BACKGROUND:Pathologic complete response (pCR) after neoadjuvant therapy has been associated with improved survival in several malignancies, but its prognostic value in gastric cancer remains unclear. METHODS:Using the National Cancer Database, we identified non-metastatic gastric adenocarcinoma patients diagnosed 2004-2021 treated with neoadjuvant chemotherapy followed by curative-intent resection. Patients receiving neoadjuvant radiation were excluded. We analyzed pCR rates, overall survival (OS), and factors associated with pCR using a generalized estimating equations model. Kaplan-Meier and Cox proportional hazards models were used to assess OS. Trends in pCR over time were evaluated with time-trend analysis. RESULTS:Among 7258 patients, 672 (9.3%) achieved pCR. Median OS was significantly higher in patients with pCR compared to those without (167.9 vs. 65.8 months, p < 0.001). Subgroup analysis of cT2N1 or higher stage patients revealed the highest survival in patients with both tumor and nodal pCR (median OS 181.8 months). Patients diagnosed after 2018 were more likely to achieve pCR (OR: 1.26, 95% CI: 1.07-1.49, p = 0.005), correlating with the adoption of the FLOT regimen. Completion of adjuvant therapy in patients who achieved pCR did not significantly improve OS. CONCLUSION:pCR is associated with significantly improved OS in gastric cancer, especially when both tumoral and nodal pCR are achieved. Increasing pCR rates in recent years may reflect the uptake of modern chemotherapy regimens, underscoring the value of neoadjuvant strategies.

: This review explores the current state of the sentinel lymph node biopsy (SLNB) in melanoma management, including agents used for SLNB, imaging modalities for localization, special considerations, and novel adjuncts for predicting sentinel node positivity. : Technetium-99 m Tilmanocept (Lymphoseek) has proven a novel, safe, and effective agent for lymphatic mapping. Melanoma on the trunk, head, and neck regions requires thoughtful operative planning and benefits from preoperative imaging. Planar lymphoscintigraphy and SPECT-CT remain the primary imaging for SLNB. Finally, validated nomograms and gene expression profile (GEP) tests have emerged as promising adjuncts for prognostic and predictive testing and may reduce unnecessary surgery in the future. : The SLNB remains a critical procedure for melanoma management. It provides invaluable information for prognostication, decision-making for adjuvant systemic therapy, surveillance intensity, and clinical trial eligibility and stratification. Success with SLNB requires understanding of the pertinent surgical anatomy, familiarity with the lymphatic mapping process, and diligent interpretation of pertinent imaging.

Pancreatic ductal adenocarcinoma (PDAC) remains among the most aggressive malignancies in the United States. Advances in treatments have slowly increased survival rates; however, outcomes remain dismal, largely due to the insidious onset of the disease and lack of screening tests leading to diagnosis at more advanced disease stages. As we better understand the molecular mechanisms that drive PDAC, we can leverage this technology for early detection of new PDAC or recurrences and find more effective methods to track treatment response. Liquid biopsies are increasingly common for the treatment of many malignancies, leveraging better technology to detect scant quantities of circulating tumor cells (CTCs) or byproducts of tumor biology (e.g., exosomes and microRNA [miRNA]) in the blood stream. When combined with existing biomarkers like CA 19-9, there is promising research that improved diagnostic modalities may be available in the future. Furthermore, these technologies are being leveraged to better prognosticate patients with PDAC and potentially monitor treatment responses not captured by cross-sectional imaging, which may allow for real-time changes in therapeutic strategy. This manuscript will review the molecular mechanisms that drive PDAC development and the biomarkers available for diagnosis and prognostication. Much of the data presented is still investigational, though many trials are ongoing to translate these studies for clinical use.

OBJECTIVES:The National Accreditation Program for Rectal Cancer (NAPRC) was established in 2017 to decrease rectal cancer treatment variation and improve oncologic outcomes. Initiating curative intent treatment <60 days of first evaluation is one NAPRC standard. We evaluated whether oncologic outcomes improved with timely treatment and factors associated with its receipt. METHODS:Using the NCDB, we identified stage I to III rectal cancer patients treated from 2004 to 2020 treated with curative-intent surgery. Patients were stratified into 2 cohorts (timely [<60 d], delayed [≥60 d]) for survival analysis and exploration of variables associated with timely treatment. RESULTS:We included 117,459 patients with a median age of 61 years (interquartile range: 52 to 70 y). Most patients were male (61.1%), White (86.2%), Charlson 0 (77.1%) with stage II (33.5%) or III (44.3%) cancer treated with chemoradiation (58.1%), or surgery (27.0%) first. Timely treatment was associated with improved overall survival (OS; median OS: 153.26 vs. 128.59 m). Patients in the highest income bracket (odds ratio [OR] 1.30) with stage II (OR: 1.27) or III (OR: 1.50) cancer receiving neoadjuvant chemotherapy (OR: 2.24) or chemoradiation (OR: 1.73) as the first treatment received more timely treatment. Patients with Charlson ≥2 (OR: 0.83) of Black (OR: 0.56) or Hispanic (OR: 0.73) race received more delayed treatment (all P <0.01). CONCLUSIONS:Timely rectal cancer treatment is associated with improved survival. Socioeconomic disparities limit timely treatment with attendant worse survival, supporting national homogenization of care. As multimodal care for rectal cancer becomes increasingly complex, timely treatment remains paramount.

Background: Immune checkpoint inhibitors are a promising new therapy for advanced Merkel Cell Carcinoma (MCC). We investigated real-world utilization and survival outcomes of first-line immunotherapies in a contemporary cohort. Methods: Using the National Cancer Database (NCDB), we identified 759 patients with MCC between 2015 and 2020 with stage IV disease and known status of first-line systemic therapy. Univariable and multivariable analyses were used to determine predictors of immunotherapy usage. Overall survival (OS) was compared for patients receiving immunotherapy, chemotherapy, or no systemic therapies. Results: We identified 759 patients meeting our inclusion criteria: 329 patients received immunotherapy, 161 received chemotherapy, and 269 received no systemic therapy. Adjusting for demographic, clinical, and facility factors, high facility volume significantly predicted first-line immunotherapy use (OR 1.99; P=0.017). Median OS was 16.2, 12.3, and 8.7 months, among patients who received immunotherapy, chemotherapy, or no systemic therapy, respectively (P<0.001). On Cox multivariable survival analysis, first-line immunotherapy treatment (HR=0.79, P=0.041) and treatment at high-volume centers (HR=0.58, P=0.004) were associated with improved OS. Conclusions: Consistent with clinical trial results, first-line immunotherapy associated with improvement in median overall survival for patients with stage IV MCC, significantly outperforming chemotherapy in this real-world cohort. Treatment at high-volume centers associated with first-line immunotherapy utilization suggesting that familiarity with this rare disease is important to achieving optimal outcomes for metastatic MCC.

Objectives: Immune checkpoint inhibitors are a promising new therapy for advanced Merkel Cell Carcinoma (MCC). We investigated real-world utilization and survival outcomes of first-line immunotherapies in a contemporary cohort. Methods: Using the National Cancer Database (NCDB), we identified 759 patients with MCC between 2015 and 2020 with stage IV disease and known status of first-line systemic therapy. Univariable and multivariable analyses were used to determine predictors of immunotherapy usage. Overall survival (OS) was compared for patients receiving immunotherapy, chemotherapy, or no systemic therapies. Results: We identified 759 patients meeting our inclusion criteria: 329 patients received immunotherapy, 161 received chemotherapy, and 269 received no systemic therapy. Adjusting for demographic, clinical, and facility factors, high facility volume significantly predicted first-line immunotherapy use (OR 1.99; P=0.017). Median OS was 16.2, 12.3, and 8.7 months, among patients who received immunotherapy, chemotherapy, or no systemic therapy, respectively (P<0.001). On Cox multivariable survival analysis, first-line immunotherapy treatment (HR=0.79, P=0.041) and treatment at high-volume centers (HR=0.58, P=0.004) were associated with improved OS. Conclusions: Consistent with clinical trial results, first-line immunotherapy associated with improvement in median overall survival for patients with stage IV MCC, significantly outperforming chemotherapy in this real-world cohort. Treatment at high-volume centers associated with first-line immunotherapy utilization suggesting that familiarity with this rare disease is important to achieving optimal outcomes for metastatic MCC.

Cutaneous melanoma is becoming more prevalent in the United States and has the highest mortality among cutaneous malignancies. The majority of melanomas are diagnosed at an early stage and, as such, survival is generally favorable. However, there remains prognostic uncertainty among subsets of early- and intermediate-stage melanoma patients, some of whom go on to develop advanced disease while others remain disease-free. Melanoma gene expression profiling (GEP) has evolved with the notion to help bridge this gap and identify higher- or lower-risk patients to better tailor treatment and surveillance protocols. These tests seek to prognosticate melanomas independently of established AJCC 8 cancer staging and clinicopathologic features (sex, age, primary tumor location, thickness, ulceration, mitotic rate, lymphovascular invasion, microsatellites, and/or SLNB status). While there is a significant opportunity to improve the accuracy of melanoma prognostication and diagnosis, it is equally important to understand the current landscape of molecular profiling for melanoma treatment. Society guidelines currently do not recommend molecular testing outside of clinical trials for melanoma clinical decision making, citing insufficient high-quality evidence guiding indications for the testing and interpretation of results. The goal of this chapter is to review the available literature for GEP testing for melanoma diagnosis and prognostication and understand their place in current treatment paradigms.

Table S2 shows data concerning the association between baseline characteristics and presence of BRCA reversion mutations in pretreatment circulating cell-free DNA

A list of copy number alterations, rearrangements and short variants detected by Foundation Medicine NGS

Supplementary Tables, Figures and Video legends, Tables 2,3,5 and all Supplementary Figures. Supplementary Table 2. Confirmation of cis configuration of BRCA1 primary and secondary mutations in case 4 by colony PCR. Supplementary Table 3. IC50 (mircoM) values of the PARPi and platinum drugs in parental OVCAR8 cell line and OVCAR8 RAD51C KO clone, and the fold change in IC50 values. Supplementary Table 5. Sequences of primers used for site-directed mutagenesis. Supplementary Figure 1. Foundation Medicine NGS analysis of the 12 cases with archival tissue and/or pre-treatment and post-progression biopsies. Supplementary Figure 2. Sanger sequencing trace of the primary and secondary BRCA1 mutations in cis configuration in case 4 post-progression biopsy sample. Supplementary Figure 3. In vitro response to PARP inhibitor therapy and platinum agents in RAD51C deficient cell lines, with primary or secondary mutations in RAD51C. Supplementary Figure 4. RAD51 foci formation in geminin positive cells deficient for RAD51C, complemented with primary or secondary mutations in RAD51C. Supplementary Figure 5. Diagram of HR reporter assay. Supplementary Figure 6. RAD51C expression in MCF10A cells and in yeast. Supplementary Figure 7. Analysis of serial sections by direct PCR sequencing approach of a post-progression biopsy containing multiple secondary mutations in RAD51C. Supplementary Figure 8. Molecular Dynamics Modeling of WT RAD51D protein and RAD51D protein with secondary mutation c.770_776delinsA, p.S257_R259delinsK. Supplementary Figure 9. In vitro response to PARP inhibitor therapy and cisplatin in RAD51D deficient CHO cell line, with primary or secondary mutation in RAD51D. Supplementary Figure 10. Examination of the parental PEO4 cell line, PEO4 cells with the homozygous frameshift RAD51D mutation (c.762_763del, D254E*fs72) in the same exon as the primary mutation and PEO4 cells with the homozygous secondary RAD51D mutation (c.770_776delinsA, S257_R259delinsK). Supplementary Figure 11. Modeling of tumor clonal fractions in the post-progression biopsy sample with germline RAD51C mutation and multiple secondary mutations.

Molecular Dynamics Modeling of WT RAD51D monofilament interaction with dsDNA.

Background and Objectives Primary cutaneous leiomyosarcoma (cLMS), a rare, typically intradermal tumor, has previously been reported to exhibit an indolent course of disease with zero-to-low risk of local recurrence or distant metastasis. This study seeks to evaluate recurrence and survival of cLMS patients through study of its clinicopathologic and treatment characteristics. Methods All patients included underwent resection of primary cLMS at this institution between 2006 and 2019. A retrospective cohort study analysis of clinicopathologic characteristics, treatment, recurrence, and overall survival was performed. Data was assessed through descriptive statistics and outcome measures assessed by Cox proportional models and log-rank tests. Results Eighty-eight patients with cLMS were evaluated. The majority were men (n = 68, 77%) and Caucasian (n = 85, 97%), with median age at diagnosis of 66 years (range 20–96). 65% of tumors were located on the extremities, with a median size of 1.3 cm (range .3–15). Assessment revealed low (n = 41, 47%), intermediate (n = 29, 33%), and high (n = 18, 20%) grade tumors, demonstrating extension into subcutaneous tissue in 38/60 (60%), with 3 patients exhibiting extension into muscle (3%). All underwent resection as primary treatment with median 1 cm margins (range .5–2). With median follow-up of 27.5 months (IQR 8–51; range 1–131), no low-grade cases had recurrence or death while there was a recurrence rate of 19.1% (9/47) and death rate of 8.5% (4/47) in intermediate- to high-grade cases. Conclusions Primary tumor resection of cLMS provides excellent local control for low-grade tumors as no low-grade cases experienced recurrence. For patients with intermediate- to high-grade tumors, there is potential for local recurrence, distant metastasis, and death, and therefore surveillance following treatment is encouraged.

Supplementary Data from Relapsed Classic E-Cadherin (CDH1)–Mutated Invasive Lobular Breast Cancer Shows a High Frequency of HER2 (ERBB2) Gene Mutations

Figure S1 shows a consort diagram of patients with pretreatment and postprogression circulating cell-free DNA samples sequenced; Figure S2 shows a bar graph showing that a significantly lower level of the serum marker CA-125 was found at study enrollment in patients with no TP53 or BRCA mutations detected in the pretreatment circulating cell-free DNA; Figure S3 shows a scatter plot showing significant correlation between mutant allele frequency of primary somatic BRCA and TP53 mutations detected in pretreatment circulating cell-free DNA; Figure S4 shows a graph indicating the location of deleterious BRCA mutations where reversion mutations were detected in pretreatment and postprogression circulating cell-free DNA; Figure S5 shows a scatter plot showing a significant correlation of mutation allele frequency for the detected primary deleterious BRCA mutations between two independent next-generation sequencing-based circulating cell-free DNA assays; Figure S6 shows a swimlane graph showing the duration on rucaparib treatment of patients with or without BRCA reversion mutations detected in pretreatment circulating cell-free DNA; Figure S7 shows a graph from a linear regression analysis between the sum of mutation allele frequency of BRCA reversion mutations from pretreatment plasma and rucaparib progression-free survival; Figure S8 shows a bar graph of changes in BRCA reversion allele frequencies detected in pretreatment and postprogression circulating cell-free DNA from one patient.

PDF file - 187K, Supplementary Table 1: Detailed demographic information of all patients with metastatic breast cancer, including cohorts LM+ and EM+. Supplementary Table 2: ESR1 variant sequence data details. Abbreviations: cvg, coverage, N/A, non-applicable. Supplementary Table 3: List of genes sequenced by captured next generation sequencing. Supplementary figure 1: Genomic profiles of primary and metastatic tumors. Genomic alterations were found in 32 genes in primary and metastatic ER+ breast cancers. Genes are listed from the most frequently altered to least altered gene. Supplementary figure 2: No change in WT and mutant ER activity across a wide range of E2 doses. Luciferase activity in 293T cells after co-transfection of the ERE-TK-Luc reporter vector along with WT-ER, Y537N or D538G and E2 stimulation using doses of E2 ranging from 0.01nM to 100nM or vehicle treatment.

To the Editor: Merkel cell carcinoma (MCC) is a rare neuroendocrine skin tumor with a high risk of local and distant spread. Despite the increase in the use of sentinel lymph node biopsy as a result of recent National Comprehensive Cancer Network recommendations, there remains a paucity of data regarding outcomes in patients with clinically localized MCC with complete pathologic nodal microstaging.1 In MCC, disease relapse is a poor prognostic sign and efforts to prevent recurrences may result in improved survival.

Gene lists for Version 1 of the FoundationOne Assay (S1); Gene lists for Version 2 of the FoundationOne Assay (S2); Gene lists for Version 3 of the FoundationOne Assay (S3); Gene lists for Version 4 of the FoundationOne Assay (S4); Gene lists for Version 5 of the FoundationOne Assay (S5); Distribution of samples across different FoundationOne assays (S6); Filtered variants of unknown significance (S7).