ABSTRACT
Ampullary carcinomas are rare but increasing in incidence. Ampullary cancers have molecular alterations that guide choice of therapy, particularly in nonresectable cases. These alterations can be more common by subtype (intestinal, pancreaticobiliary, or mixed), and next-generation sequencing is recommended for all patients who cannot undergo surgery. In this article, we review the approach to tissue acquisition and consideration for molecular testing. Common molecular targets of interest in ampullary cancer are also discussed in this review, including HER2/ERBB2, HER3, tumor mutational burden, microsatellite instability, KRAS, and germline BRCA and ATM mutations, along with emerging and rarer alterations.
Subject(s)
Ampulla of Vater , Common Bile Duct Neoplasms , Molecular Targeted Therapy , Humans , Ampulla of Vater/pathology , Molecular Targeted Therapy/methods , Common Bile Duct Neoplasms/therapy , Common Bile Duct Neoplasms/diagnosis , Common Bile Duct Neoplasms/genetics , Common Bile Duct Neoplasms/pathology , Mutation , Biomarkers, Tumor/geneticsABSTRACT
INTRODUCTION: A significant proportion of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor mutations in homologous recombination (HR) repair genes, with some of these mutations associating with increased tumor susceptibility to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy. While mutations in some HR repair genes (e.g., BRCA1/2) have been associated with a more aggressive clinical course, prior studies correlating HR mutational status with treatment response to androgen receptor (AR) signaling inhibitors (ARSIs) or taxane-based chemotherapy have yielded conflicting results. METHODS: We conducted a single-center retrospective analysis to assess clinical outcomes to conventional, regulatory-approved therapies in mCRPC patients with somatic (monoallelic and biallelic) and/or germline HR repair mutations compared to patients without alterations as determined by clinical-grade next-generation sequencing assays. The primary endpoint was PSA30/PSA50 response, defined as ≥30%/≥50% prostate-specific antigen (PSA) reduction from baseline. Secondary endpoints of PSA progression-free survival (pPFS) and clinical/radiographic progression-free survival (crPFS) were estimated using Kaplan-Meier methods. RESULTS: A total of 90 consecutively selected patients were included in this analysis, of which 33 (37%) were identified to have HR repair gene mutations. Age, race, Gleason score, prior surgery, and receipt of prior radiation therapy were comparable between carriers and non-carriers. There was no evidence that PSA30/PSA50 differed by HR gene mutational status. Median pPFS and crPFS ranged 3-14 months across treatment modalities, but there was no evidence either differed by HR gene mutational status (all p>0.05). There was also no difference in outcomes between those with BRCA2 or PALB2 mutations (n = 17) compared to those without HR repair mutations. CONCLUSION: HR gene mutational status was associated with comparable clinical outcomes following treatment with ARSIs or taxane-based chemotherapy. Additional prospective studies are needed to confirm these findings.
Subject(s)
Mutation , Prostatic Neoplasms, Castration-Resistant/genetics , Recombinational DNA Repair/genetics , Aged , Antineoplastic Agents/therapeutic use , Ataxia Telangiectasia Mutated Proteins/genetics , BRCA2 Protein/genetics , Cyclin-Dependent Kinases/genetics , Drug Resistance, Neoplasm , Fanconi Anemia Complementation Group N Protein/genetics , Humans , MRE11 Homologue Protein/genetics , Male , Middle Aged , Neoplasm Metastasis , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Progression-Free Survival , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Steroid Synthesis Inhibitors/therapeutic useABSTRACT
OBJECTIVE: The National Lung Screening Trial demonstrated the benefits of lung cancer screening, but the potential high incidence of unnecessary invasive testing for ultimately benign radiologic findings causes concern. We aimed to review current biopsy patterns and outcomes in our community-based program, and retrospectively apply malignancy prediction models in a lung cancer screening population, to identify the potential impact these calculators could have on biopsy decisions. METHODS: Retrospective review of lung cancer-screening program participants from 2013 to 2016. Demographic, biopsy, and outcome data were collected. Malignancy risk calculators were retrospectively applied and results compared in patients with positive imaging findings. RESULTS: From 520 individuals enrolled in the screening program, pulmonary nodule(s) ≥6 mm were identified in 166, with biopsy in 30. Malignancy risk probabilities were significantly higher (Brock p < 0.00001; Mayo p < 0.00001) in those undergoing diagnostic sampling than those not undergoing sampling. However, there was no difference in the Brock ( p = 0.912) or Mayo ( p = 0.435) calculators when discriminating a final diagnosis of cancer from not cancer in those undergoing sampling. CONCLUSIONS: In our screening program, 5.7% of individuals undergo invasive testing, comparable with the National Lung Screening Trial (6.1%). Both Brock and Mayo calculators perform well in indicating who may be at risk of malignancy, based on clinical and radiologic factors. However, in our invasive testing group, the Brock and Mayo calculators and Lung Cancer Screening Program clinical assessment all lacked clarity in distinguishing individuals who have a cancer from those with a benign abnormality.
