Background
Colorectal cancer (CRC) consensus molecular subtypes (CMS) have different immunological, stromal cell, and clinicopathological characteristics. Single-cell characterization of CMS subtype tumor microenvironments is required to elucidate mechanisms of tumor and stroma cell contributions to pathogenesis which may advance subtype-specific therapeutic development. We interrogate racially diverse human CRC samples and analyze multiple independent external cohorts for a total of 487,829 single cells enabling high-resolution depiction of the cellular diversity and heterogeneity within the tumor and microenvironmental cells.
Results
Tumor cells recapitulate individual CMS subgroups yet exhibit significant intratumoral CMS heterogeneity. Both CMS1 microsatellite instability (MSI-H) CRCs and microsatellite stable (MSS) CRC demonstrate similar pathway activations at the tumor epithelial level. However, CD8+ cytotoxic T cell phenotype infiltration in MSI-H CRCs may explain why these tumors respond to immune checkpoint inhibitors. Cellular transcriptomic profiles in CRC exist in a tumor immune stromal continuum in contrast to discrete subtypes proposed by studies utilizing bulk transcriptomics. We note a dichotomy in tumor microenvironments across CMS subgroups exists by which patients with high cancer-associated fibroblasts (CAFs) and C1Q+TAM content exhibit poor outcomes, providing a higher level of personalization and precision than would distinct subtypes. Additionally, we discover CAF subtypes known to be associated with immunotherapy resistance.
Conclusions
Distinct CAFs and C1Q+ TAMs are sufficient to explain CMS predictive ability and a simpler signature based on these cellular phenotypes could stratify CRC patient prognosis with greater precision. Therapeutically targeting specific CAF subtypes and C1Q + TAMs may promote immunotherapy responses in CRC patients.
Tumor heterogeneity, especially intratumoral heterogeneity, is a primary reason for treatment failure. A single biopsy may not reflect the complete genomic architecture of the tumor needed to make therapeutic decisions. Circulating tumor DNA (ctDNA) is believed to overcome these limitations. We analyzed concordance between ctDNA and whole-exome sequencing/whole-genome sequencing (WES/WGS) of tumor samples from patients with breast (n = 12), gastrointestinal (n = 20), lung (n = 19), and other tumor types (n = 13). Correlation in the driver, hotspot, and actionable alterations was studied. Three cases in which more-in-depth genomic analysis was required have been presented. A total 58% (37/64) of patients had at least one concordant mutation. Patients who had received systemic therapy before tissue next-generation sequencing (NGS) and ctDNA analysis showed high concordance (78% (21/27) vs. 43% (12/28) p = 0.01, respectively). Obtaining both NGS and ctDNA increased actionable alterations from 28% (18/64) to 52% (33/64) in our patients. Twenty-one patients had mutually exclusive actionable alterations seen only in either tissue NGS or ctDNA samples. Somatic hotspot mutation analysis showed significant discordance between tissue NGS and ctDNA analysis, denoting significant tumor heterogeneity in these malignancies. Increased tissue tumor mutation burden (TMB) positively correlated with the number of ctDNA mutations in patients who had received systemic therapy, but not in treatment-naïve patients. Prior systemic therapy and TMB may affect concordance and should be taken into consideration in future studies. Incorporating driver, actionable, and hotspot analysis may help to further refine the correlation between these two platforms. Tissue NGS and ctDNA are complimentary, and if done in conjunction, may increase the detection rate of actionable alterations and potentially therapeutic targets.
100 Background: KEYNOTE-365 (NCT02861573) is a phase 1b/2 study evaluating pembro + other agents in mCRPC. Updated results from cohort A (pembro + olaparib) are reported. Methods: Docetaxel-pretreated, molecularly unselected pts with mCRPC with progression within 6 mo of screening per PSA or radiologic bone/soft tissue progression enrolled. Pts may have received 1 other chemotherapy and ≤2 2nd-generation hormone therapy (HT). Pts received pembro 200 mg IV Q3W + olaparib 400 mg PO BID. Primary end points: safety, PSA response rate (confirmed PSA decline ≥50%), and ORR per blinded independent central review. Results: Of 84 treated pts, 42 discontinued, primarily due to progression (n=29). Median age was 71 y (range, 47-83); 26% were PD-L1+, 26% had visceral disease, and 57% had RECIST-measurable disease. Median follow-up was 3 mo for all pts (n=81) and 14 mo for pts with ≥27 wks’ follow-up (n=41). See Table for efficacy outcomes. Treatment-related AEs occurred in 70 (83%) pts. Most frequent (≥30%) were nausea (33%) and anemia (31%). Grade 3-5 treatment-related AEs occurred in 29 (35%) pts. Three pts died of AEs (2 treatment related [l myocardial infarction, 1 unknown cause]). Conclusions: With additional follow-up, pembro + olaparib continued to show activity in docetaxel-pretreated, molecularly unselected pts who previously received HT for mCRPC. Safety of the combination was consistent with individual profiles of each agent. Clinical trial information: NCT02861573. [Table: see text]
Conclusions: OLA tolerability in mCRPC pts was consistent with other tumour types. Common AEs of anaemia, nausea, decreased appetite and fatigue/asthenia occurred early, gave no indication of cumulative toxicity, were manageable and led to few treatment discontinuations. There was insufficient evidence to confirm or refute a causal association between PE and OLA.Clinical trial identification: NCT02987543.
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