Purpose Risk stratification in localized colorectal cancer (CRC) remains inadequate. Transcriptome-based classifiers such as consensus molecular subtyping (CMS) improve this, but are challenging to implement. We determined the performance of a novel image-based method for CRC CMS subtyping (imCMS) using routine pathology images from the SCOT trial and investigated association of imCMS subtypes with clinicopathologic and tumor molecular and immune factors, treatment benefit, and survival. Methods We applied a novel imCMS classifier to stage II/III CRCs from the SCOT trial (ISRCTN59757862) which examined 3 versus 6 months of adjuvant oxaliplatin-based chemotherapy following curative-intent surgery. We determined correlates of imCMS subgroups and investigated imCMS prognostic and predictive value for CRC recurrence-free interval, overall survival (OS), and survival after CRC recurrence (SAR) by univariable and multivariable Cox regression. Results A total of 2,816 cases were informative for imCMS classification, of which 664 (24%) were imCMS1 (immune), 987 (35%) imCMS2 (canonical), 433 (15%) imCMS3 (metabolic), 653 (23%) imCMS4 (mesenchymal), and 79 (3%) of mixed subtype. Analysis confirmed expected associations of imCMS1 with deficient DNA mismatch repair (dMMR) and imCMS3 with KRAS mutation and revealed substantially lower intraepithelial CD8 + and intrastromal FoxP3 + T-cell infiltrate (CD8 IE -FoxP3 IS ) in imCMS4 tumors. imCMS classification was strongly prognostic independent of clinicopathologic factors, dMMR, and CD8 IE -FoxP3 IS in multivariable analysis but did not predict differential benefit from chemotherapy duration or regimen. The combination of imCMS with CD8 IE -FoxP3 IS groups defined CRC subgroups with substantially different recurrence risk. Analysis of OS and SAR revealed notable discordance in imCMS3 and imCMS4 prognostic value before and after relapse. Conclusion imCMS classification improves CRC prognostication beyond existing tumor factors and is potentially deliverable in clinical practice. imCMS prediction of therapeutic benefit requires further study.
Purpose Although mechanistic evidence suggests that some per- and polyfluoroalkyl substances (PFASs) may be carcinogenic, epidemiologic findings for PFAS and breast cancer remain inconsistent, partly because of differing study designs and limited evaluation by hormone receptor status. Methods We conducted a case-cohort study within the Sister Study that included 1,609 breast cancer cases and 2,269 subcohort participants. We oversampled estrogen receptor (ER)–negative cases (324 ER-negative, 1,120 ER-positive) to improve statistical power. Seventeen PFASs were quantified in prediagnostic plasma using liquid chromatography-high-resolution mass spectrometry. Sampling-weighted Cox models were used to estimate associations with overall breast cancer incidence and by hormone receptor status, adjusting for confounders and coexposures. We conducted a meta-analysis of seven studies with prediagnostic blood PFAS measurements. Results We observed associations between certain PFAS and ER-negative tumors. Positive associations were observed for perfluoro-n-octanoic acid (PFOA; hazard ratio [HR] Q4 v Q1 , 1.67 [95% CI, 1.10 to 2.53], P trend = .09), perfluorooctane-1-sulfonic acid (PFOS; HR Q4 v Q1 , 1.93 [95% CI, 1.15 to 3.22], P trend = .01), and potentially n-methylperfluoro-1-octanesulfonamidoacetic acid (N-MeFOSAA; HR Q4 v Q1 , 1.42 [95% CI, 0.99 to 2.04], P trend = .12). By contrast, perfluoro-n-tridecanoic acid was inversely associated with ER-negative tumors (PFTrDA; HR Q4 v Q1 , 0.63 [95% CI, 0.41 to 0.97], P trend = .05). Perfluorooctane sulfonamide (PFOSA), which was infrequently detected (6.9%), was positively associated with ER+ tumors (HR detectable v nondetectable , 1.36 [95% CI, 1.03 to 1.81]). The meta-analysis further supported associations for both PFOA (relative risk [RR], 1.30 [95% CI, 1.05 to 1.62]) and PFOS with ER-negative breast cancer (RR, 1.20 [95% CI, 0.91 to 1.58]). Conclusion Findings from this large prospective study, together with meta-analyses, suggest that PFOA and PFOS may increase ER-negative breast cancer risk. Given the widespread exposure to PFAS and limited established risk factors for ER-negative tumors, these results have important public health implications.
PURPOSE Patients with breast cancer requiring postmastectomy radiation therapy (PMRT) often desire breast reconstruction. Reconstructions can be adversely affected by PMRT, and fear of reconstruction complications has discouraged adoption of short-course radiation therapy used after lumpectomy. To fill the evidence gap, we conducted a noninferiority trial of hypofractionated versus conventional PMRT in patients undergoing breast reconstruction. The primary outcome was reconstruction complication rate, a composite of wound healing, readmission, capsular contracture, unplanned reoperation, and reconstruction failure. METHODS Women with unilateral invasive breast cancer with planned immediate or delayed reconstruction and PMRT were randomly assigned (1:1) to 50 Gy (25 fractions/5 weeks) or 42.56 Gy (16 fractions/3 weeks). This study was designed with a noninferiority margin of 10%, assuming a 2-year reconstruction complication rate of 25% with conventional PMRT. Randomization was stratified by immediate versus delayed and autologous versus implant-only reconstruction. RESULTS Between 2018 and 2021, 898 patients enrolled with a median follow-up of 3.9 years; 825 patients were evaluable for the primary end point. The 24-month reconstruction complication rates were 12.3% (52/422) with hypofractionated PMRT and 10.2% (41/403) with conventional PMRT, corresponding to an estimated difference of -2.1% (95% CI, -6.5 to 2.2). The complication rate was higher (regardless of arm) with implant-only versus autologous reconstruction (odds ratio = 1.65). There was no statistically significant difference in 36-month locoregional recurrence rates: 1.5% (95% CI, 0.7 to 3.2) with hypofractionated and 2.2% (95% CI, 1.1 to 4.3) with conventional PMRT. Acute and late toxicity rates were not statistically different. CONCLUSION A 16-fraction course of hypofractionated PMRT is safe and noninferior to conventional PMRT in women undergoing breast reconstruction after mastectomy.
