tbuckley/cabot-search huggingface dataset:
Predominance of the luminal B molecular subtype in a group of women with infiltrating breast ductal carcinoma in the Colombian coffee region: Analysis by immunohistochemistry.
Authors: Paula Toro, Juliana Pava-De Los Rios, Alex Enrique Pava-Ripoll, Sebastian Chica, Edgar Perez, Manuel Villegas, Juan Paulo Preciado, Camilo Celis, Andrés Felipe Mejía
Journal: Journal of Clinical Oncology (2021)

e12571 Background: Breast cancer is the most common cancer in women and constitutes a public health problem due to its high rates of morbidity and mortality. Diagnosis is made through routine histopathology studies that are complemented by phenotypic expression studies of hormone receptors (estrogen and progesterone receptors), human epidermal growth factor 2 (HER2) and cell proliferation index (Ki67) for their subtyping into molecular groups (luminal A, luminal B, Her2, and triple negative), which have different prognostic and therapeutic implications. Globally, a high prevalence of the Luminal A subtype has been reported, predominantly in North America, Europe, and some Latin American countries; however, the reports in the Colombian population are heterogeneous. The objective of this research is to establish an incidence profile of these molecular subtypes in a population of the coffee region in Colombia. Methods: Samples of 377 patients with a diagnosis of infiltrating breast cancer were collected retrospectively between 2015 and 2018. Inclusion criteria included: 1) Availability of personal data (year of diagnosis and age) 2) Infiltrating breast carcinoma. 3) Diagnosis between 2015 and 2018. 4) Study of complete immunohistochemistry and/or in situ hybridization (ISH) markers. Results: The histological subtypes included: NOS infiltrating ductal carcinomas (339 cases; 89.9 %), infiltrating lobular (23 cases; 6.1 %), infiltrating mucinous (6 cases; 1.5 %), infiltrating papillary (1 case; 0.2 %) and mixed patterns: ductal - lobular (3 cases; 0.7 %) and mucinous - ductal (5 cases; 1.3 %), of whom 56.2% (212 cases) correspond to luminal B, 22.2% (84 cases) to Luminal A, 14.8% (56 cases) to triple negative and 6.6% (25 cases) to HER2. Conclusions: These findings contrast with the prevalence reported worldwide. Therefore, in the population of the Colombian coffee region, this predominance of the molecular subtype luminal B should be considered when establishing prognosis and treatment plan by the medical staff.
Breast cancer surgical delays in a racially and ethnically diverse California cancer registry cohort.
Authors: Stephanie Navarro, Yifei Yang, Carol Ochoa, Sue Kim, Lihua Liu, Caryn Lerman, Albert Farias
Journal: Journal of Clinical Oncology (2021)

e12589 Background: Surgical delays for invasive breast cancer have been increasing over time and are associated with an increased risk of mortality. Black and Hispanic breast cancer patients are more likely to experience surgical delays than white patients; however, surgical delays among Asian ethnic subgroups remain unstudied. Methods: We used data from the population-based California Cancer Registry to identify all females diagnosed with stage I-III invasive breast cancer from 2012-2017. Our main independent variable was patient race/ethnicity, including five Asian ethnic subgroups. Covariates captured tumor, treatment-related, and patient sociodemographic characteristics. We conducted multivariable logistic regression to determine the odds of receiving surgery within 30 and 90 days of diagnosis and multivariable Cox proportional hazards regression to determine the risk of shorter time to surgical treatment. Results: Of 106,441 breast cancer patients, 57.5% were non-Hispanic white (NHW), 20.7% were Hispanic, 5.9% were non-Hispanic black (NHB), and 12.6% were Asian (consisting of 33.7% Filipino, 24.6% Chinese, 8.1% Asian Indian or Pakistani (AIP), 7.7% Japanese, 6.7% Korean, and 19.2% other Asian (OA) patients). Compared to NHWs, Hispanics and NHBs were less likely to receive surgical treatment within 30 and 90 days of diagnosis (Hispanic, 30-day: OR = 0.94, 95% CI = 0.89-0.98; Hispanic, 90-day: 0.89, 0.85-0.92; NHB, 30-day: 0.91, 0.85-0.98; NHB, 90-day: 0.86, 0.80-0.92). However, Chinese and AIP patients were more likely than NHWs to receive surgery within 30 and 90 days of diagnosis (Chinese, 30 day: OR = 1.30, 95% CI = 1.19-1.41; Chinese 90-day: 1.26, 1.08-1.47; AIP 30-day: 1.29, 1.11-1.50; AIP 90-day: 1.34, 1.17-1.53). In addition, Koreans were more likely than NHWs to receive surgery within 90 days of diagnosis (OR = 1.26, 95% CI = 1.08-1.47). Hispanics, NHBs, and OAs were less likely to receive timely treatment compared to NHWs (Hispanic: HR = 0.95, 95% CI = 0.94-0.97; NHB: 0.91, 0.89-0.94; OA: 0.95, 0.92-0.99), while Chinese, AIP, and Korean patients were more likely to receive timely treatment compared to NHWs (Chinese: HR = 1.15, 95% CI = 1.11-1.20; AIP: 1.10, 1.04-1.17; Korean: 1.10, 1.03-1.17). Lastly, patients diagnosed in 2017 were 14% less likely to receive timely treatment than those diagnosed in 2012 (HR: 0.86, 95% CI = 0.84-0.88). Conclusions: In this population-based cohort of female breast cancer patients in California, Hispanics and NHBs continue to experience surgical treatment delays and Asian American minority subgroups experience similar delays compared to NHWs. In addition, increasing delays over time could potentially exacerbate racial/ethnic disparities in breast cancer mortality. Continued work investigating the causes of breast cancer treatment delays among Asian ethnic subgroups is necessary to fully elucidate and target racial/ethnic treatment disparities.
Germline alterations among Hispanic men with prostate cancer.
Authors: Justin Shaya, Sarah M. Nielsen, Kathryn E. Hatchell, Edward D. Esplin, Robert Luke Nussbaum, Nicole Weise, Lisa Madlensky, James Don Murphy, Elena Martinez, Rana R. McKay
Journal: Journal of Clinical Oncology (2021)

10534 Background: With the growing indications for germline testing in prostate cancer (PCa), there is accumulating evidence that African American and Hispanic men with PCa are significantly under-tested compared to non-Hispanic white (NHW) men. Given this, little is known about the pathogenic germline variant landscape in Hispanic men with PCa. Methods: This was a retrospective cohort analysis of 17,256 men with PCa who underwent diagnostic germline testing through a commercial laboratory (Invitae) from 2015-2020. Self-identified Hispanic and NHW men were selected for comparative analysis. The primary endpoint was the rate of pathogenic/likely pathogenic (PLP) germline alterations in Hispanic men among 25 genes associated with PCa. Secondary endpoints included comparison of PLP rates in Hispanic vs NHW men, the rate of specific PLP alterations, and the rate of variants of uncertain significance (VUS). Fisher’s exact test was used to compare germline alteration rates for significance. Results: We identified 508 Hispanic and 12,542 NHW men with PCa who underwent testing during the study period. Median age at the time of testing was 69 vs 67 years in Hispanic vs NHW cohorts. A family history of PCa was reported in 21.1% (N=108) vs 27.3% (N=3428) in the Hispanic vs NHW cohorts, respectively (p=0.002). The PLP alteration rate was 7.1% in the Hispanic cohort and this rate was numerically lower but not significantly different when compared to the NHW cohort (9.7%) (p=0.058). A significantly higher rate of VUS was seen in the Hispanic cohort (Table). The four most frequently detected genes with PLP alterations in both cohorts were ATM, BRCA1, BRCA2, and CHEK2. Only the rate of CHEK2 alterations was significantly different between cohorts among all 25 genes analyzed (Table). Conclusions: In this analysis, the PLP alteration rate among Hispanic men was 7.1%, a much higher rate than has been previously reported, and the germline genomic landscape was similar to that of NHW men. The VUS rate was significantly higher among Hispanic men, a known consequence of under-testing among minority populations.These data support germline testing in Hispanic men with prostate cancer and emphasize the importance of improving testing rates.[Table: see text]
Societal Involvement in Prenatal Diagnosis—Reply
Authors: Roberta Springer Loewy
Journal: JAMA (2002)

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Does concurrent COX inhibition and immune checkpoint blockade improve clinical outcome in patients with metastatic renal cell carcinoma?
Authors: Yumeng Zhang, Jacob J. Adashek, Premsai Kumar, William Paul Skelton, Jiannong Li, Jad Chahoud, Brandon J Manley, Philippe E. Spiess
Journal: Journal of Clinical Oncology (2021)

e16558 Background: Cyclooxygenase (COX) inhibition is postulated to restore the immune environment and synergizes with immune checkpoint inhibitors (ICI). The concurrent use of COX inhibitors (COXi) and ICI was associated with longer disease control in metastatic melanoma and non-small cell lung cancer. However, its role in mRCC remains unclear. Methods: We retrospectively reviewed 194 patients with mRCC treated with ICI (PD-(L)1 inhibitors +/- CTLA-4 inhibitors or TKIs) at Moffitt Cancer Center between 6/2014-7/2019. Concurrent use of COXi (aspirin [ASA] or NSAIDs) was defined as at least 3 weeks of COXi use during the first ICI course. Clinical characteristics of both arms were compared using Chi-squared or Kruskal-Wallis Rank Sum test. Time to progression (TTP) and Overall survival (OS) were compared using Kaplan Meier’s estimates. Univariate and multivariate Cox proportional hazards model was performed to evaluate the association between clinical factors, TTP, and OS. Results: Of 194 patients, 126 patients (64.9%) took COXi. Median age was 59.7 years and 80.4% were male. COXi arm had fewer patients with &lt; 1 year from diagnosis to systemic treatment (45.9% vs 69.5%, p = 0.006) and more advanced age (median: 66 years vs 60 years, p = 0.01). IDMC risk group, number of prior therapies, neutrophil to lymphocytes ratio were similar between both arms. Median TTP was 8 months (m) for COXi arm and 12m for ICI only (HR 1.38; 95% CI [0.98, 1.94]). Median OS was 27m for COXi arm and 33m for ICI only (HR 1.05, 95% CI [0.69, 1.59]). Early mortality rate (within 3m of ICI treatments) were similar between both arms. Conclusions: In contrast to melanoma and lung cancer, concurrent use of COXi and ICI did not improve TTP and OS in patients with mRCC. The dual blockade showed a trend for shorter TTP. Further validation studies with larger cohorts are needed to confirm this finding.[Table: see text]
ALDH1 expression in primary and recurrent vulvar carcinoma.
Authors: Nina M. Abdullaeva, Ekaterina V. Verenikina, Elena Yu. Zlatnik, Elena P. Ulianova, Inna A. Novikova, Aleksandr B. Sagakyants, Anna P. Menshenina, Meri L. Adamyan
Journal: Journal of Clinical Oncology (2021)

e17573 Background: Our aim was to evaluate ALDH1 expression as a stem cell marker in primary and recurrence vulvar squamous cell carcinoma. Methods: 27 patients aged 27-80 years with vulvar squamous cell carcinomas, together with their verified histopathological and clinical data were included in the study. All of them underwent treatment the first stage of which was surgery in National Research Centre for Oncology in 2015-2020. In 10 of them I stage of vulvar squamous cell carcinomas was diagnosed, in 13 – II stage, 4 had relapses after complex treatment and 2-10 years` remission. All paraffin-embedded samples of the primary and recurrent vulvar carcinoma were recruited. The presence of ALDH1 was detected by immunohistochemistry using murine monoclonal antibodies to ALDH1 (clone B-5 Santa Cruz Biotechnology) diluted 1:800 and Reveal Polyvalent HRP-DB Detection System. Positively stained cells were counted among all the tumor cells as well as a part of tumors positive for ALDH1 ( &gt; 10% of cells). Statistics analysis was performed by program STATISTICA 13.0 (StatSoftInc., the USА). Results: By immunohistochemical staining, the expression of ALDH1 was observed in 5 patients with I stage of vulvar squamous cell carcinomas, in 5 patients with II stage and in all the patients with recurrence. Mean values of ALDH1 expression in patients with I stage were 14.1±4.3%, in patients with II stage – 16.0±3.6%, in patients with recurrence – 29.6±3.6%. Maximal ALDH1 accumulation was observed in tumor cells of patients with recurrence, it was 1.9 times higher than in the II stage (p = 0.03) and 2.1 times exceeded ones of the I stage (p = 0.027). All the differences were statistically significant according to Student`s t-test (p &lt; 0.05). The was no statistically significant difference between values of the patients with I and II stages (p = 0.738), but it is noteworthy that ALDH1-expressing cells prevailed in tumor stroma especially in II stage. Conclusions: There is some discrepancy in the assessment of ALDH1 prognostic value in vulvar carcinoma patients as well as in understanding if it is related predominantly to cancer stem cells or to normal stem cells either. Our results though obtained on a few cases of vulvar squamous cell carcinomas show that ALDH1 expression in recurrent carcinomas markedly exceeds that in primary tumors and is related to tumor cells while in primary tumors is related rather to stromal cells.
Noninvasive identification of emergent mutations following cytotoxic therapy for lung cancer.
Authors: Everett James Moding, Angela B. Hui, Yonina R. Murciano-Goroff, Barzin Nabet, Andre Schultz, Yawei Qiao, Bob T. Li, Steven H. Lin, Ash A. Alizadeh, Maximilian Diehn
Journal: Journal of Clinical Oncology (2021)

8533 Background: Lung cancer is the leading cause of cancer death world-wide, and chemotherapy and radiation remain backbones of therapy for patients with locoregionally advanced and metastatic disease. However, the genetic mechanisms that mediate resistance to chemotherapy and radiation are largely unclear due to a lack of available tissue at the time of relapse. We hypothesized that circulating tumor DNA (ctDNA) analysis could identify emergent mutations after chemotherapy and radiation that may lead to treatment resistance. Methods: To identify emergent mutations at the time of progression following an initial response to chemotherapy and/or radiation therapy for lung cancer, we utilized CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) to analyze plasma samples and matched leukocytes collected pre-treatment and at the time of relapse. We analyzed a targeted panel enriched for lung cancer drivers and recurrently mutated genes for 27 patients treated with chemoradiation therapy for locoregionally advanced lung cancer. In addition, we performed ultra-deep whole exome sequencing ( &gt; 2000X deduped depth) of pre-treatment and relapse cell-free DNA for 5 patients treated with combination chemotherapy for metastatic lung cancer. Functional enrichment analysis was performed on emergent mutation gene lists to identify significantly enriched pathways. Results: We identified emergent variants in 6 out of 27 patients using targeted sequencing after chemoradiation therapy. Emergent mutations after chemoradiation were enriched for plasma membrane adhesion molecules such as PCDH17, PCDH10, and FAT3 (adjusted P = 0.03). Using ultra-deep whole exome sequencing, we observed emergent mutations in 3 out of 5 patients treated with combination chemotherapy. After combination chemotherapy, there was a trend towards enrichment in mutations in ATP-binding cassette transporters, including ABCA13 and ABCB4 (adjusted P = 0.057). Notably, there were no recurrent emergent mutations within our cohort. Conclusions: Our results suggest that ultra-deep whole exome sequencing can non-invasively identify emergent mutations at the time of progression. Resistance to cytotoxic therapy is likely multi-factorial and analysis in expanded cohorts will be helpful to identify recurrently mutated pathways that may contribute to disease progression after an initial response to therapy.
Identification of TGFBR2 mutation as a negative predictor of immunotherapy in NSCLC.
Authors: Teng Li, Han Wang, Jiachen Xu, Chengcheng Li, Yudong Zhang, Guoqiang Wang, Shangli Cai, Li Junling, Zhijie Wang
Journal: Journal of Clinical Oncology (2021)

e21002 Abstract Background: Immune adaptive resistance is one of the reasons contributing to the resistance of immune checkpoint inhibitors (ICIs). Previous studies have demonstrated the role of TGFβ-SMAD signaling in the dysfunction of immune response. We hypothesized that transforming growth factor beta receptor 2 (TGFBR2) mutation in non-small cell lung cancer (NSCLC) might be a predictor of immunotherapeutic resistance. Methods: Genomic and transcriptomic data of NSCLC patients from The Cancer Genome Atlas (TCGA) were analyzed by the in silico Pathway Activation Network Decomposition Analysis (iPNADA) to study the association between TGFBR2 mutation and intracellular signaling pathway activation. Clinical and genomic data from public cohorts with patients treated with ICIs including POPLAR/OAK, MSKCC and Van Allen cohorts were obtained and analyzed. An independent China cohort was used to demonstrate the association between TGFBR2 mutation and immunotherapeutic efficacy and we further demonstrated a case with mutated TGFBR2 treated with ICI. Results: TGF-β signaling was decreased and JAK-STAT signaling was increased in patients with mutated TGFBR2 (P &lt; 0.05). The immune checkpoints including CD274, LAG3, TIGHT, CTLA-4, PDCD1 and PDCD1LG2 were significantly increased in patients with mutated TGFRB2 (P &lt; 0.05). The immune dysfunction score tended to be increased in patients with mutated TGFBR2 though no significant difference was observed (P = 0.23). In the POPLAR/OAK cohort, patients with mutated TGFBR2 had shorter progression-free survival (P = 0.004; HR, 2.83; 95% CI, 1.34-6.00) and overall survival (OS) (P = 0.0006; HR, 3.46; 95% CI, 1.63-7.35) than patients with wild-type TGFBR2 when treated with ICIs. While in patients treated with chemotherapy, there was no difference in PFS (P = 0.69; HR, 0.86; 95% CI, 0.41-1.82) and OS (P = 0.61; HR, 1.21; 95% CI, 0.57-2.57) between patients with mutated and wild-type TGFBR2. In the merged MSKCC and Van Allen cohorts, similar result was observed that the OS was shorter in patients with mutated TGFBR2 (P = 0.007; HR, 2.53; 95% CI, 1.25-5.12). At last, we demonstrated a 39-year-old case with TGFBR2 mutation who was treated with 3 mg/kg nivolumab as second-line treatment. The patient progressed after three cycles of nivolumab and the PFS was only 1.3 months. Conclusions: We identified TGFBR2 mutation as a negative predictor for ICIs in NSCLC and the clinical use of ICIs needs to be cautious in those patients, highlighting the importance of genomic profiling in the treatment of ICIs. Combination ICIs and TGF-β signaling inhibitors may overcome the resistance for those patients harboring TGFBR2 mutation and need to be developed in the future.
Correlation of microsatellite-instable (MSI) status and genomic characteristics in 12,000 Chinese lung cancer patients.
Authors: Liufu Su, Xinyi Liu, Xiaochun Huang, Mengli Huang
Journal: Journal of Clinical Oncology (2021)

e21019 Background: Microsatellite-instable-high (MSI-H) is a strong biomarker for favorable response to immune checkpoint blockade (ICI) therapies. The objective response rate was 30%̃40% in advanced MSI-H solid tumors receiving ICI treatment, while MSI status is rarely considered in lung cancer in setting of ICI treatment. MSI-H occurred in 0.8%̃2% lung cancer patients tested by PCR method. Immune microenvironment of MSI-H lung cancer had not been studied on a large scale. We explored the association of MSI status, genetic profile and PD-L1 expression in a large Chinese lung cancer cohort to elucidate the molecular characteristics of MSI-H lung cancer. Methods: MSI status was determined by PCR test in tumor tissue and by an in-house algorithm in blood specimen. The tumor samples were sequenced by next-generation sequencing to call single nucleotide variants (SNVs) and copy number variants (CNVs). PD-L1 expression was evaluated by TPS. Results: 67 pts were determined as MSI-H in total of 12,485 pts, namely the frequency of MSI-H was 0.5% in Chinses lung cancer. 26 MSI-H pts were harboring EGFR mutations, including Ex19del in 10 pts, L858R in 6 pts, T790M in 5 pts, EGFR gain in 4 pts, and other uncommon mutations such as C797, L861Q. Interestingly, no EGFR Ex20ins was detected. In the other 41 non-EGFR-mutant pts, RET fusion were detected in 2 pts, FGFR2/3 SNV were detected in 5 pts, KRAS activating SNVs were detected in 5 pts, and PIK3CA SNV/amplification were detected in 8 pts. No ICI response negative alterations (CDKN2A/B loss, MDM2/4 gain) were detected in MSI-H patients. 125 genes, including MSH6, MLH1, BRCA2, NOTCH1, TGFBR2, ACVR2A and etc, had higher frequency in MSI-H lung cancers than MSS lung cancers in our cohort. Moreover, only MAP3K1 gene SNV occurred more frequently in MSS lung cancers (4.5% vs 7.7%, p &lt; 0.001). MSI-H lung cancer had a trend for enrichment of PD-L1 positivity (TPS &gt; 1%) but no significance (58% vs 43%, p = 0.205). Conclusions: About 50% MSI-H lung cancers harbored actionable mutations for targeted agents (EGFR TKIs or other TKIs), while EGFR Ex20ins might exist mutually exclusively with MSI-H. MSI-H lung cancer had much more mutational genes than MSS lung cancer, which was consistent with previous studies. On the other hand, MAP3K1 was the only gene with lower mutational frequency in MSI-H lung cancer. Our results revealed the genetic mutational characteristics of MSI-H lung cancer and provided suggestions for treatment decisions of this patient population.