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Macrophage density is an adverse prognosticator for ipsilateral recurrence in ductal carcinoma in situ

Darvishian, Farbod; Wu, Yinxiang; Ozerdem, Ugur; Chun, Jennifer; Adams, Sylvia; Guth, Amber; Axelrod, Deborah; Shapiro, Richard; Troxel, Andrea B; Schnabel, Freya; Roses, Daniel
INTRODUCTION/BACKGROUND:There is evidence that supports the association of dense tumor infiltrating lymphocyte (TILs) with an increased risk of ipsilateral recurrence in ductal carcinoma in situ (DCIS). However, the association of cellular composition of DCIS immune microenvironment with the histopathologic parameters and outcome is not well understood. METHODS:We queried our institutional database for patients with pure DCIS diagnosed between 2010 and 2019. Immunohistochemical studies for CD8, CD4, CD68, CD163, and FOXP3 were performed and evaluated in the DCIS microenvironment using tissue microarrays. Statistical methods included Fisher's exact test for categorical variables and the two-sample t-test or the Wilcoxon Rank-Sum test for continuous variables. RESULTS:The analytic sample included 67 patients. Median age was 62 years (range = 53 to 66) and median follow up was 6.7 years (range = 5.3 to 7.8). Thirteen patients had ipsilateral recurrence. Of all the clinicopathologic variables, only the DCIS size and TIL density were significantly associated with recurrence (p = 0.023 and 0.006, respectively). After adjusting for age and TIL density, only high CD68 (>50) and high CD68/CD163 ratio (>0.46) correlated with ipsilateral recurrence (p = 0.026 and 0.013, respectively) and shorter time to recurrence [hazard ratio 4.87 (95% CI: 1.24-19, p = 0.023) and 10.32 (95% CI: 1.34-80, p = 0.025), respectively]. CONCLUSIONS:macrophage density and CD68/CD163 ratio also predict a shorter time to recurrence.
PMCID:9062471
PMID: 35489232
ISSN: 1532-3080
CID: 5217782

Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer

Chang, Chewei Anderson; Jen, Jayu; Jiang, Shaowen; Sayad, Azin; Mer, Arvind Singh; Brown, Kevin R; Nixon, Allison M L; Dhabaria, Avantika; Tang, Kwan Ho; Venet, David; Sotiriou, Christos; Deng, Jiehui; Wong, Kwok-Kin; Adams, Sylvia; Meyn, Peter; Heguy, Adriana; Skok, Jane A; Tsirigos, Aristotelis; Ueberheide, Beatrix; Moffat, Jason; Singh, Abhyudai; Haibe-Kains, Benjamin; Khodadadi-Jamayran, Alireza; Neel, Benjamin G
Resistance to targeted therapies is an important clinical problem in HER2-positive (HER2+) breast cancer. "Drug-tolerant persisters" (DTPs), a sub-population of cancer cells that survive via reversible, non-genetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKIs) in other malignancies, but DTPs following HER2 TKI exposure have not been well characterized. We found that HER2 TKIs evoke DTPs with a luminal-like or a mesenchymal-like transcriptome. Lentiviral barcoding/single cell RNA-sequencing reveal that HER2+ breast cancer cells cycle stochastically through a "pre-DTP" state, characterized by a G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting show that pre-DTPs preferentially yield DTPs upon HER2 TKI exposure. Cells with similar transcriptomes are present in HER2+ breast tumors and are associated with poor TKI response. Finally, biochemical experiments indicate that luminal-like DTPs survive via estrogen receptor-dependent induction of SGK3, leading to rewiring of the PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation.
PMID: 34911733
ISSN: 2159-8290
CID: 5085072

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

A Multicenter Phase II Trial of Ipilimumab and Nivolumab in Unresectable or Metastatic Metaplastic Breast Cancer: Cohort 36 of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART, SWOG S1609)

Adams, Sylvia; Othus, Megan; Patel, Sandip Pravin; Miller, Kathy D; Chugh, Rashmi; Schuetze, Scott M; Chamberlin, Mary D; Haley, Barbara J; Storniolo, Anna Maria V; Reddy, Mridula P; Anderson, Scott A; Zimmerman, Collin T; O'Dea, Anne P; Mirshahidi, Hamid R; Rodon Ahnert, Jordi; Brescia, Frank J; Hahn, Olwen; Raymond, Jane M; Biggs, David D; Connolly, Roisin M; Sharon, Elad; Korde, Larissa A; Gray, Robert J; Mayerson, Edward; Plets, Melissa; Blanke, Charles D; Chae, Young Kwang; Kurzrock, Razelle
PURPOSE/OBJECTIVE:Metaplastic breast cancer (MpBC) is a rare aggressive subtype that responds poorly to cytotoxics. Median survival is approximately eight months for metastatic disease. We report results for advanced MpBC treated with ipilimumab+nivolumab, a cohort of S1609 for rare cancers (DART: NCT02834013). METHODS:Prospective, open-label, multicenter phase II (two-stage) trial of ipilimumab (1mg/kg IV q6weeks) plus nivolumab (240mg IV q2weeks) for advanced MpBC. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS:Overall, 17 evaluable patients enrolled. Median age was 60 years (26-85); median number of prior therapy lines, 2 (0-5). ORR was 18%; 3/17 patients achieved objective responses (1 complete, 2 partial responses) (2 spindle cell, 1 chondromyxoid histology), which are ongoing at 28+, 33+ and 34+ months, respectively. Median PFS and OS were 2 and 12 months, respectively. Altogether, 11 patients (65%) experienced adverse events (AEs), including one grade 5 AE. Eight patients (47%) developed an immune-related AE (irAE); with adrenal insufficiency observed in all three responders. Responses occurred in tumors with low tumor mutational burden, low PD-L1 and absent TILs. CONCLUSION/CONCLUSIONS:The ipilimumab and nivolumab combination showed no new safety signals and met its primary endpoint with 18% ORR in advanced, chemotherapy-refractory MpBC. All responses are ongoing at >2 to almost 3 years later. The effect of ipilimumab and nivolumab was associated with exceptional responses in a subset of patients versus no activity. This combination warrants further investigation in MpBC, with special attention to understanding mechanism of action, and carefully designed to weigh against the significant risks of irAEs.
PMID: 34716198
ISSN: 1557-3265
CID: 5042922

Tumor infiltrating lymphocyte stratification of prognostic staging of early-stage triple negative breast cancer

Loi, Sherene; Salgado, Roberto; Adams, Sylvia; Pruneri, Giancarlo; Francis, Prudence A; Lacroix-Triki, Magali; Joensuu, Heikki; Dieci, Maria Vittoria; Badve, Sunil; Demaria, Sandra; Gray, Robert; Munzone, Elisabetta; Drubay, Damien; Lemonnier, Jerome; Sotiriou, Christos; Kellokumpu-Lehtinen, Pirkko Liisa; Vingiani, Andrea; Gray, Kathryn; André, Fabrice; Denkert, Carsten; Piccart, Martine; Roblin, Elvire; Michiels, Stefan
The importance of integrating biomarkers into the TNM staging has been emphasized in the 8th Edition of the American Joint Committee on Cancer (AJCC) Staging system. In a pooled analysis of 2148 TNBC-patients in the adjuvant setting, TILs are found to strongly up and downstage traditional pathological-staging in the Pathological and Clinical Prognostic Stage Groups from the AJJC 8th edition Cancer Staging System. This suggest that clinical and research studies on TNBC should take TILs into account in addition to stage, as for example patients with stage II TNBC and high TILs have a better outcome than patients with stage I and low TILs.
PMID: 35017545
ISSN: 2374-4677
CID: 5118652

RE: Adjuvant Aromatase Inhibitors or Tamoxifen Following Chemotherapy for Perimenopausal Breast Cancer Patients [Comment]

Klar, Natalie; Adams, Sylvia
PMID: 34396392
ISSN: 1460-2105
CID: 5166772

The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group

El Bairi, Khalid; Haynes, Harry R; Blackley, Elizabeth; Fineberg, Susan; Shear, Jeffrey; Turner, Sophia; de Freitas, Juliana Ribeiro; Sur, Daniel; Amendola, Luis Claudio; Gharib, Masoumeh; Kallala, Amine; Arun, Indu; Azmoudeh-Ardalan, Farid; Fujimoto, Luciana; Sua, Luz F; Liu, Shi-Wei; Lien, Huang-Chun; Kirtani, Pawan; Balancin, Marcelo; El Attar, Hicham; Guleria, Prerna; Yang, Wenxian; Shash, Emad; Chen, I-Chun; Bautista, Veronica; Do Prado Moura, Jose Fernando; Rapoport, Bernardo L; Castaneda, Carlos; Spengler, Eunice; Acosta-Haab, Gabriela; Frahm, Isabel; Sanchez, Joselyn; Castillo, Miluska; Bouchmaa, Najat; Md Zin, Reena R; Shui, Ruohong; Onyuma, Timothy; Yang, Wentao; Husain, Zaheed; Willard-Gallo, Karen; Coosemans, An; Perez, Edith A; Provenzano, Elena; Ericsson, Paula Gonzalez; Richardet, Eduardo; Mehrotra, Ravi; Sarancone, Sandra; Ehinger, Anna; Rimm, David L; Bartlett, John M S; Viale, Giuseppe; Denkert, Carsten; Hida, Akira I; Sotiriou, Christos; Loibl, Sibylle; Hewitt, Stephen M; Badve, Sunil; Symmans, William Fraser; Kim, Rim S; Pruneri, Giancarlo; Goel, Shom; Francis, Prudence A; Inurrigarro, Gloria; Yamaguchi, Rin; Garcia-Rivello, Hernan; Horlings, Hugo; Afqir, Said; Salgado, Roberto; Adams, Sylvia; Kok, Marleen; Dieci, Maria Vittoria; Michiels, Stefan; Demaria, Sandra; Loi, Sherene
The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.
PMID: 34853355
ISSN: 2374-4677
CID: 5065742

Corrigendum to 'First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis': Annals of Oncology 2021; 32: 983-993

Emens, L A; Adams, S; Barrios, C H; Diéras, V; Iwata, H; Loi, S; Rugo, H S; Schneeweiss, A; Winer, E P; Patel, S; Henschel, V; Swat, A; Kaul, M; Molinero, L; Patel, S; Chui, S Y; Schmid, P
PMID: 34740469
ISSN: 1569-8041
CID: 5038552

Activating a collaborative innate-adaptive immune response to control metastasis

Sun, Lijuan; Kees, Tim; Almeida, Ana Santos; Liu, Bodu; He, Xue-Yan; Ng, David; Han, Xiao; Spector, David L; McNeish, Iain A; Gimotty, Phyllis; Adams, Sylvia; Egeblad, Mikala
Tumor-associated macrophages (TAMs) promote metastasis and inhibit T cells, but macrophages can be polarized to kill cancer cells. Macrophage polarization could thus be a strategy for controlling cancer. We show that macrophages from metastatic pleural effusions of breast cancer patients can be polarized to kill cancer cells with monophosphoryl lipid A (MPLA) and interferon (IFN) γ. MPLA + IFNγ injected intratumorally or intraperitoneally reduces primary tumor growth and metastasis in breast cancer mouse models, suppresses metastasis, and enhances chemotherapy response in an ovarian cancer model. Both macrophages and T cells are critical for the treatment's anti-metastatic effects. MPLA + IFNγ stimulates type I IFN signaling, reprograms CD206+ TAMs to inducible NO synthase (iNOS)+ macrophages, and activates cytotoxic T cells through macrophage-secreted interleukin-12 (IL-12) and tumor necrosis factor alpha (TNFα). MPLA and IFNγ are used individually in clinical practice and together represent a previously unexplored approach for engaging a systemic anti-tumor immune response.
PMID: 34478639
ISSN: 1878-3686
CID: 5061182

The journey of tumor-infiltrating lymphocytes as a biomarker in breast cancer: clinical utility in an era of checkpoint inhibition

Loi, S; Michiels, S; Adams, S; Loibl, S; Budczies, J; Denkert, C; Salgado, R
In 2014, we described a method to quantify percentage of tumor-infiltrating lymphocytes (TILs) on hematoxylin and eosin-stained slides of breast cancer samples using light microscopy that could be performed easily by pathologists with no extra stains. The aim of detailing the method was to facilitate independent research groups replicating our prognostic findings using TIL quantity in early-stage breast cancers. A global working group of breast pathologists was convened to standardize, test reproducibility, and refine the method. A website was also established which allowed free training (www.tilsinbreastcancer.org). As a result of this work, TIL data have been collected in over 20 000 primary breast cancer samples worldwide and the robust associations with better prognoses in triple-negative breast cancer (TNBC) and HER2+ BC have been confirmed. This has resulted in the inclusion of the TIL biomarker in several international breast cancer guidelines as well as in national criteria for routine pathology reporting. TIL therefore represents the first biological prognostic biomarker for early-stage TNBCs, and here its prognostic effect is linear, with values of 30%-50% being suggested as suitable for use in potential chemotherapy de-escalation studies. The efficacy of immune checkpoint-targeted agents in breast cancer now provides direct evidence that host immune responses can modify tumor growth in some patients. With the recent granting of accelerated approvals for the first PD-1/PD-L1 targeting agents in early and advanced TNBC, our focus has now moved to investigating the clinical utility of TIL in the setting of immune checkpoint agents, with or without PD-L1 protein assessment. Emerging data suggest that TIL quantity can help clinicians identify patients with breast cancer who benefit most from PD-1/PD-L1 inhibition. In patients with advanced TNBC and HER2+ disease a TIL cut-off of 5% or 10%, with PD-L1 expression can define 'immune-enriched' tumors and currently seems to have the most clinical relevance in this context.
PMID: 34311075
ISSN: 1569-8041
CID: 4972472