Outcomes in Patients With Pancreatic Adenocarcinoma With Genetic Mutations in DNA Damage Response Pathways: Results From the Know Your Tumor Program.

PURPOSE: Up to 25% of pancreatic adenocarcinomas (PDACs) harbor mutations in the homologous recombination DNA damage response (HR-DDR) pathway. Although known to affect responsiveness to DNA-damaging chemotherapy, the prognostic relevance of these mutations is unclear and outcomes in patients with PDAC who harbor HR-DDR mutations beyond BRCA1/2 remain unexplored. METHODS: We evaluated 820 patients with PDAC enrolled in the Know Your Tumor program for whom we had collected comprehensive genomic testing results and longitudinal clinical outcomes. Patients were categorized as having resected versus advanced disease, and as having received platinum-based therapy versus being platinum naïve. Tumor genomic profiles were categorized as HR-DDR mutated (HR-DDRmut) or proficient (pHR-DDR) on the basis of the presence of pathogenic mutations of somatic or germline origin in BRCA1/2 or PALB2 (group 1); ATM/ATR/ATRX (group 2); or BAP1, BARD1, BRIP1, CHEK1/2, RAD50/51/51B, or FANCA/C/D2/E/F/G/L (group 3). Overall survival was measured from the date of diagnosis until death. RESULTS: Median overall survival (mOS) was similar in all resected patients irrespective of exposure to platinum-based therapy, whereas for platinum-treated patients with advanced disease, mOS was significantly longer for HR-DDRmut versus pHR-DDR (2.37 years v 1.45 years, respectively). Of importance, no difference was identified in platinum-naïve patients. mOS in patients with mutations in all three HR-DDRmut groups was greater than that for pHR-DDR patients, but this difference was lost in platinum-naïve patients. CONCLUSION: Patients with advanced HR-DDRmut have improved mOS when treated with platinum-based therapy compared with pHR-DDR patients. In platinum-naïve patients, there is no mOS difference, which suggests that HR-DDR status has no pure prognostic value. These findings support the need to test all patients with advanced PDAC to ensure that HR-DDRmut patients receive the benefit of treatment with platinum-based therapy.

Sentinel node biopsy in patients with primary cutaneous melanoma of any thickness: A cost-effectiveness analysis.

OBJECTIVE: To assess the cost-effectiveness of the sentinel node biopsy with lymphadenectomy for nodal metastases (SNB) in patients with primary cutaneous melanoma (CM) of different Breslow thickness (intermediate, thick, thin). METHODS: Decision tree models were constructed to compare two different strategies of management of patients with CM, wide excision of the primary lesion and SNB and wide excision only (WE). Tree models were created for every Breslow thickness over 1-, 5- and 10-year time horizons. Mean and total direct healthcare costs, life years saved (LYSs), quality-adjusted life years (QALYs), cost effectiveness ratio (CER), and incremental cost effectiveness ratio (ICER) were estimated. Every model was considered as a base case, and its results tested with sensitivity analyses. RESULTS: Base case analyses showed that the best results were obtained for intermediate CM over 10-year time horizon. In this case, ICER for SNB was 130,508€/QALY, well over the threshold of acceptance (30,000€/QALY). In patients with intermediate CM over 1 and 5 years, and for those with thick and thin CM at any time horizon, negative ICER values were estimated since SNB was proved to be more expensive and less effective than WE. Sensitivity analyses confirmed the robustness of our results. CONCLUSIONS: SNB caused no improvement in health outcomes in terms of LYSs and QALYs in patients with thick and thin CM, and only a slight benefit in those with intermediate CM. WE was more cost-effective compared with SNB for any CM thickness over any time horizon up to 10 years.

Análisis de los factores relacionados con la sobreestadificación y la positividad del ganglio centinela en las pacientes con diagnóstico inicial de carcinoma ductal in situ / Analysis of factors related to upstaging and sentinel node positivity in the initial diagnosis of ductal carcinoma in situ

Objetivo. Determinar el porcentaje de pacientes con diagnóstico inicial de carcinoma ductal in situ (CDIS) que presentó infiltración tras la excisión quirúrgica e identificar los factores relacionados tanto con la sobreestadificación como con la positividad del ganglio centinela (GC) en el estudio definitivo. Material y métodos. Análisis retrospectivo de 135 pacientes diagnosticadas mediante biopsia core de CDIS a las que se les realizó biopsia selectiva del GC de forma consecutiva de 2003 a 2011. La técnica fue mixta en el período inicial y posteriormente mediante administración intraperilesional de radiocoloides. En 2009 se introdujo una gammacámara portátil y se inició el estudio intraoperatorio molecular mediante amplificación de ácido nucleico de un solo paso. Resultados. Se produjo sobreestadificación en 45 de las 135 pacientes (33,3%), de las que 30 (22,2%) presentaron CDIS con microinfiltración y 15 (11,1%) carcinoma infiltrante. Los CDIS con microinfiltración mostraron mayor tamaño, mayor porcentaje de alto grado, de HER2 positivo y de Ki-67 alto que los CDIS (p < 0,001, p < 0,001, p = 0,002 y p = 0,031, respectivamente). Los porcentajes de positividad del GC fueron del 3,6% en el CDIS, del 6,9% en el CDIS con microinfiltración y del 20% en los carcinomas infiltrantes, correspondiendo a 8 pacientes, de las cuales 6 presentaron HER2 positivo y Ki-67 alto. Conclusiones. El porcentaje global de infraestimación fue alto, principalmente debido a la presencia de microinfiltración. Tanto esta como la afectación metastásica del GC mostró relación con el HER2 positivo y el Ki-67 alto, por tanto, disponer de estos datos en la biopsia percutánea podría ser relevante para establecer la indicación de realización de biopsia selectiva del GC en el CDIS

Objective. To determine the percentage of patients with ductal carcinoma in situ (DCIS) with infiltration after surgical excision and to identify the factors related to both upstaging and sentinel node (SN) positivity in the final study. Material and methods. A retrospective analysis was performed in 135 patients diagnosed with DCIS by core biopsy who subsequently underwent sentinel lymph node biopsy from 2003 to 2011. In the first period of the study, the technique was mixed and subsequently consisted of intra-perilesional radiocolloid administration. In 2009, a portable gamma camera was introduced and we began to use intraoperative one-step nucleic acid amplification. Results. Upstaging occurred in 45 of the 135 patients (33.3%), of which 30 (22.2%) had DCIS with microinfiltration and 15 (11.1%) had invasive carcinoma. Compared with DCIS, DCIS with microinfiltration were larger and showed a higher percentage of high grade, HER2 positivity and high Ki-67 (P < .001, P < .001, P = .002 and P = .031, respectively). SN positivity rates were 3.6% in DCIS, 6.9% in DCIS with microinfiltration, and 20% in invasive carcinomas, corresponding to 8 patients, of whom 6 showed HER2-positivity and high Ki-67. Conclusions. Overall underestimation was high, mainly due to the presence of microinfiltration. Both microinfiltration and metastatic SN involvement were associated with HER2-positivity and high Ki-67. Therefore, the availability of this information in core needle biopsy could be relevant in establishing the indication for sentinel lymph node biopsy in DCIS