Pathology and Prognosis of Colonic Adenocarcinomas With Intermediate Primary Tumor Stage Between pT2 and pT3

Context.— Primary tumor stage (pT) is an important prognostic indicator in colonic adenocarcinomas; however, cases that have no muscle fibers beyond the advancing tumor edge but also show no extension beyond the apparent outer border of muscularis propria (termed pT2int), have not been previously studied. Objective.— To address the clinicopathologic characteristics and prognosis of pT2int tumors. Design.— We recharacterized 168 colon carcinomas and compared pT2int cases to bona fide pT2 and pT3 tumors. Results.— In side-by-side analysis, 21 pT2int cases diverged from 29 pT2 tumors only in terms of larger size (P = .03), but they were less likely to show high-grade (P = .03), lymphovascular (P < .001), and extramural venous invasion (P = .04); discontinuous tumor deposits (P = .02); lymph node involvement (P = .001); and advanced stage (P = .001), compared with 118 pT3 tumors. Combining pT2int with pT2 cases (versus pT3) was a better independent predictor of negative lymph nodes in multivariate analysis (P = .04; odds ratio [OR], 3.96; CI, 1.09–14.42) and absent distant metastasis in univariate analysis (P = .04), compared with sorting pT2int with pT3 cases (versus pT2). Proportional hazards regression showed that pT2 and pT2int cases together were associated with better disease-free survival compared with pT3 tumors (P = .04; OR, 3.65; CI, 1.05–12.70). Kaplan-Meier analysis demonstrated that when pT2int were grouped with pT2 tumors, they were significantly less likely to show disease progression compared with pT3 (P = .002; log-rank test) and showed a trend toward better disease-specific survival (P = .06), during a mean patient follow-up of 44.9 months. Conclusions.— These data support the conclusion that pT2int carcinomas have clinicopathologic characteristics and are associated with patient outcomes more closely aligned with pT2 rather than pT3 tumors.

Case Report: Coinheritance of Germline Mutations in APC and BRCA1 in Colorectal Cancer

Deleterious mutations inAPCgene cause the autosomal dominant familial adenomatous polyposis (FAP) which is typically characterized by the occurrence of hundreds to thousands of colorectal adenomas that eventually lead to colorectal cancers (CRCs).BRCA1/2are the two major susceptibility genes for breast and ovarian cancers. Here, we reported a coinheritance of mutations inAPCandBRCA1genes in a 20-year-old CRC patient with typical clinical features for FAP. Multiple relatives in the family of the patient were affected by colorectal and other cancers. Next-generation sequencing analysis using a panel consisting of 53 hereditary cancer related genes revealed a maternally inheritedAPC(exon15cn_del) mutation and a paternally inheritedBRAC1(p.lle1824AspfsX3) mutation. This is the first coexistence ofAPCandBRCA1mutations in a CRC patient with the mutation inheritance pattern comprehensively characterized in the family. The patient underwent a colonoscopy and a subtotal colectomy and was subsequently diagnosed with colonic adenocarcinomas accompanied with hundreds of tubulovillous adenomas. The case reveals the scenario where two disease-causing mutations of different hereditary tumor syndromes coexist, and illustrates the importance of evaluating detailed family history and performing a multiple-gene panel test in patients with hereditary cancer.

Targeted therapy for HER2 driven colorectal cancer.

3583 Background: ERBB2 ( HER2) genomic alterations (GA) are evolving therapy taregets in metastatc coorectal cancer (mCRC). Methods: Hybrid capture based comprehensive genomic profiling (CGP) was performed on 8874 (9.6%) mCRC including both colonic adenocarcinomas (7587 cases; 85%) and rectal adenocarcinomas (1287 cases, 15%) Tumor mutational burden (TMB) was calculated from a minimum of 1.2 Mb of sequenced DNA. Results: ERBB2 amplifications or a short variant (SV) alterations or both were found in 433 (4.9%) of the total mCRC. 195 (45%) of the ERBB2 positive mCRC were female and 238 (55%) were male. Median age was 54 years (range 22 to 88 years). The most frequently co-altered genes were SV GA in TP53 (82%), APC (70%), KRAS (26%), SMAD4 (15%) and PIK3CA (13%). Clinically relevant GA significantly under-represented in ERBB2-altered CRC included significantly reduced GA in KRAS at 26% (p = 0.001) and BRAF at 4% (p = 0.003) as well as other kinases at 1% including EGFR, KIT, MET and RET. The frequency of TMB at > 10 mut/Mb (p < 0.0001), but at > 20 mut/Mb mCRC cases demonstrated virtually the same results regardless to ERBB2 status at a frequency of x%. The overall ERBB2 GA frequency at 5.3% in rectal mCRC is slightly higher than that seen in colonic mCRC at 4.9%, (p = 0.36). The frequency of TMB > 10 mut/Mb in ERBB2 WT mCRC is greater in the colonic mCRC than the rectal mCRC (p < 0.0001 for both comparisons). When > 20 mut/Mb is used as the cut-off, the greater frequency of TMB in colonic mCRC versus rectal mCRC remains significant (p < 0.0001). When the ERBB2altered mCRC cases are evaluated, the greater frequency of TMB > 10 mu/Mb in colonic mCRC versus rectal mCRC remains significant (p = 0.009), but the greater frequency in colonic verses rectal mCRC at the > 20 mut/Mb is not significant (p = 0.37). Conclusions: Although lower than observed in breast and upper gastrointestinal carcinomas where anti-HER2 therapies are approved indications, the frequency of ERBB2 GA in CRC at 4.9% is significant. Importantly, nearly half of CRC ERBB2 alterations are SVs, not detectable by routine IHC and FISH testing. However, the success of anti-HER2 therapies shown here and progress in on-going clinical trials indicates that targeting ERBB2 has potential to become an approved advance in precision therapy for mCRC patients.