Background Colorectal cancer (CRC) incidence is increasing in adults younger than 50 years. This study evaluated clinical and molecular features to identify those features unique to early‐onset CRC that differentiate these patients from patients 50 years old or older. Methods Baseline characteristics were evaluated according to the CRC onset age with 3 independent cohorts. A fourth cohort was used to describe the impact of age on the consensus molecular subtype (CMS) prevalence. Results This retrospective review of more than 36,000 patients with CRC showed that early‐onset patients were more likely to have microsatellite instability (P = .038), synchronous metastatic disease (P = .009), primary tumors in the distal colon or rectum (P < .0001), and fewer BRAF V600 mutations (P < .001) in comparison with patients 50 years old or older. Patients aged 18 to 29 years had fewer adenomatous polyposis coli (APC) mutations (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.35‐0.90; P = .015) and an increased prevalence of signet ring histology (OR, 4.89; 95% CI, 3.23‐7.39; P < .0001) in comparison with other patients younger than 50 years. In patients younger than 40 years, CMS1 was the most common subtype, whereas CMS3 and CMS4 were uncommon (P = .003). CMS2 was relatively stable across age groups. Early‐onset patients with inflammatory bowel disease were more likely to have mucinous or signet ring histology (OR, 5.54; 95% CI, 2.24‐13.74; P = .0004) and less likely to have APC mutations (OR, 0.24; 95% CI, 0.07‐0.75; P = .019) in comparison with early‐onset patients without predisposing conditions. Conclusions Early‐onset CRC is not only distinct from traditional CRC: special consideration should be given to and further investigations should be performed for both very young patients with CRC (18‐29 years) and those with predisposing conditions. The etiology of the high rate of CMS1 in patients younger than 40 years deserves further exploration.

ABSTRACT"Liquid biopsy" approaches analyzing cell-free DNA (cfDNA) from the blood of patients with cancer are increasingly utilized in clinical practice. However, it is not yet known whether cfDNA sequencing from large cohorts of patients with cancer can detect genomic alterations at frequencies similar to those observed by direct tumor sequencing, and whether this approach can generate novel insights. Here, we report next-generation sequencing data from cfDNA of 1,397 patients with colorectal cancer. Overall, frequencies of genomic alterations detected in cfDNA were comparable to those observed in three independent tissue-based colorectal cancer sequencing compendia. Our analysis also identifi ed a novel cluster of extracellular domain (ECD) mutations in EGFR , mediating resistance by blocking binding of anti-EGFR antibodies. Patients with EGFR ECD mutations displayed striking tumor heterogeneity, with 91% harboring multiple distinct resistance alterations (range, 1-13; median, 4). These results suggest that cfDNA profi ling can effectively defi ne the genomic landscape of cancer and yield important biological insights. SIGNIFICANCE:This study provides one of the fi rst examples of how large-scale genomic profi ling of cfDNA from patients with colorectal cancer can detect genomic alterations at frequencies comparable to those observed by direct tumor sequencing. Sequencing of cfDNA also generated insights into tumor heterogeneity and therapeutic resistance and identifi ed novel EGFR ectodomain mutations. Cancer Discov; 8(2);

Colorectal cancers are classified as right/left-sided based on whether they occur before/after the splenic flexure, with established differences in molecular subtypes and outcomes. However, it is unclear if this division is optimal and whether precise tumor location provides further information. In 1,876 patients with colorectal cancer, we compared mutation prevalence and overall survival (OS) according to side and location. Consensus molecular subtype (CMS) was compared in a separate cohort of 608 patients. Mutation prevalence differed by side and location for , and Within left- and right-sided tumors, there remained substantial variations in mutation rates. For example, within right-sided tumors, mutations decreased from 70% for cecal, to 43% for hepatic flexure location ( = 0.0001), while V600 mutations increased from 10% to 22% between the same locations ( < 0.0001). Within left-sided tumors, the sigmoid and rectal region had more mutations ( = 0.027), less ( = 0.0009), ( = 0.0033), or mutations ( < 0.0001), and less MSI ( < 0.0001) than other left-sided locations. Despite this, a left/right division preceding the transverse colon maximized prognostic differences by side and transverse colon tumors had K-modes mutation clustering that appeared more left than right sided. CMS profiles showed a decline in CMS1 and CMS3 and rise in CMS2 prevalence moving distally. Current right/left classifications may not fully recapitulate regional variations in tumor biology. Specifically, the sigmoid-rectal region appears unique and the transverse colon is distinct from other right-sided locations. .

Background: Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay; however, the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy.Patients and methods: We present the post-progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS/ BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy. Our validation cohort consisted of an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling. A separate retrospective cohort of 80 patients was used to evaluate overall response rate and progression free survival during re-challenge therapies.Results: Our analysis showed that RAS and EGFR relative mutant allele frequency decays exponentially (r 2 ¼0.93 for RAS; r 2 ¼0.94 for EGFR) with a cumulative half-life of 4.4 months. We validated our findings using an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling, confirming exponential decay with an estimated half-life of 4.3 months. A separate retrospective cohort of 80 patients showed that patients had a higher overall response rate during re-challenge therapies after increasing time intervals, as predicted by our model. Conclusion:These results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation.

Importance Chemotherapy may result in a detrimental effect on ovarian function and fertility in premenopausal women undergoing curative treatment for early breast cancer (EBC). For this subgroup of patients, a careful consideration for techniques to minimize this risk should be given and the role of gonadotropin-releasing hormone agonists (GnRHa) for protection of ovarian function is not fully resolved. Objective To determine efficacy of GnRHa administered concurrently with chemotherapy for ovarian function preservation. Data sources The search for studies published between 1975 and March/2015 encompassed PubMed, SCOPUS and Cochrane databases, as well as ASCO Annual Meeting and San Antonio Breast Cancer Symposium abstracts. Study selection Prospective, randomized, controlled trials addressing the role of ovarian suppression with GnRHa in preventing early ovarian dysfunction in premenopausal women undergoing treatment for EBC were selected. Data extraction and synthesis Data extraction was performed independently by two authors. The methodology and the risk of bias were assessment based on the description of randomization method, withdrawals and blinding process. Main Outcomes Measures Rate of resumption of regular menses after a minimal follow-up period of 6 months following chemotherapy was used as surrogate to assess the incidence of ovarian dysfunction. Additional secondary outcomes included hormone levels and number of pregnancies. Risk ratio estimates were calculated based on the number of evaluable patients. Analyses were conducted using a random effect model. Results Seven studies were selected, totaling 1047 randomized patients (856 evaluable patients).. The use of GnRHa was associated with a higher rate of recovery of regular menses after 6 months (OR = 2.41; 95% CI 1.40–4.15; p= 0. 002) and at least 12 months (OR 1.85; 95% CI 1.33–2.59; p = 0.0003) following last chemotherapy cycle. The use of GnRHa was also associated with a higher number of pregnancies (OR 1.85; 95% IC 1.02–3.36; p=0.04), although this outcome was not uniformly reported. Conclusions and Relevance GnRHa given with chemotherapy resulted in increased rates of recovery of regular menses and should be considered an option for ovarian function preservation in young women undergoing treatment for EBC. Additional outcomes related to ovarian function and fertility need to be further investigated.