Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we assembled MSK-MET, a pan-cancer ...cohort of over 25,000 patients with metastatic diseases. By analyzing genomic and clinical data from this cohort, we identified associations between genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma, and HR+/HER2+ breast ductal carcinoma, but not in others, including colorectal cancer and high-grade serous ovarian cancer, where copy-number alteration patterns may be established early in tumor development. We also identified somatic alterations associated with metastatic burden and specific target organs. Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression.
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•A large clinico-genomic database to study metastatic patterns across 50 tumor types•Oncogenic alteration frequency and chromosomal instability are increased in metastases•Correlations between chromosomal instability and metastatic burden depend on cancer type•Genomic features associated with metastasis are identified for specific target organs
Clinico-genomic analysis of MSK-MET, a cohort of over 25,000 patients with metastasis across 50 cancer types, identifies somatic alterations associated with organ-specific metastasis and highlights that chromosomal instability correlates with metastatic burden in a cancer type-dependent manner.
Background and Aim
Genetic alterations in intrahepatic cholangiocarcinoma (iCCA) are increasingly well characterized, but their impact on outcome and prognosis remains unknown.
Approach and Results
...This bi‐institutional study of patients with confirmed iCCA (n = 412) used targeted next‐generation sequencing of primary tumors to define associations among genetic alterations, clinicopathological variables, and outcome. The most common oncogenic alterations were isocitrate dehydrogenase 1 (IDH1; 20%), AT‐rich interactive domain–containing protein 1A (20%), tumor protein P53 (TP53; 17%), cyclin‐dependent kinase inhibitor 2A (CDKN2A; 15%), breast cancer 1–associated protein 1 (15%), FGFR2 (15%), polybromo 1 (12%), and KRAS (10%). IDH1/2 mutations (mut) were mutually exclusive with FGFR2 fusions, but neither was associated with outcome. For all patients, TP53 (P < 0.0001), KRAS (P = 0.0001), and CDKN2A (P < 0.0001) alterations predicted worse overall survival (OS). These high‐risk alterations were enriched in advanced disease but adversely impacted survival across all stages, even when controlling for known correlates of outcome (multifocal disease, lymph node involvement, bile duct type, periductal infiltration). In resected patients (n = 209), TP53mut (HR, 1.82; 95% CI, 1.08‐3.06; P = 0.03) and CDKN2A deletions (del; HR, 3.40; 95% CI, 1.95‐5.94; P < 0.001) independently predicted shorter OS, as did high‐risk clinical variables (multifocal liver disease P < 0.001; regional lymph node metastases P < 0.001), whereas KRASmut (HR, 1.69; 95% CI, 0.97‐2.93; P = 0.06) trended toward statistical significance. The presence of both or neither high‐risk clinical or genetic factors represented outcome extremes (median OS, 18.3 vs. 74.2 months; P < 0.001), with high‐risk genetic alterations alone (median OS, 38.6 months; 95% CI, 28.8‐73.5) or high‐risk clinical variables alone (median OS, 37.0 months; 95% CI, 27.6‐not available) associated with intermediate outcome. TP53mut, KRASmut, and CDKN2Adel similarly predicted worse outcome in patients with unresectable iCCA. CDKN2Adel tumors with high‐risk clinical features were notable for limited survival and no benefit of resection over chemotherapy.
Conclusions
TP53, KRAS, and CDKN2A alterations were independent prognostic factors in iCCA when controlling for clinical and pathologic variables, disease stage, and treatment. Because genetic profiling can be integrated into pretreatment therapeutic decision‐making, combining clinical variables with targeted tumor sequencing may identify patient subgroups with poor outcome irrespective of treatment strategy.
Isocitrate dehydrogenase-mutant (IDH-mt) gliomas are incurable primary brain tumors characterized by a slow-growing phase over several years followed by a rapid-growing malignant phase. We ...hypothesized that tumor volume growth rate (TVGR) on MRI may act as an earlier measure of clinical benefit during the active surveillance period.
We integrated three-dimensional volumetric measurements with clinical, radiologic, and molecular data in a retrospective cohort of IDH-mt gliomas that were observed after surgical resection in order to understand tumor growth kinetics and the impact of molecular genetics.
Using log-linear mixed modeling, the entire cohort (n = 128) had a continuous %TVGR per 6 months of 10.46% 95% confidence interval (CI), 9.11%-11.83% and a doubling time of 3.5 years (95% CI, 3.10-3.98). High molecular grade IDH-mt gliomas, defined by the presence of homozygous deletion of CDKN2A/B, had %TVGR per 6 months of 19.17% (95% CI, 15.57%-22.89%) which was significantly different from low molecular grade IDH-mt gliomas with a growth rate per 6 months of 9.54% (95% CI, 7.32%-11.80%; P < 0.0001). Using joint modeling to comodel the longitudinal course of TVGR and overall survival, we found each one natural logarithm tumor volume increase resulted in more than a 3-fold increase in risk of death (HR = 3.83; 95% CI, 2.32-6.30; P < 0.0001).
TVGR may be used as an earlier measure of clinical benefit and correlates well with the WHO 2021 molecular classification of gliomas and survival. Incorporation of TVGR as a surrogate endpoint into future prospective studies of IDH-mt gliomas may accelerate drug development.
To evaluate the efficacy of chemotherapy in patients with microsatellite instability (MSI)-high gastric cancer.
Although MSI-high gastric cancer is associated with a superior prognosis, recent ...studies question the benefit of perioperative chemotherapy in this population.
Locally advanced gastric adenocarcinoma patients who either underwent surgery alone or also received neoadjuvant, perioperative, or adjuvant chemotherapy between 2000 and 2018 were eligible. MSI status, determined by next-generation sequencing or mismatch repair protein immunohistochemistry, was determined in 535 patients. Associations among MSI status, chemotherapy administration, overall survival (OS), disease-specific survival, and disease-free survival were assessed.
In 535 patients, 82 (15.3%) had an MSI-high tumor and ∼20% better OS, disease-specific survival, and disease-free survival. Grade 1 (90%-100%) pathological response to neoadjuvant chemotherapy was found in 0 of 40 (0%) MSI-high tumors versus 43 of 274 (16%) MSS. In the MSI-high group, the 3-year OS rate was 79% with chemotherapy versus 88% with surgery alone ( P =0.48). In the MSS group, this was 61% versus 59%, respectively ( P =0.96). After multivariable interaction analyses, patients with MSI-high tumors had superior survival compared with patients with MSS tumors whether given chemotherapy (hazard ratio=0.53, 95% confidence interval: 0.28-0.99) or treated with surgery alone (hazard ratio=0.15, 95% confidence interval: 0.02-1.17).
MSI-high locally advanced gastric cancer was associated with superior survival compared with MSS overall, despite worse pathological chemotherapy response. In patients with MSI-high gastric cancer who received chemotherapy, the survival rate was ∼9% worse compared with surgery alone, but chemotherapy was not significantly associated with survival.
There is increasing use of neoadjuvant chemotherapy in the management of localized pancreatic ductal adenocarcinoma (PDAC), yet there are few validated biomarkers to guide therapy selection. We aimed ...to determine whether somatic genomic biomarkers predict response to induction FOLFIRINOX or gemcitabine/nab-paclitaxel.
This single-institution cohort study included consecutive patients (N = 322) with localized PDAC (2011-2020) who received at least one cycle of FOLFIRINOX (N = 271) or gemcitabine/nab-paclitaxel (N = 51) as initial treatment. We assessed somatic alterations in four driver genes (KRAS, TP53, CDKN2A, and SMAD4) by targeted next-generation sequencing, and determined associations between these alterations and (1) rate of metastatic progression during induction chemotherapy, (2) surgical resection, and (3) complete/major pathologic response.
The alteration rates in driver genes KRAS, TP53, CDKN2A, and SMAD4 were 87.0%, 65.5%, 26.7%, and 19.9%, respectively. For patients receiving first-line FOLFIRINOX, SMAD4 alterations were uniquely associated with metastatic progression (30.0% vs. 14.5%; P = 0.009) and decreased rate of surgical resection (37.1% vs. 66.7%; P < 0.001). For patients receiving induction gemcitabine/nab-paclitaxel, alterations in SMAD4 were not associated with metastatic progression (14.3% vs. 16.2%; P = 0.866) nor decreased rate of surgical resection (33.3% vs. 41.9%; P = 0.605). Major pathologic response was rare (6.3%) and not associated with type of chemotherapy regimen.
SMAD4 alterations were associated with more frequent development of metastasis and lower probability of reaching surgical resection during neoadjuvant FOLFIRINOX but not gemcitabine/nab-paclitaxel. Confirmation in a larger, diverse patient cohort will be important before prospective evaluation of SMAD4 as a genomic biomarker to guide treatment selection.
Background
Despite curative hepatectomy, most colorectal liver metastasis (CRLM) patients relapse locally within 2 years. Genomic predictors for hepatic recurrence are poorly understood. This study ...was designed to identify genomic signatures for recurrence in resected CRLM patients treated with adjuvant hepatic artery infusion (HAI) and/or systemic (SYS) chemotherapy.
Methods
Patients undergoing curative hepatectomy and adjuvant HAI+SYS or SYS between January 2000 and October 2017 with next-generation sequencing data were catalogued. Gene and signaling-level alterations were checked for association with time to any (AR), liver (LR), and extrahepatic recurrence (ER) by using Kaplan-Meier analysis.
Results
Of 172 receiving HAI+SYS, 100 patients recurred, with 69 LR and 83 ER. Five- and ten-year LR-free rates were 57% (95% confidence interval CI 48–65%) and 51% (95% CI 41–60%), respectively. Five- and 10-year ER-free, rates were 51% (95% CI 43–58%) and 45% (95% CI 36–54%), respectively. More ER was observed with tumors harboring altered
KRAS
(38% 95% CI 25–50% vs. 63% 95% CI 53–71%,
p
-adj = 0.003) and RAS/RAF (36% 95% CI 25–48% vs. 66% 95% CI 56–74%,
p
-adj < 0.001) than wild-type. Co-altered RAS/RAF-
TP53
was associated with worse AR (26% 95% CI 14–40% vs. 48% 95% CI 39–57%,
p
-unadj < 0.001), ER (30% 95% CI 17–45% vs. 62% 95% CI 53–70%,
p
-unadj < 0.001), and LR rate (40% 95% CI 24–57% vs. 70% 95% CI 60–77%,
p
-unadj = 0.002). On multivariable analysis, controlling for clinical risk score, ablation, margin status, and primary T-stage, co-altered RAS/RAF-
TP53
was associated with increased risk for AR (HR = 2.14, 95% CI 1.38–3.31,
p
-unadj < 0.001), LR (HR = 1.79, 95% CI 1.06–3.02,
p
-unadj = 0.029), and ER (HR = 2.81, 95% CI 1.78–4.44,
p
-unadj < 0.001).
Conclusions
Altered
KRAS
, RAS/RAF, and RAS/RAF-
TP53
associated with earlier local and distant recurrence in resected CRLM patients receiving adjuvant HAI+SYS. Co-altered RAS/RAF-
TP53
was a novel predictor of LR warranting investigation of whether genomic cooperativity is associated with this relapsing phenotype. Systemic therapies tailored to high-risk tumor biology are needed to reduce distant relapse after hepatectomy.
In patients with locally advanced esophageal adenocarcinoma, response to neoadjuvant therapy strongly predicts survival, but robust molecular predictors of response have been lacking. We therefore ...sought to discover meaningful predictors of response in these patients.
We retrospectively identified all patients with adenocarcinoma of the lower esophagus or gastroesophageal junction who (i) were treated with multimodality therapy with curative intent at our institution from 2014 through 2020 and (ii) underwent prospective sequencing by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. Clinicopathologic and genomic data were analyzed to identify potential genomic features, somatic alterations, and oncogenic pathways associated with treatment response.
In total, 237 patients were included. MDM2 amplification was independently associated with poor response to neoadjuvant therapy OR, 0.10 (95% confidence interval, 0.01-0.55); P = 0.032, when accounting for significant clinicopathologic variables, including clinical stage, tumor grade, and chemotherapy regimen. Moreover, TP53 pathway alterations, grouped according to inferred severity of TP53 dysfunction, were significantly associated with response to neoadjuvant therapy (P = 0.004, q = 0.07). Patients with MDM2 amplifications or truncating biallelic TP53 mutations had similar outcomes in terms of poor responses to neoadjuvant therapy and, consequently, shorter progression-free survival, compared with patients with TP53 pathway wild-type tumors. Thus, worsening TP53 dysfunction was directly correlated with worse outcomes.
MDM2 amplification and TP53 status are associated with response to therapy in patients with esophageal adenocarcinoma. Given the dearth of actionable targets in esophageal adenocarcinoma, MDM2 inhibition, in combination with cytotoxic chemotherapy, may represent an important therapeutic strategy to overcome treatment resistance and improve outcomes in these patients.
To determine the safety and efficacy of adding the anti-PD-L1 antibody durvalumab to induction FOLFOX and preoperative chemotherapy in locally advanced esophageal adenocarcinoma.
Neoadjuvant ...induction FOLFOX followed by positron emission tomography (PET) directed chemoradiation has demonstrated improved survival for esophageal adenocarcinoma. There is clear benefit now for the addition of immune checkpoint inhibitors both in early and advanced stage disease. Given these results we investigated the safety and efficacy of adding durvalumab to induction FOLFOX and preoperative chemoradiotherapy.
Patients with locally advanced resectable esophageal/gastroesophageal junction adenocarcinoma received PET-directed chemoradiation with durvalumab before esophagectomy. Patients who had R0 resections received adjuvant durvalumab 1500 mg every 4 weeks for 6 treatments. The primary endpoint of the study was pathologic complete response.
We enrolled 36 patients, 33 of whom completed all preoperative treatment and underwent surgery. Preoperative treatment was well tolerated, with no delays to surgery nor new safety signals. Pathologic complete response was identified in 8 22% (1-sided 90% lower bound: 13.3%) patients with major pathologic response in 22 61% (1-sided 90% lower bound: 50%) patients. Twelve and 24-month overall survival was 92% and 85%, respectively.
The addition of durvalumab to induction FOLFOX and PET-directed chemoradiotherapy before surgery is safe, with a high rate of pathologic response, as well as encouraging survival data.
Background
Immune checkpoint blockade (ICI) of programmed cell death protein 1 (PD-1) or PD-1 ligand (PD-L1) can induce durable responses in patients who have colorectal cancer (CRC) with a high ...tumor mutational burden (TMB). Two recurring clinical dilemmas show how to manage oligoprogressive disease and stable disease after ICI.
Methods
A cohort study was conducted to analyze patients with metastatic CRC who underwent PD-1 or PD-L1 blockade. Tumors were mismatch repair (MMR) deficient or had more than 25 mutations per megabase. Patients were identified who had local therapy (surgery, ablation, or radiotherapy) for one to three sites of progressive disease (PD) or surgery to consolidate SD. The study evaluated clinical and biologic factors associated with patient selection, outcomes, and pathologic response rates.
Results
From 2014 to 2020, treatment was administered to 111 patients with ICI. Of these 111 patients, 19 (17%) survived fewer than 6 months, whereas to date, 50 have not had progression of disease. The remaining 42 patients experienced PD, and 16 (38%) were treated with local therapy for oligoprogression. Selection for local therapy was associated with response to ICI. The 2-year progression-free survival (PFS) after local therapy was 62%. Finally, 6 of the 50 patients without PD had consolidation of SD, and 5 had complete or near complete pathologic responses.
Conclusions
Oligoprogression, a frequent pattern of failure after ICI, can be managed effectively with local therapy. In contrast, it may not be necessary to consolidate SD for selected patients. Further research is essential to define management algorithms better and to explore heterogeneity in response patterns.
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