated in preclinical models. A prospective clinical trial was conducted. Fifty patients with advanced PDAC were enrolled. Before treatment, 10 mL of peripherally drawn blood was collected. CTICs isolated from this blood sample were expression profiled and the PGx model was used to predict effective and ineffective chemotherapeutic agents. The treating physicians were blinded to PGx prediction.Results: We found that CTICs could be reliably isolated, total RNA extracted and profiled from 10 mL of peripheral blood from patients with unresectable PDAC before chemotherapy treatment and at disease progression. Using previously created PGx models to predict chemotherapy sensitivity, we found that clinical benefit was seen for study participants treated with chemotherapy regimens predicted to be effective versus chemotherapy regimens predicted to be ineffective with regard to progression-free (10.4 mo vs. 3.6 mo; P < 0.0001; HR, 0.14) and overall survival (17.2 mo vs. 8.3 mo; P < 0.0249; HR, 0.29).Conclusions: These findings suggest that PGx profiling of CTICs can predict treatment response. Clin Cancer Res; 20(20); 5281–9. ©2014 AACR.

Supplementary Figures 1-3, Tables 1-9, Methods from Genomic and Biological Characterization of Exon 4 KRAS Mutations in Human Cancer

Mutations in RAS proteins occur widely in human cancer. Prompted by the confirmation of KRAS mutation as a predictive biomarker of response to epidermal growth factor receptor (EGFR)–targeted therapies, limited clinical testing for RAS pathway mutations has recently been adopted. We performed a multiplatform genomic analysis to characterize, in a nonbiased manner, the biological, biochemical, and prognostic significance of Ras pathway alterations in colorectal tumors and other solid tumor malignancies. Mutations in exon 4 of KRAS were found to occur commonly and to predict for a more favorable clinical outcome in patients with colorectal cancer. Exon 4 KRAS mutations, all of which were identified at amino acid residues K117 and A146, were associated with lower levels of GTP-bound RAS in isogenic models. These same mutations were also often accompanied by conversion to homozygosity and increased gene copy number, in human tumors and tumor cell lines. Models harboring exon 4 KRAS mutations exhibited mitogen-activated protein/extracellular signal-regulated kinase kinase dependence and resistance to EGFR-targeted agents. Our findings suggest that RAS mutation is not a binary variable in tumors, and that the diversity in mutant alleles and variability in gene copy number may also contribute to the heterogeneity of clinical outcomes observed in cancer patients. These results also provide a rationale for broader KRAS testing beyond the most common hotspot alleles in exons 2 and 3. Cancer Res; 70(14); 5901–11. ©2010 AACR.

Background Colon cancer (CC) incidence in young adults (age 20-49 years), termed early-onset CC (EO-CC), is increasing. Methods Individual patient data on 35 713 subjects with stage III colon cancer from 25 randomized studies in the Adjuvant Colon Cancer ENdpoint database were pooled. The distributions of demographics, clinicopathological features, biomarker status, and outcome data were summarized by age group. Overall survival, disease-free survival, time to recurrence, and survival after recurrence were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for sex, race, body mass index, performance status, disease stage, grade, risk group, number of lymph nodes examined, disease sidedness, and molecular markers. All statistical tests were 2-sided. Results Using a 5% difference between age groups as the clinically meaningful cutoff, patients with stage III EO-CC had similar sex, race, performance status, risk group, tumor sidedness, and T stage compared with patients with late-onset CC (age 50 years and older). EO-CC patients were less likely to be overweight (30.2% vs 36.2%) and more commonly had 12 or more lymph nodes resected (69.5% vs 58.7%). EO-CC tumors were more frequently mismatch repair deficient (16.4% vs 11.5%) and less likely to have BRAFV600E (5.6% vs 14.0%), suggesting a higher rate of Lynch syndrome in EO-CC. Patients with EO-CC had statistically significantly better overall survival (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.74 to 0.89; P Conclusion Tumor biology was found to be a more important prognostic factor than age of onset among stage III colon cancer patients in the Adjuvant Colon Cancer ENdpoint database.

ImportanceThe risk of recurrence in patients with locally advanced rectal cancer has historically been determined after surgery, relying on pathologic variables. A growing number of patients are being treated without surgery, and their risk of recurrence needs to be calculated differently.ObjectiveTo develop a dynamic calculator for estimating the probability of recurrence-free survival (RFS) in patients with rectal cancer who undergo total neoadjuvant therapy (TNT) (induction systemic chemotherapy and chemoradiotherapy) and either surgery or watch-and-wait management.Design, Setting, and ParticipantsThis cohort study included patients who presented with stage II or III rectal cancer between June 1, 2009, and March 1, 2015, at a comprehensive cancer center. Conditional modeling was incorporated into a previously validated clinical calculator to allow the probability of RFS to be updated based on whether the patient remained in watch-and-wait management or underwent delayed surgery. Data were analyzed from November 2021 to March 2022.ExposureTNT followed by immediate surgery or watch-and-wait management with the possibility of delayed surgery.Main Outcomes and MeasuresRFS, concordance index, calibration curves.ResultsOf the 302 patients in the cohort, 204 (68%) underwent surgery within 3 months from TNT completion (median [range] age, 51 [22-82] years; 78 [38%] women), 54 (18%) underwent surgery more than 3 months from TNT completion (ie, delayed surgery; median [range] age, 62 [31-87] years; 30 [56%] female), and 44 (14%) remained in watch-and-wait management as of April 21, 2021 (median [range] age, 58 [32-89] years; 16 [36%] women). Among patients who initially opted for watch-and-wait management, migration to surgery due to regrowth or patient choice occurred mostly within the first year following completion of TNT, and RFS did not differ significantly whether surgery was performed 3.0 to 5.9 months (73%; 95% CI, 52%-92%) vs 6.0 to 11.9 months (71%; 95% CI, 51%-99%) vs more than 12.0 months (70%; 95% CI, 49%-100%) from TNT completion (P = .70). RFS for patients in the watch-and-wait cohort at 12 months from completion of TNT more closely resembled patients who had undergone surgery and had a pathologic complete response than the watch-and-wait cohort at 3 months from completion of TNT. Accordingly, model performance improved over time, and the concordance index increased from 0.62 (95% CI, 0.53-0.71) at 3 months after TNT to 0.66 (95% CI, 0-0.75) at 12 months.Conclusions and RelevanceIn this cohort study of patients with rectal cancer, the clinical calculator reliably estimated the likelihood of RFS for patients who underwent surgery immediately after TNT, patients who underwent delayed surgery after entering watch-and-wait management, and patients who remained in watch-and-wait management. Delayed surgery following attempted watch-and-wait did not appear to compromise oncologic outcomes. The risk calculator provided conditional survival estimates at any time during surveillance and could help physicians counsel patients with rectal cancer about the consequences of alternative treatment pathways and thereby support informed decisions that incorporate patients’ preferences.

Purpose: The prevalence and clinical characteristics of small bowel adenocarcinomas (SBA) in the setting of Lynch syndrome have not been well studied. We characterized SBA according to DNA mismatch repair and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes. Experimental Design: A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via IHC staining. Germline DNA was analyzed for mutations in known cancer predisposition genes, including MMR (MLH1, MSH2, MSH6, PMS2, and EPCAM). Clinical variables were correlated with MMR/MSI status. Results: Twenty-six percent (26/100; 95% confidence interval, 18.4–35.4) of SBAs exhibited MMR deficiency (MMR-D). Lynch syndrome prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-Lynch syndrome MMR-D versus MMR-proficient (MMR-P) SBAs (65 vs. 61; P = 0.75), but significantly younger in Lynch syndrome (47.5 vs. 61; P = 0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P versus 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in Lynch syndrome (P = 0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared with 23.1% (6/26) in the MMR-D group (P = 0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared with 18.2% (2/11) in the MMR-D group (P = 0.0002). Conclusions: When compared with MMR-P SBA, MMR-D SBA was associated with earlier stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline Lynch syndrome testing in MMR-D SBA is warranted.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation–positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org. Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.

Micrometastatic disease that is present at the time of surgery is responsible for the overwhelming majority of deaths in patients with what is otherwise perceived to be local and regional colon cancer. The goal of perioperative therapy is to eliminate microscopic residual disease that would otherwise be left behind following surgery. A secondary goal specific to neoadjuvant (preoperative) therapy is to downstage tumors deemed potentially not amenable to an R0 resection on the basis of a suspected T4b primary (locally invading into a surrounding structure). In this landmark series paper, we review the current standard for perioperative therapy in patients with colon cancer.

Purpose: We aimed to investigate genomic correlates underlying extremes of survivorship in metastatic colorectal cancer and their applicability in informing survival in distinct subsets of patients with metastatic colorectal cancer. Experimental Design: We examined differences in oncogenic somatic alterations between metastatic colorectal cancer cohorts demonstrating extremes of survivorship following complete metastasectomy: ≤2-year (n = 17) and ≥10-year (n = 18) survivors. Relevant genomic findings, and their association with overall survival (OS), were validated in two independent datasets of 935 stage IV and 443 resected stage I–IV patients. Results: In the extremes-of-survivorship cohort, significant co-occurrence of KRAS hotspot mutations and TP53 alterations was observed in ≤2-year survivors (P < 0.001). When validating these findings in the independent cohort of 935 stage IV patients, incorporation of the cumulative effect of any oncogenic Ras/B-raf (i.e., either KRAS, NRAS, or BRAF) and TP53 alteration generated three prognostic clusters: (i) TP53-altered alone (median OS, 132 months); (ii) Ras/B-raf–altered alone (65 months) or Ras/B-raf- and TP53 pan-wild-type (60 months); and (iii) coaltered Ras/B-raf–TP53 (40 months; P < 0.0001). Coaltered Ras/B-raf–TP53 was independently associated with mortality (HR, 2.47; 95% confidence interval, 1.91–3.21; P < 0.001). This molecular profile predicted survival in the second independent cohort of 443 resected stage I–IV patients. Coaltered Ras/B-raf–TP53 was associated with worse OS in patients with liver (n = 490) and lung (n = 172) but not peritoneal surface (n = 149) metastases. Moreover, coaltered Ras/B-raf–TP53 tumors were significantly more likely to involve extrahepatic metastatic sites with limited salvage options. Conclusions: Genomic analysis of extremes of survivorship following colorectal cancer metastasectomy identifies a prognostic role for coaltered Ras/B-raf–TP53 and its association with distinct patterns of colorectal cancer metastasis.

Patients with cancer who have exhausted standard treatments often seek access to investigational drugs. Often, however, such access is unavailable, due to either the unavailability of a trial, lack of an open recruiting spot on the trial, even when the trial itself is open, or the inability of the patient to meet one or more trial eligibility criteria. In such settings patients often seek access to investigational agents outside of a trial. The federal “Right to Try” legislation was passed to create an additional avenue, different from the FDA's Expanded Access, or “Compassionate Use” Program, through which patients might obtain access to investigational drugs. A year after this legislation was signed into law, there remains both a limited awareness of it and a substantial degree of misunderstanding on the part of those who are aware of it. The law creates an avenue to greatly facilitate off-study administration when patient, physician, and the manufacturer are all in agreement regarding the off study use of an eligible investigational agent. The law does not, however, empower a patient to impose a demand on either a provider or a drug manufacturer, nor does it require any entity to provide financial coverage for the drug. Eligible drugs are those which are not approved by the FDA for any indication, have completed a phase I trial, have an ongoing pivotal trial, and have an active registration plan. We review the specific law with commentary on its implications for improved access to investigational drugs outside of clinical trials.

Metastasis-initiating cells with stem-like properties drive cancer lethality, yet their origins and relationship to primary-tumor-initiating stem cells are not known. We show that L1CAM+ cells in human colorectal cancer (CRC) have metastasis-initiating capacity, and we define their relationship to tissue regeneration. L1CAM is not expressed in the homeostatic intestinal epithelium, but is induced and required for epithelial regeneration following colitis and in CRC organoid growth. By using human tissues and mouse models, we show that L1CAM is dispensable for adenoma initiation but required for orthotopic carcinoma propagation, liver metastatic colonization and chemoresistance. L1CAMhigh cells partially overlap with LGR5high stem-like cells in human CRC organoids. Disruption of intercellular epithelial contacts causes E-cadherin–REST transcriptional derepression of L1CAM, switching chemoresistant CRC progenitors from an L1CAMlow to an L1CAMhigh state. Thus, L1CAM dependency emerges in regenerative intestinal cells when epithelial integrity is lost, a phenotype of wound healing deployed in metastasis-initiating cells. The authors identify a population of L1CAM-positive cells that, following loss of epithelial integrity, promote intestinal tissue regeneration and mediate metastasis initiation and chemoresistance in colorectal cancer.

The American Cancer Society and American Institute for Cancer Research recommend that cancer survivors limit intake of red and processed meats. This recommendation is based on consistent associations between red and processed meat intake and cancer risk, particularly risk of colorectal cancer, but fewer data are available on red and processed meat intake after cancer diagnosis.To examine whether intake of unprocessed red meat or processed meat is associated with risk of cancer recurrence or mortality in patients with colon cancer.This prospective cohort study used data from participants with stage III colon cancer enrolled in the Cancer and Leukemia Group B (CALGB 89803/Alliance) trial between 1999 and 2001. The clinical database for this analysis was frozen on November 9, 2009; the current data analyses were finalized in December 2021.Quartiles of unprocessed red meat and processed meat intake assessed using a validated food frequency questionnaire during and 6 months after chemotherapy.Hazard ratios (HRs) and 95% CIs for risk of cancer recurrence or death and all-cause mortality.This study was conducted among 1011 patients with stage III colon cancer. The median (IQR) age at enrollment was 60 (51-69) years, 442 patients (44%) were women, and 899 patients (89%) were White. Over a median (IQR) follow-up period of 6.6 (1.9-7.5) years, we observed 305 deaths and 81 recurrences without death during follow-up (386 events combined). Intake of unprocessed red meat or processed meat after colon cancer diagnosis was not associated with risk of recurrence or mortality. The multivariable HRs comparing the highest vs lowest quartiles for cancer recurrence or death were 0.84 (95% CI, 0.58-1.23) for unprocessed red meat and 1.05 (95% CI, 0.75-1.47) for processed meat. For all-cause mortality, the corresponding HRs were 0.71 (95% CI, 0.47-1.07) for unprocessed red meat and 1.04 (95% CI, 0.72-1.51) for processed meat.In this cohort study, postdiagnosis intake of unprocessed red meat or processed meat was not associated with risk of recurrence or death among patients with stage III colon cancer.

Over the past year, studies have demonstrated better ways of using the agents that we have to improve outcomes for patients with colon and Rectal cancers.

118 Background: Anti-VEGF is widely used in the treatment (trt) of metastatic colorectal cancer (mCRC). Only studies with bevacizumab (BEV) have shown survival benefit (bnf) in first line trt. The magnitude of bnf might differ based on the metastatic (met) site and the chemotherapy regimen (CTR) with which BEV is partnered. ARCAD database contains individual patient data (IPD) of randomized trials that evaluated BEV+ CT. In this pooled analysis, we aimed to evaluate BEV bnf in mCRC with lung metastases (mets) either as single or multiple sites. Methods: IPD from four trials (AVF2107g, N016966, AVF2192g, AGITG) comparing CT +/- BEV were pooled. The primary endpoint, overall survival (OS), was estimated using Kaplan-Meier method and prognostic value of lung mets was evaluated by stratified Cox models according to number and type of met sites and CTRs, oxaliplatin or irinotecan (OX/IRI) based. The predictive bnf of BEV was evaluated by interaction test (int) between trt and lung mets status in subgroups and considered as significant (sig) with a P < 0.1. Results: 2728 patients (pts) with known met sites and survival data were pooled. 1020 pts had single met site, 133 had only lung mets. 1708 pts had multiple met sites, 1008 had lung mets. Pts characteristics were well balanced. Sig OS bnf of BEV was observed in the whole population. In pts subgroup according to the presence or absence of lung mets, sig bnf of BEV were observed with a non-sig int ( Pint=.590). Non-sig bnf of BEV was observed in pts with single site regardless of met site (lung or no lung) or CTR. Sig bnf of BEV was observed in pts with multiple sites without lung mets whatever the CTRs. While sig bnf of BEV was observed in pts with multiple sites with lung mets, we found a sig int between BEV and OX/IRI-based regimens ( Pint=.022). The bnf of BEV was observed with IRI-based regimen but not in OX-based regimen. The bnf of BEV appears greater in multiple sites without lung mets than with lung mets with a sig stratified log-rank test ( PLRT

10 Background: Interest in organ preservation (OP) strategies for rectal cancer (RC) patients persists. The efficacy of long course chemoradiation (LCRT) vs. short course radiation therapy (SCRT) relative to OP is unknown. We compared OP rates between SCRT and LCRT total neoadjuvant therapy (TNT) strategies. Methods: During the COVID-19 pandemic we established an institutional SCRT mandate with no exceptions. For comparison, we identified RC patients treated with LCRT immediately before and after the mandate period. After completion of TNT, patients were restaged by clinical exam, endoscopy, and MRI. A watch and wait (WW) approach was recommended for patients with a clinical complete response (cCR), defined by the MSK regression schema. Total mesorectal excision (TME) was recommended for non-cCR patients. OP was defined as alive, TME-free, and with no evidence of disease in the pelvis. We performed survival analysis for: local regrowth rate, OP, disease-free survival (DFS), and overall survival (OS). Results: We identified 563 consecutive patients with RC treated with TNT, of whom 231 were excluded due to either metastatic disease, synchronous/metachronous malignancies, or non-adenocarcinoma histology (Jan. 2018-Jan. 2021). Patient and tumor characteristics were similar in the LCRT (n = 256) and SCRT (n = 76) cohorts. No significant differences in high-risk features were noted. Most patients had clinical stage III disease (82% in LCRT vs. 83% in SCRT). Induction chemotherapy followed by consolidative radiation was the most common treatment order (78% (LCRT) vs. 70% (SCRT)). The median interval from end of TNT to clinical restaging was 8 weeks (LCRT) and 9 weeks (SCRT). The cCR rate was 46% in both cohorts. The cCR rate was numerically higher in patients treated with radiation first, as compared to chemotherapy first (53% vs. 44% (LCRT) and 52% vs. 43% (SCRT)). Among patients with a cCR, the likelihood of WW management was similar (98% (LCRT) vs. 94% (SCRT)). From start of TNT, the median follow-up was 32 and 28 months respectively for LCRT and SCRT. The 2-year OS (95% vs. 92%), DFS (78% vs 70%), and distant recurrence (20% vs. 21%) rates were similar. Among all patients, the 2-year OP rate was 40% (95% CI 35-47%) for LCRT and 29% (95% CI 20-42%) with SCRT. In those patients managed by WW, the 2-year local regrowth rate was 20% (95% CI 12-27%) with LCRT vs. 36% (95% CI 16-52%) with SCRT. Conclusions: In this nonrandomized comparison, while cCR rates were similar, we observed a numerically higher OP rate with LCRT-TNT than with SCRT-TNT. The ongoing ACO/ARO/AIO-18.1 trial, hypothesizing that LCRT-TNT will increase OP rates relative to SCRT-TNT, should definitively answer this question.