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Akt Inhibition Is Associated With Favorable Immune Profile Changes Within the Tumor Microenvironment of Hormone Receptor Positive, HER2 Negative Breast Cancer

Marks, Douglas K; Gartrell, Robyn D; El Asmar, Margueritta; Boboila, Shuobo; Hart, Thomas; Lu, Yan; Pan, Qingfei; Yu, Jiyang; Hibshoosh, Hanina; Guo, Hua; Andreopoulou, Eleni; Wiechmann, Lisa; Crew, Katherine; Sparano, Joseph; Hershman, Dawn; Connolly, Eileen; Saenger, Yvonne; Kalinsky, Kevin
Background: The PI3K/Akt/mTOR pathway in part impacts tumorigenesis through modulation of host immune activity. To assess the effects of Akt inhibition on the tumor micro-environment (TME), we analyzed tumor tissue from patients with operable hormone receptor positive, HER2 negative breast cancer (BC) treated on a presurgical trial with the Akt inhibitor MK-2206. Methods: Quantitative multiplex immunofluorescence (qmIF) was performed using CD3, CD8, CD4, FOXP3, CD68, and pancytokeratin on biopsy and surgical specimens of MK-2206 and untreated, control patients. nanoString was performed on surgical specimens to assess mRNA expression from MK-2206-treated vs. control patients. Results: Increased CD3+CD8+ density was observed in post vs. pre-treatment tissue in the MK-2206-treated vs. control patients (87 vs. 0.2%, p < 0.05). MK-2206 was associated with greater expression of interferon signaling genes (e.g., IFI6, p < 0.05) and lower expression of myeloid genes (CD163, p < 0.05) on differential expression and gene set enrichment analyses. Greater expression of pro-apoptotic genes (e.g., BAD) were associated with MK-2206 treatment (p < 0.05). Conclusion: Akt inhibition in operable BC was associated with a favorable immune profile in the TME, including increased CD3+CD8+ density and greater expression of interferon genes. Additional studies are warranted, as this may provide rationale for combining Akt inhibition with immunotherapy.
PMCID:7308467
PMID: 32612958
ISSN: 2234-943x
CID: 4502772

Tumor Immune Microenvironment and Response to Neoadjuvant Chemotherapy in Hormone Receptor/HER2+ Early Stage Breast Cancer

Vanguri, Rami S; Fenn, Kathleen M; Kearney, Matthew R; Wang, Qi; Guo, Hua; Marks, Douglas K; Chin, Christine; Alcus, Claire F; Thompson, Julia B; Leu, Cheng-Shiun; Hibshoosh, Hanina; Kalinsky, Kevin M; Mathews, James C; Nadeem, Saad; Hollmann, Travis J; Connolly, Eileen P
BACKGROUND:Pathologic response at the time of surgery after neoadjuvant therapy for HER2 positive early breast cancer impacts both prognosis and subsequent adjuvant therapy. Comprehensive descriptions of the tumor microenvironment (TME) in patients with HER2 positive early breast cancer is not well described. We utilized standard stromal pathologist-assessed tumor infiltrating lymphocyte (TIL) quantification, quantitative multiplex immunofluorescence, and RNA-based gene pathway signatures to assess pretreatment TME characteristics associated pathologic complete response in patients with hormone receptor positive, HER2 positive early breast cancer treated in the neoadjuvant setting. METHODS:We utilized standard stromal pathologist-assessed TIL quantification, quantitative multiplex immunofluorescence, and RNA-based gene pathway signatures to assess pretreatment TME characteristics associated pathologic complete response in 28 patients with hormone receptor positive, HER2 positive early breast cancer treated in the neoadjuvant setting. RESULTS:Pathologist-assessed stromal TILs were significantly associated with pathologic complete response (pCR). By quantitative multiplex immunofluorescence, univariate analysis revealed significant increases in CD3+, CD3+CD8-FOXP3-, CD8+ and FOXP3+ T-cell densities as well as increased immune cell aggregates in pCR patients. In subsets of paired pre/post-treatment samples, we observed significant changes in gene expression signatures in non-pCR patients and significant decreases in CD8+ densities after treatment in pCR patients. No RNA based pathway signature was associated with pCR. CONCLUSION/CONCLUSIONS:TME characterization HER2 positive breast cancer patients revealed several stromal T-cell densities and immune cell aggregates associated with pCR. These results demonstrate the feasibility of these novel methods in TME evaluation and contribute to ongoing investigations of the TME in HER2+ early breast cancer to identify robust biomarkers to best identify patients eligible for systemic de-escalation strategies.
PMID: 35610143
ISSN: 1938-0666
CID: 5247952

Outcomes of Breast Cancer Patients Treated with Chemotherapy, Biologic Therapy, Endocrine Therapy, or Active Surveillance During the COVID-19 Pandemic

Marks, Douglas K; Budhathoki, Nibash; Kucharczyk, John; Fa'ak, Faisal; D'Abreo, Nina; Kwa, Maryann; Plasilova, Magdalena; Dhage, Shubhada; Soe, Phyu Phyu; Becker, Daniel; Hindenburg, Alexander; Lee, Johanna; Winner, Megan; Okpara, Chinyere; Daly, Alison; Shah, Darshi; Ramdhanny, Angela; Meyers, Marleen; Oratz, Ruth; Speyer, James; Novik, Yelena; Schnabel, Freya; Jones, Simon A; Adams, Sylvia
PURPOSE:Provide real-world data regarding the risk for SARS-CoV-2 infection and mortality in breast cancer (BC) patients on active cancer treatment. METHODS:Clinical data were abstracted from the 3778 BC patients seen at a multisite cancer center in New York between February 1, 2020 and May 1, 2020, including patient demographics, tumor histology, cancer treatment, and SARS-CoV-2 testing results. Incidence of SARS-CoV-2 infection by treatment type (chemotherapy [CT] vs endocrine and/or HER2 directed therapy [E/H]) was compared by Inverse Probability of Treatment Weighting. In those diagnosed with SARS-CoV-2 infection, Mann-Whitney test was used to a assess risk factors for severe disease and mortality. RESULTS:Three thousand sixty-two patients met study inclusion criteria with 641 patients tested for SARS-COV-2 by RT-PCR or serology. Overall, 64 patients (2.1%) were diagnosed with SARS-CoV-2 infection by either serology, RT-PCR, or documented clinical diagnosis. Comparing matched patients who received chemotherapy (n = 379) with those who received non-cytotoxic therapies (n = 2343) the incidence of SARS-CoV-2 did not differ between treatment groups (weighted risk; 3.5% CT vs 2.7% E/H, P = .523). Twenty-seven patients (0.9%) expired over follow-up, with 10 deaths attributed to SARS-CoV-2 infection. Chemotherapy was not associated with increased risk for death following SARS-CoV-2 infection (weighted risk; 0.7% CT vs 0.1% E/H, P = .246). Advanced disease (stage IV), age, BMI, and Charlson's Comorbidity Index score were associated with increased mortality following SARS-CoV-2 infection (P ≤ .05). CONCLUSION:BC treatment, including chemotherapy, can be safely administered in the context of enhanced infectious precautions, and should not be withheld particularly when given for curative intent.
PMID: 35641208
ISSN: 1549-490x
CID: 5235912

Quantitative Multiplex Immunofluorescence evaluation of the tumor microenvironment in pretreatment tumors of patients with metastatic breast cancer and serous ovarian carcinoma treated with liposomal eribulin

Marks, Douglas K; Kucharczyk, John; Kim, Pan; Chyong, Donian I; Gartrell, Robyn D; Lu, Yan; Hibshoosh, Hanina; Guo, Hua; Evans, Thomas R Jeffry; Lopez, Juanita; Kristeleit, Rebecca; Connolly, Eileen; Saenger, Yvonne; Kalinsky, Kevin
Eribulin inhibits microtubule polymerization and suppresses epithelial-mesenchymal transition. Conventional pathology approaches have not identified a precise predictive biomarker for Eribulin. We performed qmIF on pre-treatment tissue from 11 patients (6 TNBC, 5 HGSOC) treated with Eribulin-LF. T-lymphocytes were the dominant immune-subset in TME, with higher levels detected in stroma vs tumor (9% vs 2%). Greater density of CD3+ (p = 0.01) and CD3 + CD8+ (p = 0.03) cells and closer proximity between CD3 + CD8+ and tumor cells was observed in the patients with disease control (PR + SD) vs. progressive disease. QmIF identified an association between TIL infiltration and eribulin-LF sensitivity, which should evaluated further in prospective studies.
PMID: 34075851
ISSN: 1532-4192
CID: 4907312

Anal Cancer with Mediastinal Lymph Node Metastasis [Case Report]

Shenoy, Mangalore Amith; Winnicka, Lydia; Mirsadraei, Leili; Marks, Douglas
Squamous cell carcinoma of the anal canal remains rare, with metastatic disease even less commonly reported. We present a case of a patient with both a prior history of squamous cell carcinoma of the anal canal as well as breast cancer, who was without evidence of disease for 1 year. She was subsequently found to have FDG-avid mediastinal lymphadenopathy, initially assumed to be related to her more recent breast cancer. However, a biopsy confirmed recurrent anal cancer, with HPV infection. This represents a novel site of spread for anal cancer, one not yet reported in the literature.
PMCID:8280435
PMID: 34307312
ISSN: 2296-3774
CID: 4949022

Bone marrow necrosis and fat embolism syndrome: a near fatal complication in previously undiagnosed sickle beta + thalassaemia

Budhathoki, Nibash; Timilsina, Sunita; Ram, Bebu; Marks, Douglas
Prevalence of haemoglobin sickle-β+ thalassaemia (Hb S/β+thal) is variable with geography ranging from 0.2% to 10% among sickle cell patients. Clinical presentation of Hb S/β+thal patients depends on HbA level, with milder disease often going undiagnosed. However, rarely these patients can present with a fulminant vaso-occlusive crisis (VOC). Given VOC can present with non-specific symptoms, the diagnosis and treatment is often delayed. Here, we present a patient who initially developed altered mental status, pancytopenia and multiorgan failure due a critical VOC resulting in bone marrow necrosis and fat embolism. Subsequent workup confirmed that our patient had Sickle-β+ thalassaemia, which had gone undiagnosed, despite subclinical evidence of haemolysis on routine lab work for years. Following diagnosis and initiation of RBC exchange, he improved significantly and was discharged home. High index of suspicion and bone marrow biopsy is vital for early diagnosis and management of this rare condition.
PMCID:7789434
PMID: 33408108
ISSN: 1757-790x
CID: 4785272

Breast abscess as initial manifestation of extensive DCIS: a rare presentation and literature review

Ranjbar, Suedeh; Marks, Douglas K; Natoli, Noel B; Sarmiento, Ruth; Flieder, Andrea; Rossmer, Irene E
PMID: 32914488
ISSN: 1524-4741
CID: 4590242

Distinguishing melanophages from tumor in melanoma patients treated with talimogene laherparepvec

Audrey-Bayan, Claire; Trager, Megan H; Gartrell-Corrado, Robyn D; Rizk, Emanuelle M; Pradhan, Jaya; Silverman, Andrew M; Lopez, Adriana; Marks, Douglas K; Niedt, George; Geskin, Larisa J; Saenger, Yvonne M
Response to talimogene laherparepvec (T-Vec) is difficult to assess as pigmented macrophages that have ingested melanoma cells ('melanophages') persist after injection, mimicking melanoma. We used quantitative immunofluorescence (qIF) to (1) distinguish melanophages from melanoma in biopsies from two patients treated with T-Vec and (2) evaluate the tumor microenvironment pretreatment and posttreatment. Tissues were stained with 4',6-diamidino-2-phenylindole, cluster of differentiation (CD) 3, CD8, CD68, human leukocyte antigen-DR isotype (HLA-DR), and SRY-Box Transcription Factor 10 (SOX10), and multispectral images were analyzed. Post-T-Vec samples showed melanophages with cytoplasmic costaining of CD68, SOX10, and HLA-DR, without nuclear SOX10 expression. qIF revealed a dense immune infiltrate of CD3, CD8, and CD68 cells in post-T-Vec samples. Melanophages from tumors post-T-Vec stain the nuclear melanoma marker SOX10 in their cytoplasms as compared to melanoma cells that stain nuclear SOX10. This novel finding highlights the phagocytosis of melanoma cell components by macrophages after treatment with T-Vec. qIF may assist pathologists in determining whether lesions treated with immunotherapy contain residual viable melanoma.
PMID: 32379409
ISSN: 1473-5636
CID: 4428862

Linking transcriptomic and imaging data defines features of a favorable tumor immune microenvironment and identifies a combination biomarker for primary melanoma

Gartrell-Corrado, Robyn D; Chen, Andrew X; Rizk, Emanuelle M; Marks, Douglas K; Bogardus, Margaret H; Hart, Thomas D; Silverman, Andrew M; Bayan, Claire-Audrey Y; Finkel, Grace G; Barker, Luke W; Komatsubara, Kimberly M; Carvajal, Richard D; Horst, Basil A; Chang, Rui; Monod, Anthea; Rabadan, Raul; Saenger, Yvonne M
Patients with resected stage II-III melanoma have approximately a 35% chance of death from their disease. A deeper understanding of the tumor immune microenvironment (TIME) is required to stratify patients and identify factors leading to therapy resistance. We previously identified that the melanoma immune profile (MIP), an interferon-based gene signature, and the ratio of CD8+ cytotoxic T lymphocytes (CTLs) to CD68+ macrophages both predict disease-specific survival (DSS). Here, we compared primary to metastatic tumors and found that the nuclei of tumor cells were significantly larger in metastases. The CTL/macrophage ratio was significantly different between primary tumors without distant metastatic recurrence (DMR) and metastases. Patients without DMR had higher degrees of clustering between tumor cells and CTLs, and between tumor cells and HLA-DR+ macrophages, but not HLA-DR- macrophages. The HLA-DR- subset co-expressed CD163+CSF1R+ at higher levels than CD68+HLA-DR+ macrophages, consistent with an M2 phenotype. Finally, combined transcriptomic and multiplex data revealed that densities of CD8 and M1 macrophages correlated with their respective cell phenotype signatures. Combination of the MIP signature with the CTL/macrophage ratio stratified patients into three risk groups that were predictive of DSS, highlighting the potential use of combination biomarkers for adjuvant therapy.
PMID: 31948941
ISSN: 1538-7445
CID: 4264572

Distinguishing melanophages from tumor in melanoma patients treated with talimogene laherparepvec (T-VEC) [Meeting Abstract]

Trager, M H; Audrey-Bayan, C; Gartrell-Corrado, R; Rizk, E; Pradhan, J; Silverman, A M; Hart, T D; Lopez, A T; Marks, D K; Niedt, G; Geskin, L; Saenger, Y M
Talimogene laherparepvec (T-VEC) is the first FDA-approved oncolytic virus for the treatment of advanced melanoma. T-VEC is injected into melanoma lesions, but response may be difficult to assess because pigmented macrophages that have ingested melanoma cells (termed "melanophages") persist after immunotherapy at injected sites mimicking melanoma. Thus, novel methods are critically needed to clearly identify the nature of the cells found in tissue specimens from patients treated with T-VEC. We evaluated skin biopsy specimens which were obtained pre-and post-T-VEC therapy of the melanoma patients (stages III-IV) at Columbia University. We used quantitative immunofluorescence (qIF) to: 1) Distinguish melanophages from melanoma in biopsies from patients treated with T-VEC; 2) Evaluate tumor immune micro-environment pre-and post-T-VEC. Tissue specimens were stained with the antibody panel: DAPI, CD3, CD8, CD68, HLA-DR, and Sox10. Multispectral images were acquired and analyzed using machine learning. Using multiplex staining, post T-VEC samples showed only a few residual melanoma cells within the skin biopsies confirmed by nuclear Sox10+ expression, and many melanophages with cytoplasmic co-staining of CD68, Sox10, and HLA-DR, with no nuclear expression of Sox10. This is a novel finding and highlights the phagocytosis of melanoma cells by macrophages following immunotherapy. QIF also revealed a dense immune infiltrate of CD3+ CD8+ and CD68+ cells in post T-VEC samples. QIF methods may assist pathologists in determining whether lesions from patients treated with immunotherapy contain residual viable melanoma. It also maybe helpful to assess immune response to the therapy
EMBASE:631885312
ISSN: 1755-148x
CID: 4472782