We describe clinical, pathologic, and molecular characteristics of never-smoker patients with small-cell lung cancers (SCLCs).
We identified cases of SCLCs evaluated at our institution from 2005 to ...2012. We collected smoking history, demographic, treatment, and survival data. EGFR, KRAS, PIK3CA, ALK testing, RB protein expression, and next generation sequencing were performed on available samples.
Two percent (23 of 1040) of patients with SCLCs were never-smokers. Eighty-three percent (19 of 23) had de novo SCLCs, whereas 17% had SCLC transformation as acquired resistance to erlotinib after treatment for EGFR-mutant lung carcinomas. Median survival from SCLC diagnosis was 23 months. Of de novo SCLCs, ALK rearrangement, KRAS mutations, EGFR mutations, and RB loss were identified in zero of five, zero of eight, two of eight, and six of seven, respectively. Two de novo samples underwent next generation sequencing. One had mutations in p53 and RB1 with amplification in TERT, and a second had mutations in CBL and GNAS with amplification in MYCL1.
Two percent of patients with SCLCs are never-smokers. Although transformation to SCLC can rarely occur in acquired resistance to erlotinib, 83% of never-smokers with SCLCs had de novo SCLC. RB loss was noted in 86% of cases. Multiplexed genotyping can be performed on tissues to identify potentially actionable oncogenic drivers.
Tumor type guides clinical treatment decisions in cancer, but histology-based diagnosis remains challenging. Genomic alterations are highly diagnostic of tumor type, and tumor-type classifiers ...trained on genomic features have been explored, but the most accurate methods are not clinically feasible, relying on features derived from whole-genome sequencing (WGS), or predicting across limited cancer types. We use genomic features from a data set of 39,787 solid tumors sequenced using a clinically targeted cancer gene panel to develop Genome-Derived-Diagnosis Ensemble (GDD-ENS): a hyperparameter ensemble for classifying tumor type using deep neural networks. GDD-ENS achieves 93% accuracy for high-confidence predictions across 38 cancer types, rivaling the performance of WGS-based methods. GDD-ENS can also guide diagnoses of rare type and cancers of unknown primary and incorporate patient-specific clinical information for improved predictions. Overall, integrating GDD-ENS into prospective clinical sequencing workflows could provide clinically relevant tumor-type predictions to guide treatment decisions in real time.
We describe a highly accurate tumor-type prediction model, designed specifically for clinical implementation. Our model relies only on widely used cancer gene panel sequencing data, predicts across 38 distinct cancer types, and supports integration of patient-specific nongenomic information for enhanced decision support in challenging diagnostic situations. See related commentary by Garg, p. 906. This article is featured in Selected Articles from This Issue, p. 897.
Background
Patients with germline/somatic BRCA1/BRCA2 mutations (g/sBRCA1/2) comprise a distinct biologic subgroup of pancreas ductal adenocarcinoma (PDAC).
Methods
Institutional databases were ...queried to identify patients who had PDAC with g/sBRCA1/2. Demographics, clinicopathologic details, genomic data (annotation sBRCA1/2 according to a precision oncology knowledge base for somatic mutations), zygosity, and outcomes were ed. Overall survival (OS) was estimated using the Kaplan‐Meier method.
Results
In total, 136 patients with g/sBRCA1/2 were identified between January 2011 and June 2020. Germline BRCA1/2 (gBRCA1/2) mutation was identified in 116 patients (85%). Oncogenic somatic BRCA1/2 (sBRCA1/2) mutation was present in 20 patients (15%). Seventy‐seven patients had biallelic BRCA1/2 mutations (83%), and 16 (17%) had heterozygous mutations. Sixty‐five patients with stage IV disease received frontline platinum therapy, and 52 (80%) had a partial response. The median OS for entire cohort was 27.6 months (95% CI, 24.9‐34.5 months), and the median OS for patients who had stage IV disease was 23 months (95% CI, 19‐26 months). Seventy‐one patients received a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor (PARPi), and 52 received PARPi monotherapy. For maintenance PARPi, 10 patients (36%) had a partial response, 12 (43%) had stable disease, and 6 (21%) had progression of disease as their best response. Six patients (21%) received maintenance PARPi for >2 years. For those with stage IV disease who received frontline platinum, the median OS was 26 months (95% CI, 20‐52 months) for biallelic patients (n = 39) and 8.66 months (95% CI, 6.2 months to not reached) for heterozygous patients (n = 4). The median OS for those who received PARPi therapy was 26.5 months (95% CI, 24‐53 months) for biallelic patients (n = 25) and 8.66 months (95% CI, 7.23 months to not reached) for heterozygous patients (n = 2).
Conclusions
g/sBRCA1/2 mutations did not appear to have different actionable utility. Platinum and PARPi therapies offer therapeutic benefit, and very durable outcomes are observed in a subset of patients who have g/sBRCA1/2 mutations with biallelic status.
In a cohort of 136 patients with pancreas cancer and a germline or somatic BRCA mutation, the median overall survival is 27.6 months (95% CI, 24.9‐34.5 months) for the entire cohort and 23 months for the stage IV cohort (n = 81). Biallelic zygosity enriches the response to platinum and poly(adenosine diphosphate ribose) polymerase inhibitor therapies.
Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have ...potential benefit in these patients.
To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC.
A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded.
Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin.
The primary outcome was progression-free survival (PFS) of 80% at 6 months.
For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 34% men; median range age at diagnosis, 64 39-81 years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 47%) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4).
Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.
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.
The use of genomic technologies for the molecular characterization of tumors has propelled our understanding of cancer biology and is transforming the way patients with cancer are diagnosed and ...treated.
Highlights • Sonidegib with etoposide/cisplatin in newly diagnosed SCLC patients is safe and effective. • Creatine kinase elevations were noted, similar to other studies evaluating sonidegib. • ...Genomic characterization of an exceptional responder reveals SOX2 amplification on 3q26.
We sought to compare overall survival (OS) and disease control for patients with localized pancreatic ductal adenocarcinoma (PDAC) treated with ablative dose radiotherapy (A-RT) versus resection.
...Locoregional treatment for PDAC includes resection when possible or palliative RT. A-RT may offer durable tumor control and encouraging survival.
This was a single-institution retrospective analysis of patients with PDAC treated with induction chemotherapy followed by A-RT ≥98 Gy biologically effective dose (BED) using 15-25 fractions in 3-4.5 Gy/fraction or pancreatectomy.
One hundred and four patients received A-RT (49.8%) and 105 (50.2%) underwent resection. Patients receiving A-RT had larger median tumor size after induction chemotherapy 3.2 cm (undetectable-10.9) vs 2.6 cm (undetectable-10.7), P < 0.001, and were more likely to have celiac or hepatic artery encasement (48.1% vs 11.4%, P <0.001), or superior mesenteric artery encasement (43.3% vs 9.5%, P < 0.001); however, there was no difference in the degree of SMV/PV involvement (P = 0.123). There was no difference in locoregional recurrence/progression at 18-months between A-RT and resection; cumulative incidence was 16% (95% confidence interval (CI) 10%-24% versus 21% (95% CI 14%-30%), respectively (P= 0.252). However, patients receiving A-RT had a 19% higher 18-month cumulative incidence of distant recurrence/progression 58% (95% CI 48%-67%) vs 30% (95% CI 30%-49%), P= 0.004. Median OS from completion of chemotherapy was 20.1 months for A-RT patients (95% CI 16.4-23.1 months) versus 32.9 months (95% CI 29.7-42.3 months) for resected patients (P < 0.001).
Ablative radiation is a promising new treatment option for PDAC, offering locoregional disease control similar to that associated with resection and encouraging survival.
Diagnosing the site of origin for cancer is a pillar of disease classification that has directed clinical care for more than a century. Even in an era of precision oncologic practice, in which ...treatment is increasingly informed by the presence or absence of mutant genes responsible for cancer growth and progression, tumor origin remains a critical factor in tumor biologic characteristics and therapeutic sensitivity.
To evaluate whether data derived from routine clinical DNA sequencing of tumors could complement conventional approaches to enable improved diagnostic accuracy.
A machine learning approach was developed to predict tumor type from targeted panel DNA sequence data obtained at the point of care, incorporating both discrete molecular alterations and inferred features such as mutational signatures. This algorithm was trained on 7791 tumors representing 22 cancer types selected from a prospectively sequenced cohort of patients with advanced cancer.
The correct tumor type was predicted for 5748 of the 7791 patients (73.8%) in the training set as well as 8623 of 11 644 patients (74.1%) in an independent cohort. Predictions were assigned probabilities that reflected empirical accuracy, with 3388 cases (43.5%) representing high-confidence predictions (>95% probability). Informative molecular features and feature categories varied widely by tumor type. Genomic analysis of plasma cell-free DNA yielded accurate predictions in 45 of 60 cases (75.0%), suggesting that this approach may be applied in diverse clinical settings including as an adjunct to cancer screening. Likely tissues of origin were predicted from targeted tumor sequencing in 95 of 141 patients (67.4%) with cancers of unknown primary site. Applying this method prospectively to patients under active care enabled genome-directed reassessment of diagnosis in 2 patients initially presumed to have metastatic breast cancer, leading to the selection of more appropriate treatments, which elicited clinical responses.
These results suggest that the application of artificial intelligence to predict tissue of origin in oncologic practice can act as a useful complement to conventional histologic review to provide integrated pathologic diagnoses, often with important therapeutic implications.
Acute cholangitis (AC) is a common complication of pancreatic ductal adenocarcinoma (PDAC). Herein, we evaluated outcomes after the first AC episode and predictors of mortality and AC recurrence in ...patients with stage IV PDAC.
We conducted a single-center, retrospective observational study using institutional databases. Clinical data and outcomes for patients with stage IV PDAC and at least one documented episode of AC, were assessed. Overall survival (OS) was estimated using the Kaplan-Meier method, and Cox regression model was employed to identify predictors of AC recurrence and mortality.
One hundred and twenty-four patients with stage IV PDAC and AC identified between January 01, 2014 and October 31, 2020 were included. Median OS after first episode of AC was 4.1 months (95 % CI, 4.0–5.5), and 30-day, 6, and 12-month survival was 86.2 % (95 % CI, 80.3–92.5), 37 % (95 % CI, 29.3–46.6 %) and 18.9 % (95 % CI, 13.1–27.3 %), respectively. Primary tumor in pancreatic body/tail (HR 2.29, 95 % CI: 1.26 to 4.18, p = 0.011), concomitant metastases to liver and other sites (HR 1.96, 95 % CI: 1.16 to 3.31, p = 0.003) and grade 3 AC (HR 2.26, 95 % CI: 1.45 to 3.52, p < 0.001), predicted worse outcomes. Intensive care unit admission, sepsis, systemic therapy, treatment regimen, and time to intervention did not predict survival or risk of recurrence of AC.
AC confers significant morbidity and mortality in advanced PDAC. Worse outcomes are associated with higher grade AC, primary tumor location in pancreatic body/tail, and metastases to liver and other sites.
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