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Breast cancer is a major health concern for many women, but despite the current standard therapies, many women still die of metastatic disease. Angiogenesis has been evaluated as a possible target for therapy and bevacizumab (Avastin(®), Genentech/Roche, CA, USA), a monoclonal antibody against VEGF-A, has been developed to target this. Current clinical trials utilizing bevacizumab have shown an increase in progression-free survival, but this has not translated to an increase in overall survival in breast cancer patients. In this article, we summarize the currently published trials utilizing bevacizumab in the treatment of breast cancer and describe various methods of measuring angiogenesis in vitro and in vivo. We also describe the related process of lymphangiogenesis, as this may contribute to the mechanism of cancer progression and may be a potential target for therapy in the future. Understanding these processes may help us develop new treatments for breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: NRG Oncology (NRG)/NSABP B-39/RTOG 0413 compared whole-breast irradiation (WBI) to accelerated partial-breast irradiation (APBI). APBI was not equivalent to WBI in local tumor control. Secondary outcome was Quality-of-life (QOL)., Methods: The QOL sub-study used validated self-report questionnaires including the Breast Cancer Treatment Outcome Scale (BCTOS) and SF-36 vitality scale. Assessments occurred: before randomization, at treatment completion (chemotherapy or radiotherapy), 4-weeks later, at 6-, 12-, 24-, and 36-months. Primary aims: cosmesis change equivalency (baseline to 3 years; a priori margin of equivalence 0.4 standard deviations) and fatigue change superiority (baseline to end-of-treatment (EOT)) for APBI vs WBI, by patient groups treated with or without chemotherapy when appropriate., Results: From 3/21/05-5/25/09, 975 patients enrolled in this sub-study; 950 had follow-up data. APBI had 3-year cosmesis equivalent to WBI (95%CI,-0.0001-0.16; equivalence margin -0.22-0.22) in all patients. The APBI group without chemotherapy had less EOT fatigue (p = .011; mean score APBI 63 vs WBI 59); APBI group receiving chemotherapy had worse EOT fatigue (p = .011; APBI 43 vs WBI 49). The APBI group reported less pain (BCTOS) at EOT (WBI 2.29 vs APBI 1.97), but worse pain at 3-years (WBI 1.62 vs APBI 1.71). APBI patients reported greater convenience of care than with WBI and reported less symptom severity at EOT and 4-weeks later., Conclusion: Cosmetic outcomes were similar for APBI and WBI groups, with small statistically significant differences in other outcomes that varied over time. Differences in fatigue and other symptoms appeared to resolve by ≥ 6 months. APBI may be preferred by some patients, for whom extended treatment is burdensome., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Tumor-draining lymph nodes (tumor-DLNs) provide a rich source of tumor-reactive lymphocytes which can be used in adoptive immunotherapy (AIT) and that circumvent the need to resect autologous tumor, without the challenges and shortcomings associated with using autologous tumor or anti-CD3 monoclonal antibody. Bryostatin/Ionomycin (Bryo/Io) provide a useful method of activating tumor-DLNs such that they can readily be expanded to sufficient numbers to be used in AIT, and growing the tumor-DLN lymphocytes in the gamma chain cytokines IL-7 plus IL-15 is superior to IL-2 in terms of T cell numbers and phenotype. AIT with these cells induces tumor regression and provides protection against metastases and future tumor challenge. Here, we provide a stepwise protocol to sensitize tumor-DLN cells in donor mice, activate tumor-DLN T cells ex vivo using Bryo/Io, expansion of these cells in gamma chain cytokines and adoptive transfer of the expanded cells back into tumor-bearing hosts. Methods relevant to these experiments, such as injecting tumor cells intravenously and monitoring for pulmonary metastases, tumor volume measurement and resection, and use of luciferase-expressing tumor cells to monitor for metastases following resection, are described in detail. The methods outlined herein can be easily adapted to suit similar experiments across multiple tumor cell lines and syngeneic mouse models., (Copyright © 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: The primary aim of this randomized neoadjuvant trial in operable, HER2-positive breast cancer, was to determine the efficacy on pathologic complete response (pCR) of substituting lapatinib (L) for trastuzumab (T) or adding L to T, in combination with weekly paclitaxel (WP) following AC. Results on pCR were previously reported. Here, we report data on planned secondary endpoints, recurrence-free interval (RFI) post-surgery, and overall survival (OS)., Methods: All patients received standard AC q3 weeks × 4 cycles followed by WP (80 mg/m 2 ) on days 1, 8, and 15, q28 days × 4 cycles. Concurrently with WP, patients received either T (4 mg/kg load, then 2 mg/kg) weekly until surgery, L (1250 mg) daily until surgery, or weekly T plus L (750 mg) daily until surgery. Following surgery, all patients received T to complete 52 weeks of HER2-targeted therapy. 522 of 529 randomized patients had follow-up. Median follow-up was 5.1 years., Results: RFI at 4.5 years was 87.2%, 79.4% (p = 0.34; HR = 1.37; 95% CI 0.80, 2.34), and 89.4% (p = 0.37; HR = 0.70; 0.37, 1.32) for arms T, L, and TL, respectively. The corresponding five-year OS was 94.8%, 89.1% (p = 0.34; HR = 1.46; 0.68, 3.11), and 95.8% (p = 0.25; HR = 0.58; 0.22, 1.51), respectively. Patients with pCR had a much better prognosis, especially in the ER-negative cohort: RFI (HR = 0.23, p < 0.001) and OS (HR = 0.28, p < 0.001)., Conclusions: Although pCR, RFI, and OS were numerically better with the dual combination and less with L, the differences were not statistically significant. However, achievement of pCR again correlated with improved outcomes, especially remarkable in the ER-negative subset., Clinical Trials Registration: NCT00486668., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies., Patients and Methods: Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response., Results: There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model., Conclusion: Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy.

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare tumor of soft tissue. It typically presents as a low-grade sarcoma with myxoid stroma, has a predilection for distal extremities, and displays a high propensity for local recurrence, but low metastatic potential. The risk factors associated with high-risk lesions metastasizing are poorly defined. In cases where the tumor metastasizes, therapeutic options are few, and death is rare. Our case discusses an aggressive MIFS that progressed from a painless lesion on a patient's calf, to her death from a malignant pleural effusion within 21 months. The 58-year-old woman presented with a mass on her left calf. It was excised and was originally thought to be a benign process. It re-grew quickly after the initial resection, and she underwent re-excision of the mass. The pathologic examination was consistent with an MIFS. Despite negative margins on her second resection and an attempt at local control with radiotherapy, it metastasized to her lungs within less than 2 years. This resulted in a malignant pleural effusion that caused her death. An MIFS is typically benign but can metastasize in atypical cases. Even if the disease is metastatic, it is unlikely to be the cause of death. Treatment of metastatic MIFS is poorly defined, but there are suggested therapies beyond surgical resection and radiotherapy. Successful treatment of an MIFS should include a high index of suspicion in extremity lesions, screening for metastasis, and possible targeted therapies based on tumor genomics., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Patients with hormone receptor-positive, HER2-negative breast cancer who have residual invasive disease after neoadjuvant chemotherapy (NACT) are at a high risk of relapse. PENELOPE-B was a double-blind, placebo-controlled, phase III trial that investigated adding palbociclib (PAL) for thirteen 28-day cycles to adjuvant endocrine therapy (ET) in these patients. Clinical results showed no significant improvement in invasive disease-free survival with PAL., Methods: We performed a pre-planned cost-effectiveness analysis of PAL within PENELOPE-B from the perspective of the German statutory health insurance. Health-related quality of life scores, collected in the trial using the EQ-5D-3L instrument, were converted to utilities based on the German valuation algorithm. Resource use was valued using German price weights. Outcomes were discounted at 3% and modeled with mixed-level linear models to adjust for attrition, repeated measurements, and residual baseline imbalances. Subgroup analyses were performed for key prognostic risk factors. Scenario analyses addressed data limitations and evaluated the robustness of the estimated cost-effectiveness of PAL to methodological choices., Results: The effects of PAL on quality-adjusted life years (QALYs) were marginal during the active treatment phase, increasing thereafter to 0.088 (95% confidence interval: -0.001; 0.177) QALYs gained over the 4 years of follow-up. The incremental costs were dominated by PAL averaging EUR 33,000 per patient; costs were higher in the PAL arm but not significantly different after the second year. At an incremental cost-effectiveness ratio of EUR 380,000 per QALY gained, PAL was not cost-effective compared to the standard-of-care ET. Analyses restricted to Germany and other subgroups were consistent with the main results. Findings were robust in the scenarios evaluated., Conclusions: One year of PAL added to ET is not cost-effective in women with residual invasive disease after NACT in Germany., Competing Interests: KG received research funding from Novartis paid to the institution. SL received research funding from Abbvie, AstraZeneca, Celgene, Daiichi Sankyo, Immunomedics/Gilead, Novartis, and Pfizer; royalties (Digital Ki67 Evaluator) and honorarium from Abbvie, Amgen, Bayer, BMS, Celgene, Eirgenix, GSK, Lilly, Merck, AstraZeneca, Pierre Fabre, Prime/Medscape, Daiicho Sankyo, Novartis, Pfizer, Immunomedics/Gilead, Puma, Seagen, and Samsung; and reported patents (EP14153692.0, EP21152186.9, EP15702464.7, EP19808852.8, Digital Ki67 Evaluator) all paid to the institution. PS received research funding from Novartis paid to the institution. FM received research funding from Roche, Novartis, AstraZeneca, GSK/Tesaro, MED, Clovis, Vaccibody, Gilead Sciences, and Eisai, and consulting fees from Vacibody all paid to the institution; received personal consulting fees and honorarium from AstraZeneca, Clovis, GSK/Tesaro, Eli Lilly, Novartis, Pfizer, Roche, Eisai, GenomicHealth, Myriad Genetics, PharmaMar, MSD, Immunomedis/Gilead, Pierre-Fabre, AGENDIA, and Seattle Genetics, and support for meetings and travel from Pfizer, Roche, and AstraZeneca; and participated in Advisory Boards for Palles and Amgen. MU received consulting fees from Abbvie, Astra Zeneca, Amgen, Celgene, Daiichi Sankyo, Eisai, Gilead, Lilly, Molecular Health, MSD Merck, Mylan, Novartis, Pierre Fabre, Pfizer, Roche, and Seagen, and honorarium from Amgen, Astra Zeneca, BMS, Celgene, Daiichi Sankyo, Gilead, GSK, Lilly, Mundipharma, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi Aventis, and Seagen all paid to the institution. HRB received personal consulting fees from AstraZeneca, and received support for attending meetings and travel from Pfizer, Daiichi Sankyo, and Roche. S-BK received research funding from Novartis, Sanofi-Aventis, and DongKook paid to the institution; received personal consulting fees and honorarium from Novartis, AstraZeneca, Eli Lilly, Dae Hwa, ISU Abxis, Daiichi Sankyo, and BeiGene; participated in Advisory Boards for Novartis, AstraZeneca, Eli Lilly, Dae Hwa, ISU Abxis, Daiichi Sankyo, and BeiGene; serves as a Co-Chair for ESMO Breast 2021-2022; and holds stock of Genopeaks and Neogene TC. HDB received research funding from NSABP to the institution and reported stock ownership in Pfizer. NM participated in an Advisory Board for Pfizer. KAG received research funding from Pfizer, AstraZeneca, Eli Lilly, Roche, Merck, Gilead, Novartis, Ayala, BMS, and Seagen paid to the institution; received personal consulting fees and honorarium from AstraZeneca, Eli Lilly, Pfizer, Merck, Novartis, Gilead, Seagen, and GenomicHealth; received payment from expert testimony from Genetech; and participated in Advisory Boards for Ayala and AstraZeneca. JG-S received personal consulting fees and honorarium from AstraZeneca, Gilead, Novartis, Daiichi Sankyo, Eli Lilly, Exact Sciences, Seagen, Sanofi, EISAI, MSD, and Celgene. CK received research funding from Health Research Board and Mater Foundation paid to the institution; received personal consulting fees and honorarium from Exact Sciences and Daiichi Sankyo; received support for attending meetings and travel from Daiichi Sankyo and Roche; and participated in Advisory Board for Daiichi Sankyo. TR received personal consulting fees and honorarium from Pfizer. MT received research funding from Chugai, Takeda, Pfizer, Kyowa-Kirin, Taiho, JBCRG assoc., KBCRN assoc., Eisai, Eli Lilly, Daiichi Sankyo, AstraZeneca, Astellas, Shimadzu, Yakult, Nippon Kayaku, AFI technology, Luxonus, Shionogi, and GL Science paid to the institution; received honorarium from Chugai, Takeda, Pfizer, Kyowa-Kirin, Taiho, Eisai, Daiichi Sankyo, AstraZeneca, Eli Lilly, MSD, Exact Science, Novartis, Shimadzu, Yakult, Nippon Kayaku, and Devicore Medical Japan; and participated in Advisory Boards for Kyowa-Kirin, Daiichi Sankyo, Eli Lilly, BMS, Athenex Oncology, Bertis, Terumo, and Kansai Medical Net. HSR received research funding (study materials only) from Pfizer, Merck, Novartis, Eli Lilly, Roche, Daiichi Sankyo, Seattle Genetics, Macrogenics, Sermonix, Boehringer Ingelheim, Polyphor, AstraZeneca, Ayala, and Gilead paid to the institution; and received personal consulting fees and honorarium from Napo, Puma, Mylan, and Samsung. MG received personal consulting fees and honorarium from AstraZeneca, Eli Lilly, Daiichi Sankyo, Amgen, Veracyte, Novartis, Pierre Fabre, MSD, and Life Brain; received payment for expert testimony from Eli Lilly; and reported an immediate family member employed by Sandoz. AM received personal consulting fees and honoraria from Pfizer. MS received research funding from AbbVie, Biogen, Bristol Myers Squibb, Merck Sharpe and Dohme, Mundipharma, Novartis, and Roche paid to the institution; and received personal consulting fees from BMS and Sandoz. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Galactionova, Loibl, Salari, Marmé, Martin, Untch, Bonnefoi, Kim, Bear, McCarthy, Gelmon, García-Sáenz, Kelly, Reimer, Toi, Rugo, Gnant, Makris, Burchardi and Schwenkglenks.)

Living in a disadvantaged neighborhood is associated with adverse clinical outcomes among breast cancer patients, but the underlying pathway is still unclear. Limited evidence has suggested that accelerated biological aging may play an important role. In this study, using a sub-sample of 906 women with newly diagnosed breast cancer at M.D. Anderson, we examined whether levels of selected markers of biological aging (e.g., allostatic load, telomere length, and global DNA methylation) were affected by neighborhood disadvantage. The Area Deprivation Index was used to determine the neighborhood disadvantage. Based on the median ADI at the national level, the study population was divided into low and high ADI groups. Overall, breast cancer patients from the high ADI group were more likely to be younger and non-Hispanic Black than those from the low ADI group (P < 0.001, respectively). They were also more likely to have higher grade and poorly differentiated breast tumors (P = 0.029 and 0.019, respectively). For the relationship with markers, compared to the low ADI group, high ADI group had higher median levels of allostatic load (P = 0.046) and lower median levels of global DNA methylation (P < 0.001). Compared to their counterparts, those from the high ADI group were 20% more likely to have increased allostatic load and 51% less likely to have increased levels of global DNA methylation. In summary, we observed that levels of allostatic load and global DNA methylation are influenced by neighborhood disadvantage among breast cancer patients., (© 2022. The Author(s).)

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. It disproportionately affects BRCA mutation carriers and young women, especially African American (AA) women. Chemoresistant TNBC is a heterogeneous and molecularly unstable disease that challenges our ability to apply personalized therapies. With the approval of immune checkpoint blockade (ICB) for TNBC, the addition of pembrolizumab to systemic chemotherapy has become standard of care (SOC) in neoadjuvant systemic therapy (NST) for high-risk early-stage TNBC. Pembrolizumab plus chemotherapy significantly increased the pathologic complete response (pCR) and improved event-free survival in TNBC. However, clinical uncertainties remain because similarly treated TNBC partial responders with comparable tumor responses to neoadjuvant therapy often experience disparate clinical outcomes. Current methods fall short in accurately predicting which high-risk patients will develop chemo-resistance and tumor relapse. Therefore, novel treatment strategies and innovative new research initiatives are needed. We propose that the EGFR-K-RAS-SIAH pathway activation is a major tumor driver in chemoresistant TNBC. Persistent high expression of SIAH in residual tumors following NACT/NST reflects that the EGFR/K-RAS pathway remains activated (ON), indicating an ineffective response to treatment. These chemoresistant tumor clones persist in expressing SIAH (SIAH High/ON ) and are linked to early tumor relapse and poorer prognosis. Conversely, the loss of SIAH expression (SIAH Low/OFF ) in residual tumors post-NACT/NST reflects EGFR/K-RAS pathway inactivation (OFF), indicating effective therapy and chemo-sensitive tumor cells. SIAH Low/OFF signal is linked to tumor remission and better prognosis post-NACT/NST. Therefore, SIAH is well-positioned to become a novel tumor-specific, therapy-responsive, and prognostic biomarker. Potentially, this new biomarker (SIAH High/ON ) could be used to quantify therapy response, predict chemo-resistance, and identify those patients at the highest risk for tumor relapse and poor survival in TNBC., Competing Interests: All authors declared that there are no conflicts of interest., (© The Author(s) 2022.)

Background: Despite the large number of patients with early breast cancer (EBC) who have been treated with capecitabine in randomised trials, no individual patient data meta-analysis has been conducted. The primary objective was to examine the effect of capecitabine on disease-free survival (DFS), and the secondary objectives were to analyse distant DFS (DDFS), overall survival (OS), pathological complete response (for neoadjuvant studies) and the interaction between capecitabine-related toxicity and treatment effect., Methods: www., Clinicaltrials: gov and www.pubmed.ncbi.nlm.nih.gov were searched using the following criteria: use of capecitabine for EBC as adjuvant or neoadjuvant therapy; multicentre randomised trial with >100 patients; recruitment completed, and outcomes available. Required data were available for 13 trials., Results: Individual data from 15,993 patients were collected. Cox regression analyses of all included patients revealed that the addition of capecitabine did not alter DFS significantly compared with treatment without capecitabine (hazard ratio [HR] 0.952; 95% CI 0.895-1.012; P value = 0.115). There was also no effect on DFS in the subset of studies where capecitabine was given instead of another drug (HR 1.035; 95% CI 0.945-1.134; P = 0.455). However, capecitabine administered in addition to the standard systemic treatment improved DFS (HR 0.888; 95% CI 0.817-0.965; P = 0.005). An OS improvement was observed in the entire cohort (HR 0.892; 95% CI 0.824-0.965, P = 0.005) and in the subset of capecitabine addition (HR 0.837; 95% CI 0.751, 0.933, P = 0.001). Subgroup analyses revealed that triple-negative breast cancer (TNBC) patients benefitted from treatment with capecitabine overall and in addition to other systemic treatments in terms of DFS and OS., Conclusion: Capecitabine was able to improve DFS and OS in patients with TNBC and in all patients with EBC when administered in addition to systemic treatment., Competing Interests: Conflict of interest statement M.v.M. reports personal fees from AstraZeneca, personal fees from Amgen, personal fees from Novartis, personal fees from Genomic Health, personal fees from Gilead, personal fees from GSK, personal fees from Lilly, personal fees from Molecular Health, personal fees from Mylan, personal fees from Pfizer, personal fees from Roche, personal fees from Pierre Fabre, personal fees from Seagen, outside the submitted work; V.M. reports speaker honoraria from Amgen, AstraZeneca, Celgene, Roche, Teva, consultancy honoraria from Roche, Amgen, TESARO and Myelo Therapeutics; J.O.S. reports personal fees from AbbVie, personal fees from Agendia, personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb, personal fees from Celgene, personal fees from Eisai, personal fees from Genentech, personal fees from Immunomedics, personal fees from Ipsen, personal fees from Jounce, personal fees from Lilly, personal fees from Merck, personal fees from Myriad, personal fees from Novartis, personal fees from Ondonate Therapeutics, personal fees from Pfizer, personal fees from Puma, personal fees from Roche, personal fees from Seattle Genetics, personal fees from Prime Oncology, outside the submitted work; M.M. has received research grants from Roche, PUMA and Novartis, consulting/advisory fees from AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly, PUMA, Taiho Oncology, Daiichi Sankyo and Pfizer and speakers' honoraria from AstraZeneca, Lilly, Amgen, Roche/Genentech, Novartis and Pfizer, outside the submitted work. H.J. reports personal fees from Orion Pharma, personal fees from Neutron Therapeutics, other from Orion Pharma, other from Sartar Therapeutics, outside the submitted work. M.U. reports personal fees and non-financial support from AbbVie, personal fees and non-financial support from Amgen GmbH, personal fees and non-financial support from Astra Zeneca, personal fees from BMS, personal fees and non-financial support from Celgene GmbH, personal fees and non-financial support from Daiichi Sankyo, personal fees and non-financial support from Eisai GmbH, personal fees from Lilly Deutschland, personal fees and non-financial support from Lilly Int., personal fees and non-financial support from MSD Merck, personal fees and non-financial support from Mundipharma, personal fees and non-financial support from Myriad Genetics, personal fees and non-financial support from Odonate, personal fees and non-financial support from Pfizer GmbH, personal fees from PUMA Biotechnology, personal fees and non-financial support from Roche Pharma AG, personal fees and non-financial support from Sanofi Aventis Deutschland GmbH, personal fees and non-financial support from TEVA Pharmaceuticals Ind Ltd, personal fees and non-financial support from Novartis, personal fees from Pierre Fabre, personal fees and non-financial support from Clovis Oncology, personal fees from Seattle Genetics, outside the submitted work; U.N. reports grants and personal fees from Agendia, grants and personal fees from Amgen, grants and personal fees from Celgene, grants, personal fees and other from Genomic Health, grants and personal fees from NanoString Technologies, personal fees from Novartis, personal fees and other from Pfizer, grants, personal fees and other from Roche/Genentech, personal fees from Teva, grants from Sanofi, outside the submitted work. G.S. reports personal fees and non-financial support from Roche, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Novartis, personal fees from Lilly, non-financial support from TEVA, personal fees and non-financial support from Pfizer, outside the submitted work. C.H.B. reports grants/research support from (to the institution) Pfizer, Novartis, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Lilly, Sanofi, Taiho Pharmaceutical, Mylan, Merrimack, Merck, AbbVie, Astellas Pharma, BioMarin, Bristol-Myers Squibb, Daiichi Sankyo, Abraxis BioScience, AB Science, Asana Biosciences, Medivation, Exelixis, ImClone Systems, LEO Pharma, Millennium, Merck KGaA, Shanghai Henlius Biotech, Polyphor, PharmaMar; Advisory boards and consulting: Boehringer Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Bayer, MSD, Astra Zeneca, Zodiac, Lilly, Sanofi. HDB reports other from Merck, other from Pfizer, other from AbbVie, outside the submitted work. M.T. reports grants and personal fees from Chugai, grants and personal fees from Takeda, grants and personal fees from Pfizer, grants and personal fees from Kyowa-Hakko-Kirin, grants and personal fees from C & C Res Lab, grants and personal fees from Taiho, grants from JBCRG association, grants and personal fees from Eisai, grants and personal fees from Daiichi-Sankyo, grants and personal fees from Astra Zeneca, personal fees from Eli Lilly, personal fees from MSD, personal fees from Genomic Health, personal fees from Novartis, personal fees from Konica Minolta, grants from Astellas, outside the submitted work; and Board of directors; JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast cancer Research Network. H.M. reports grants from NCI grant to Alliance/CALGB, during the conduct of the study. T.R. reports personal fees from Roche, during the conduct of the study. S.L. reports grants and other from Roche, during the conduct of the study; grants and other from AbbVie, grants and other from Celgene, other from Seattle Genetics, other from PriME/Medscape, personal fees from Chugai, grants and other from Daiichi-Sankyo, other from Lilly, other from Samsung, other from BMS, other from Puma, grants from Immunomedics, grants and other from AstraZeneca, other from Pierre Fabre, other from Merck, other from GlaxoSmithKline, other from EirGenix, grants and other from Bayer, grants and other from Amgen, grants and other from Novartis, grants and other from Pfizer, outside the submitted work; In addition, S.L. has a patent EP14153692.0 pending. All remaining authors declare no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Antigen-specific immunotherapy can be limited by induced tumor immunoediting (e.g., antigen loss) or through failure to recognize antigen-negative tumor clones. Melanoma differentiation-associated gene-7/IL24 (MDA-7/IL24) has profound tumor-specific cytotoxic effects in a broad spectrum of cancers. Here we report the enhanced therapeutic impact of genetically engineering mouse tumor-reactive or antigen-specific T cells to produce human MDA-7/IL24. While mock-transduced T cells only killed antigen-expressing tumor cells, MDA-7/IL24-producing T cells destroyed both antigen-positive and negative cancer targets. MDA-7/IL24-expressing T cells were superior to their mock-engineered counterparts in suppressing mouse prostate cancer and melanoma growth as well as metastasis. This enhanced antitumor potency correlated with increased tumor infiltration and expansion of antigen-specific T cells as well as induction of a Th1-skewed immunostimulatory tumor environment. MDA-7/IL24-potentiated T-cell expansion was dependent on T-cell-intrinsic STAT3 signaling. Finally, MDA-7/IL24-modified T-cell therapy significantly inhibited progression of spontaneous prostate cancers in Hi-Myc transgenic mice. Taken together, arming T cells with tumoricidal and immune-potentiating MDA-7/IL24 confers new capabilities of eradicating antigen-negative cancer cell clones and improving T-cell expansion within tumors. This promising approach may be used to optimize cellular immunotherapy for treating heterogeneous solid cancers and provides a mechanism for inhibiting tumor escape. SIGNIFICANCE: This research describes a novel strategy to overcome the antigenic heterogeneity of solid cancers and prevent tumor escape by engineering T lymphocytes to produce a broad-spectrum tumoricidal agent., (©2021 American Association for Cancer Research.)

Background: The efficacy of cancer immunotherapy can be limited by the poor immunogenicity of cancer and the immunosuppressive tumor microenvironment (TME). Immunologically programming the TME and creating an immune-inflamed tumor phenotype is critical for improving the immune-responsiveness of cancers. Here, we interrogate the immune modulator Flagrp170, engineered via incorporation of a pathogen-associated molecular pattern (ie, flagellin) into an immunostimulatory chaperone molecule, in transforming poorly immunogenic tumors and establishing a highly immunostimulatory milieu for immune augmentation., Methods: Multiple murine cancer models were used to evaluate the immunostimulatory activity, antitumor potency, and potential side effects of Flagrp170 on administration into the tumors using a replication impaired adenovirus. Antibody neutralization and mice deficient in pattern recognition receptors, that is, toll-like receptor 5 (TLR5) and NOD like receptor (NLR) family caspase activation and recruitment domain (CARD) domain-containing protein 4 (NLRC4), both of which can recognize flagellin, were employed to understand the immunological mechanism of action of the Flagrp170., Results: Intratumoral delivery of mouse or human version of Flagrp170 resulted in robust inhibition of multiple malignancies including head and neck squamous cell carcinoma and breast cancer, without tissue toxicities. This in situ Flagrp170 treatment induced a set of cytokines in the TME known to support Th1/Tc1-dominant antitumor immunity. Additionally, granulocyte macrophage colony-stimulating factor derived from mobilized CD8 + T cells was involved in the therapeutic activity of Flagrp170. We also made a striking finding that NLRC4, not TLR5, is required for Flagrp170-mediated antitumor immune responses., Conclusion: Our results elucidate a novel immune-potentiating activity of Flagrp170 via engaging the innate pattern recognition receptor NLRC4, and support its potential clinical use to reshape cancer immune phenotype for overcoming therapeutic resistance., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although breast cancer mortality is a result of distant recurrences associated with the establishment of tumor dormancy, current clinical practice guidelines recommend a wait and watch approach for tumor recurrences. This is because of our limited understanding of tumor dormancy and insufficient evidence in support of immunological control of tumor dormancy., Methods: We used FVBN202 transgenic mice expressing rat neu oncogene in the mammary glands, and their parental FVB strain lacking neu expression. These models allowed the detection of tumor dormancy at distant sites using the rat neu protein as a tumor marker. We also used Ki67 for the detection of the indolent and quiescent types of tumor dormancy. Multicolor flow cytometry was used to detect dormant tumor cells and T cell subsets. Co-culture studies were performed to determine the role of T cells in preventing regrowth of dormant cells., Results: We demonstrated that dormant tumor cells were present at the site of primary breast cancer and at distant sites in the lungs and in the liver very early in the course of early stage breast cancer when no distant metastasis was evident. Dormant tumor cells were characterized as neu expressing Ki67 - and Ki67 low fractions associated with the induction of local immune responses predominated by CD4+ and CD8+ T effector cell subsets. The presence of neu-autoreactive T cells from FVBN202 mice only prevented regrowth of dormant cells. On the other hand, presence of neu-alloreactive anti-tumor T cells in FVB mice prior to tumor challenge resulted in the protection of mice from the dissemination of dormant tumor cells to distant organs., Conclusion: Our results suggest that immunotherapeutic targeting of semi-allogeneic mutant neoantigens during tumor dormancy might prevent distant recurrence of the disease.

Triple-negative breast cancer (TNBC), characterized by the absence or low expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), is the most aggressive subtype of breast cancer. TNBC accounts for about 15% of breast cancer cases in the U.S., and is known for high relapse rates and poor overall survival (OS). Chemo-resistant TNBC is a genetically diverse, highly heterogeneous, and rapidly evolving disease that challenges our ability to individualize treatment for incomplete responders and relapsed patients. Currently, the frontline standard chemotherapy, composed of anthracyclines, alkylating agents, and taxanes, is commonly used to treat high-risk and locally advanced TNBC. Several FDA-approved drugs that target programmed cell death protein-1 (Keytruda) and programmed death ligand-1 (Tecentriq), poly ADP-ribose polymerase (PARP), and/or antibody drug conjugates (Trodelvy) have shown promise in improving clinical outcomes for a subset of TNBC. These inhibitors that target key genetic mutations and specific molecular signaling pathways that drive malignant tumor growth have been used as single agents and/or in combination with standard chemotherapy regimens. Here, we review the current TNBC treatment options, unmet clinical needs, and actionable drug targets, including epidermal growth factor (EGFR), vascular endothelial growth factor (VEGF), androgen receptor (AR), estrogen receptor beta (ERβ), phosphoinositide-3 kinase (PI3K), mammalian target of rapamycin (mTOR), and protein kinase B (PKB or AKT) activation in TNBC. Supported by strong evidence in developmental, evolutionary, and cancer biology, we propose that the K-RAS/SIAH pathway activation is a major tumor driver, and SIAH is a new drug target, a therapy-responsive prognostic biomarker, and a major tumor vulnerability in TNBC. Since persistent K-RAS/SIAH/EGFR pathway activation endows TNBC tumor cells with chemo-resistance, aggressive dissemination, and early relapse, we hope to design an anti-SIAH-centered anti-K-RAS/EGFR targeted therapy as a novel therapeutic strategy to control and eradicate incurable TNBC in the future.

Background: Myeloid derived suppressor cells (MDSCs) present a significant obstacle to cancer immunotherapy because they dampen anti-tumor cytotoxic T cell responses. Previous groups, including our own, have reported on the myelo-depletive effects of certain chemotherapy agents. We have shown previously that decitabine increased tumor cell Class I and tumor antigen expression, increased ability of tumor cells to stimulate T lymphocytes, depleted tumor-induced MDSC in vivo and augmented immunotherapy of a murine mammary carcinoma., Results: In this study, we expand upon this observation by testing a next-generation DNA methyltransferase inhibitor (DNMTi), guadecitabine, which has increased stability in the circulation. Using the 4 T1 murine mammary carcinoma model, in BALB/cJ female mice, we found that guadecitabine significantly reduces tumor burden in a T cell-dependent manner by preventing excessive myeloid proliferation and systemic accumulation of MDSC. The remaining MDSC were shifted to an antigen-presenting phenotype. Building upon our previous publication, we show that guadecitabine enhances the therapeutic effect of adoptively transferred antigen-experienced lymphocytes to diminish tumor growth and improve overall survival. We also show guadecitabine's versatility with similar tumor reduction and augmentation of immunotherapy in the C57BL/6 J E0771 murine breast cancer model., Conclusions: Guadecitabine depleted and altered MDSC, inhibited growth of two different murine mammary carcinomas in vivo, and augmented immunotherapeutic efficacy. Based on these findings, we believe the immune-modulatory effects of guadecitabine can help rescue anti-tumor immune response and contribute to the overall effectiveness of current cancer immunotherapies.

Background: Whole-breast irradiation after breast-conserving surgery for patients with early-stage breast cancer decreases ipsilateral breast-tumour recurrence (IBTR), yielding comparable results to mastectomy. It is unknown whether accelerated partial breast irradiation (APBI) to only the tumour-bearing quadrant, which shortens treatment duration, is equally effective. In our trial, we investigated whether APBI provides equivalent local tumour control after lumpectomy compared with whole-breast irradiation., Methods: We did this randomised, phase 3, equivalence trial (NSABP B-39/RTOG 0413) in 154 clinical centres in the USA, Canada, Ireland, and Israel. Adult women (>18 years) with early-stage (0, I, or II; no evidence of distant metastases, but up to three axillary nodes could be positive) breast cancer (tumour size ≤3 cm; including all histologies and multifocal breast cancers), who had had lumpectomy with negative (ie, no detectable cancer cells) surgical margins, were randomly assigned (1:1) using a biased-coin-based minimisation algorithm to receive either whole-breast irradiation (whole-breast irradiation group) or APBI (APBI group). Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with or without a supplemental boost to the tumour bed, and APBI was delivered as 34 Gy of brachytherapy or 38·5 Gy of external bream radiation therapy in 10 fractions, over 5 treatment days within an 8-day period. Randomisation was stratified by disease stage, menopausal status, hormone-receptor status, and intention to receive chemotherapy. Patients, investigators, and statisticians could not be masked to treatment allocation. The primary outcome of invasive and non-invasive IBTR as a first recurrence was analysed in the intention-to-treat population, excluding those patients who were lost to follow-up, with an equivalency test on the basis of a 50% margin increase in the hazard ratio (90% CI for the observed HR between 0·667 and 1·5 for equivalence) and a Cox proportional hazard model. Survival was assessed by intention to treat, and sensitivity analyses were done in the per-protocol population. This trial is registered with ClinicalTrials.gov, NCT00103181., Findings: Between March 21, 2005, and April 16, 2013, 4216 women were enrolled. 2109 were assigned to the whole-breast irradiation group and 2107 were assigned to the APBI group. 70 patients from the whole-breast irradiation group and 14 from the APBI group withdrew consent or were lost to follow-up at this stage, so 2039 and 2093 patients respectively were available for survival analysis. Further, three and four patients respectively were lost to clinical follow-up (ie, survival status was assessed by phone but no physical examination was done), leaving 2036 patients in the whole-breast irradiation group and 2089 in the APBI group evaluable for the primary outcome. At a median follow-up of 10·2 years (IQR 7·5-11·5), 90 (4%) of 2089 women eligible for the primary outcome in the APBI group and 71 (3%) of 2036 women in the whole-breast irradiation group had an IBTR (HR 1·22, 90% CI 0·94-1·58). The 10-year cumulative incidence of IBTR was 4·6% (95% CI 3·7-5·7) in the APBI group versus 3·9% (3·1-5·0) in the whole-breast irradiation group. 44 (2%) of 2039 patients in the whole-breast irradiation group and 49 (2%) of 2093 patients in the APBI group died from recurring breast cancer. There were no treatment-related deaths. Second cancers and treatment-related toxicities were similar between the two groups. 2020 patients in the whole-breast irradiation group and 2089 in APBI group had available data on adverse events. The highest toxicity grade reported was: grade 1 in 845 (40%), grade 2 in 921 (44%), and grade 3 in 201 (10%) patients in the APBI group, compared with grade 1 in 626 (31%), grade 2 in 1193 (59%), and grade 3 in 143 (7%) in the whole-breast irradiation group., Interpretation: APBI did not meet the criteria for equivalence to whole-breast irradiation in controlling IBTR for breast-conserving therapy. Our trial had broad eligibility criteria, leading to a large, heterogeneous pool of patients and sufficient power to detect treatment equivalence, but was not designed to test equivalence in patient subgroups or outcomes from different APBI techniques. For patients with early-stage breast cancer, our findings support whole-breast irradiation following lumpectomy; however, with an absolute difference of less than 1% in the 10-year cumulative incidence of IBTR, APBI might be an acceptable alternative for some women., Funding: National Cancer Institute, US Department of Health and Human Services., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Historically, breast cancer tumors have been considered immunologically quiescent, with the majority of tumors demonstrating low lymphocyte infiltration, low mutational burden, and modest objective response rates to anti-PD-1/PD-L1 monotherapy. Tumor and immunologic profiling has shed light on potential mechanisms of immune evasion in breast cancer, as well as unique aspects of the tumor microenvironment (TME). These include elements associated with antigen processing and presentation as well as immunosuppressive elements, which may be targeted therapeutically. Examples of such therapeutic strategies include efforts to (1) expand effector T-cells, natural killer (NK) cells and immunostimulatory dendritic cells (DCs), (2) improve antigen presentation, and (3) decrease inhibitory cytokines, tumor-associated M2 macrophages, regulatory T- and B-cells and myeloid derived suppressor cells (MDSCs). The goal of these approaches is to alter the TME, thereby making breast tumors more responsive to immunotherapy. In this review, we summarize key developments in our understanding of antitumor immunity in breast cancer, as well as emerging therapeutic modalities that may leverage that understanding to overcome immunologic resistance., Competing Interests: Competing interestsGatti-Mays: No COI or disclosures. Balko: Receives research support from Genentech/Roche, Bristol Myers Squibb, and Incyte Corporation, has received consulting/expert witness fees from Novartis, and is an inventor on provisional patents regarding immunotherapy targets and biomarkers in cancer. Gameiro: No COIs or disclosures. Bear: Receives research support from Merck and serves on the Advisory Board for Merck. Prabhakaran: No COI or disclosures. Fukui: No COI or disclosures. Disis: COI: grants from Epithany, Celgene, EMD Serono, Pfizer, Seattle Genetics, Silverback Therapeutics, Janssen. Stockholder in Epithany. Nanda: Advisory Board: AstraZeneca, Athenex, Celgene, Daiichi Sankyo, Inc, Genentech, MacroGenics, Merck, Novartis, Pfizer, Puma, Syndax. DSMB:G1 Therapeutics Research Funding: AstraZeneca, Celgene, Corcept. Therapeutics, Genentech/Roche, Immunomedics, Merck, Odonate Therapeutics, Pfizer, Seattle Genetics, Gulley: National Cancer Institutes has several Cooperative Research and Development Agreements (CRADAs) with various biotech and pharma agencies involved in immunotherapy. Kalinsky: Consulting: Biotheranostics, Eli-Lilly, Pfizer, Amgen, Novartis, Eisai, AstraZeneca, Odonate Therapeutics, Ipsen, Genentech. Speakers’ bureau: Eli-Lilly. Institutional support: Incyte, Genentech, Eli-Lilly, Pfizer, Calithera Biosciences, Acetylon, Seattle Genetics, Amgen, Zeno Pharmaceuticals, CytomX Therapeutics. Spouse: employment at Array Biopharma Vendor-sponsored travel: Eli-Lilly, Novartis, Genentech, Ipsen and Amgen. Abdul Sater: No COI or disclosures. Sprano: Receives research support: Deciphera, Inc., Prescient Therapeutics; Paid consultant: Astra Zeneca, Pfizer; Pharmaceutical sponsored research: Genentech. Cescon: Honoraria (non-accredited CME) Pfizer, and Novartis. Consulting or advisory role: Pfizer, AstraZeneca, Novartis, GlaxoSmithKline, Merck, Roche/Genentech, Agendia, Puma Biotechnology and Dynamo Therapeutics. Research funding (to instituton): Merck, Roche/Genentech, GlaxoSmithKline, and Pfizer. Page: Research support: BMS, Merck, Brooklyn ImmunoTherapeutics. Speakers Bureau: Genentech, Novartis. Scientific Advisory Board: BMS, Merck, Syndax, Nektar, Puma, Nanostring. McArthur: Consulting: Merck, Spectrum Pharmaceuticals, Lilly, Amgen, Immunomedics, Pfizer, Genentech, Bristol-Myers Squibb, Genomic Health. Research Funding: Bristol-Myers Squibb, ZIOPHARM Oncology, Lilly, Merck; Travel expenses: Merck, Spectrum Pharmaceuticals, Lilly, Amgen, Puma Biotechnology, Immunomedics, Genentech, Pfizer. Expert panel: Lilly. Adams: Advisory Board: BMS, Merck, Genentech (all uncompensated), research funding to institution: Genentech, Merck, Amgen, Novartis, BMS, Celgene. Mittendorf: serves on advisory boards for Merck, SELLAS Lifesciences, AstraZeneca/MedImmune, TapImmune, and Peregrine Pharmaceuticals, and received institutional research funding from Genentech, Astra Zeneca/MedImmune, and SELLAS Lifesciences., (© The Author(s) 2019.)

Conventional APCs that express MHC class II (MHCII) and co-stimulatory molecules include dendritic cells (DCs) and macrophages. Beyond these conventional APCs, immune stimulatory cells have been more recently shown to extend to a class of atypical APCs, composed of mast cells, basophils, and eosinophils. Here, we describe a unique type of APC, Gr1 -/low CD11b -/low cells with a granularity and size characteristic of myeloid cells and with the ability to present Ag for crosspresentation. These cells constitutively express MHCII and the costimulatory molecules, CD80, CD86, and CD40. They do not express pan markers of myeloid DCs (CD11c), plasmacytoid DCs (Ly6C), or macrophages (F4/80), and their frequency is inversely correlated with myeloid-derived suppressor cells (MDSCs) in tumor-bearing mice. Among splenocytes, they are more abundant than DCs and macrophages, and they exhibit antitumor immune stimulatory function at a steady state without further activation, ex vivo. They are also found within the tumor bed where they retain their immune stimulatory function. Our findings suggest the use of these novel APCs in additional preclinical studies to further investigate their utility in APC-based cancer immunotherapies., (©2018 Society for Leukocyte Biology.)

Introduction: Prior to expansion of Medicaid under the Affordable Care Act, some states obtained Section 1115 waivers from the federal government that allowed them to expand eligibility for Medicaid to adult populations that were not covered previously. Expansion waivers in these states differed in their generosity and year of implementation, creating variation in coverage availability and program longevity across states. This study examined the association between generosity and duration of Medicaid expansion waivers and access to preventive services., Methods: The 2012 Medical Expenditure Panel Survey data were used to estimate adjusted logistic models in 2016, comparing outcomes among low-income non-elderly adults living in generous (Medicaid eligibility threshold ≥138% federal poverty level) and moderate (Medicaid eligibility threshold <138% federal poverty level) waiver states, relative to no-waiver states., Results: Moderate and generous waivers were associated with statistically significant (p<0.001) increases in probabilities of having a usual source of care and a blood pressure check, relative to states without a waiver to expand. Low-income individuals living in states with longer waiver durations had better access to healthcare services than a similar group living in comparison states., Conclusions: Not only is Medicaid waiver generosity associated with improving access to healthcare services, but the combination of generosity and longer duration of a waiver also intensifies the association. As states gain flexibility in designing their Medicaid programs, the healthcare benefits associated with both generosity and duration of waivers are important considerations for policy makers., (Copyright © 2018 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Neoadjuvant chemotherapy (NAC) for breast cancer is widely utilized, and we performed genome-wide association studies (GWAS) to determine whether germ-line genetic variability was associated with benefit in terms of pathological complete response (pCR), disease-free survival, and overall survival in patients entered on the NSABP B-40 NAC trial, wherein patients were randomized to receive, or not, bevacizumab in addition to chemotherapy. Patient DNA samples were genotyped with the Illumina OmniExpress BeadChip. Replication was attempted with genotyping data from 1398 HER2-negative patients entered on the GeparQuinto NAC study in which patients were also randomized to receive, or not, bevacizumab in addition to chemotherapy. A total of 920 women from B-40 were analyzed, and 237 patients achieved a pCR. GWAS with three phenotypes (pCR, disease-free survival, overall survival) revealed no single nucleotide polymorphisms (SNPs) that were genome-wide significant (i.e. P≤5E-08) signals; P values for top SNPs were 2.04E-07, 5.61E-08, and 5.63E-08, respectively, and these SNPs were not significant in the GeparQuinto data. An ad-hoc GWAS was performed in the patients randomized to bevacizumab (457 patients with 128 pCR) who showed signals on chromosome 6, located within a gene, CDKAL1, that approached, but did not reach, genome-wide significance (top SNP rs7453577, P=2.97E-07). However, this finding was significant when tested in the GeparQuinto data set (P=0.04). In conclusion, we identified no SNPs significantly associated with NAC. The observation, in a hypothesis-generating GWAS, of an SNP in CDKAL1 associated with pCR in the bevacizumab arm of both B-40 and GeparQuinto requires further validation and study.

Papillary lesions of the breast range from benign to atypical to malignant. Although papillomas without frank cancer are benign, their management remains controversial. When a core needle biopsy of a lesion yields a diagnosis of intraductal papilloma with atypia, excision is generally recommended to rule out a concurrent malignant neoplasm. For intraductal papillomas without atypia, however, recommendations for excision versus observation are variable. The aims of this study are to evaluate the rate of concurrent malignancies for intraductal papilloma diagnosed on core needle biopsy and to assess the long-term risk of developing cancer after the diagnosis of a papillary lesion. This single institution retrospective study analyzed 259 patients that were diagnosed with intraductal papilloma (IDP) by core needle biopsy from 1995 to 2010. Patients were grouped by initial diagnosis into three groups (papilloma without atypia, papilloma with atypia, and papilloma with atypical duct hyperplasia or atypical lobular hyperplasia (ADH/ALH) and followed up for long-term outcomes. After a core needle biopsy showing IDP with atypia or IDP + ADH/ALH, surgical excision yielded a diagnosis of concomitant invasive or ductal in situ cancer in greater that 30% of cases. For intraductal papilloma without atypia, the likelihood of cancer was much lower. Moreover, even with excision, the finding of intraductal papilloma with atypia carries a significant risk of developing cancer long-term, and such patients should be followed carefully and perhaps should be considered for chemoprevention., (© 2017 Wiley Periodicals, Inc.)

Breast cancer patients who initially respond to cancer therapies often succumb to distant recurrence of the disease. It is not clear why people with the same type of breast cancer respond to treatments differently; some escape from dormancy and relapse earlier than others. In addition, some tumor clones respond to immunotherapy while others do not. We investigated how autophagy plays a role in accelerating or delaying recurrence of neu-overexpressing mouse mammary carcinoma (MMC) following adriamycin (ADR) treatment, and in affecting response to immunotherapy. We explored two strategies: 1) transient blockade of autophagy with chloroquine (CQ), which blocks fusion of autophagosomes and lysosomes during ADR treatment, and 2) permanent inhibition of autophagy by a stable knockdown of ATG5 (ATG5 KD ), which inhibits the formation of autophagosomes in MMC during and after ADR treatment. We found that while CQ prolonged tumor dormancy, but that stable knockdown of autophagy resulted in early escape from dormancy and recurrence. Interestingly, ATG5 KD MMC contained an increased frequency of ADR-induced polyploid-like cells and rendered MMC resistant to immunotherapy. On the other hand, a transient blockade of autophagy did not affect the sensitivity of MMC to immunotherapy. Our observations suggest that while chemotherapy-induced autophagy may facilitate tumor relapse, cell-intrinsic autophagy delays tumor relapse, in part, by inhibiting the formation of polyploid-like tumor dormancy., Competing Interests: CONFLICTS OF INTEREST Authors have no potential conflicts of interest to disclose.

Background: States routinely may consider rollbacks of Medicaid expansions to address statewide economic conditions. To the authors' knowledge, little is known regarding the effects of public insurance contractions on health outcomes. The current study examined the effects of the 2005 Medicaid disenrollment in Tennessee on breast cancer stage at the time of diagnosis and delays in treatment among nonelderly women., Methods: The authors used Tennessee Cancer Registry data from 2002 through 2008 and estimated a difference-in-difference model comparing women diagnosed with breast cancer who lived in low-income zip codes (and therefore were more likely to be subject to disenrollment) with a similar group of women who lived in high-income zip codes before and after the 2005 Medicaid disenrollment. The study outcomes were changes in stage of disease at the time of diagnosis and delays in treatment of >60 days and >90 days., Results: Overall, nonelderly women in Tennessee were diagnosed at later stages of disease and experienced more delays in treatment in the period after disenrollment. Disenrollment was found to be associated with a 3.3-percentage point increase in late stage of disease at the time of diagnosis (P = .024), a 1.9-percentage point decrease in having a delay of >60 days in surgery (P = .024), and a 1.4-percentage point decrease in having a delay of >90 days in treatment (P = .054) for women living in low-income zip codes compared with women residing in high-income zip codes., Conclusions: The results of the current study indicate that Medicaid disenrollment is associated with a later stage of disease at the time of breast cancer diagnosis, thereby providing evidence of the potential negative health impacts of Medicaid contractions. Cancer 2017;123:3312-9. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: NRG Oncology/NSABP trial B-40 tested the impact of adding bevacizumab (bev) to neoadjuvant chemotherapy for operable breast cancer. Secondary endpoints included rates of surgical complications after surgery in patients who did or did not receive bev., Methods: A total of 1206 women with HER2-negative operable breast cancer were randomly assigned to receive one of three different docetaxel-plus-anthracycline-based regimens, without or with bev (15 mg/kg every 3 weeks) for the first 6 of 8 cycles and for 10 doses postoperatively. Surgical complications were assessed from date of surgery through 24 months following study entry., Results: Early surgical complications were significantly more frequent in the bev group (25.4 vs. 18.9%; trend test p = 0.008), but most were grade 1-2. Early noninfectious wound dehiscences were infrequent and not significantly different (5.4 vs. 3.1%; trend test p = 0.15). Long-term noninfectious wound complications were significantly higher for patients receiving bev (11.8 vs. 5.1%; trend test p = 0.0007), but the incidence of grade ≥3 wound dehiscence was low in both groups (<1%). Among 193 patients undergoing expander or implant reconstructions, 19 (19.6%) of 97 in the bev-receiving group versus 10 (10.4%) of 96 in the non-bev group had grade ≥3 complications (Pearson, p = 0.11)., Conclusions: Overall, adding bev increased surgical complications, but most serious complications were not significantly increased. In particular, the need for surgical intervention in patients undergoing breast reconstruction with prosthetic implants was higher with bev but was not statistically significantly different. With precautions, bev can be used safely perioperatively in patients undergoing surgery for breast cancer.

Objective: We hypothesized that the Oncotype Dx ® 21-gene Recurrence Score (RS) could guide neoadjuvant systemic therapy (NST) to facilitate breast conserving surgery (BCS) for hormone receptor positive (HR+) breast cancers., Methods: This study enrolled patients with HR+, HER2-negative, invasive breast cancers not suitable for BCS (size ≥ 2 cm). Core needle biopsy blocks were tested. For tumors with RS < 11, patients received hormonal therapy (NHT); patients with RS > 25 tumors received chemotherapy (NCT); patients with RS 11-25 were randomized to NHT or NCT. Primary endpoint was whether 1/3 or more of randomized patients refused assigned treatment., Results: Sixty-four patients were enrolled. Of 33 patients with RS 11-25, 5 (15%) refused assignment to NCT. This was significantly lower than the 33% target (binomial test, P = 0.0292). Results for clinical outcomes (according to treatment received for 55 subjects) included successful BCS for 75% of tumors with RS < 11 receiving NHT, 72% for RS 11-25 receiving NHT, 64% for RS 11-25 receiving NCT, and 57% for RS > 25 receiving NCT., Conclusions: Using the RS to guide NST is feasible. These results suggest that for patients with RS < 25 NHT is a potentially effective strategy., (© 2017 Wiley Periodicals, Inc.)

Purpose: Angiogenesis is one of the hallmarks of cancer and is essential for cancer progression and metastasis. However, clinical trials with vascular endothelial growth factor (VEGF) pathway inhibitors have failed to show overall survival benefit in breast cancer. Targeted therapy against the angiopoietin pathway, a downstream angiogenesis cascade, could be effective in breast cancer. This study investigates the association of angiopoietin pathway gene expression with breast cancer survival using a "big data" approach employing RNA sequencing data from The Cancer Genome Atlas (TCGA)., Methods: A total of 888 patients with adequate gene expression, disease-free survival (DFS), and overall survival (OS) data were selected for analysis. DFS and OS were calculated for patients with high and low expression of angiopoietin and VEGF pathway genes using TCGA data. Gene-specific thresholds to dichotomize patients into high and low expression were determined and survival plots were generated., Results: The TCGA cohort was representative of national breast cancer patients with respect to stage, pathology, and survival. High Ang2 gene expression was associated with not only decreased DFS (p = 0.05), but also decreased OS (p < 0.05). High co-expression of Ang2 and its receptor Tie2 was associated with both decreased DFS and OS (p < 0.05). There was strong correlation between angiopoietin and VEGF pathway genes. While high expression of VEGFA alone was not associated with survival, high co-expression with Ang2 was associated with decreased OS., Conclusions: This study validates TCGA as a representative database providing genomic data and survival outcomes in breast cancer. Our TCGA data support the angiopoietin pathway as a key mediator in the pathologic angiogenic switch in breast cancer.

We previously demonstrated that culturing antigen-sensitized draining lymph node (DLN) lymphocytes from BALB/c mice in interleukin (IL)-7/15 after activation with bryostatin/ionomycin (B/I) is superior to culture in IL-2 for expansion, differentiation to cluster of differentiation (CD)8+ cells and anti-tumor activity. We sought to determine whether the substitution or addition of IL-21 to culture had a similar effect. DLN lymphocytes were antigen-sensitized with 4T1 mammary carcinoma 10 days prior to harvest, activated with B/I, and expanded in culture for 7 days with either IL-2, IL-21, IL-2/21, IL-7/15, or IL-7/15/21. Cellular expansion, phenotype, interferon (IFN)-γ responses, and in vivo anti-tumor activity were compared. We found that T cells grown in IL7/15/21 demonstrated significantly greater lymphocyte expansion than IL-2, IL-21, IL-2/21, and IL-7/15 (38.4-fold vs. 5.5, 6.6, 9.5, and 23.9-fold, respectively). Of these expanded cells, IL-7/15/21 significantly expanded the greatest percentage of CD8+ cells (67.1% vs. 22.2%, 47.2%, 47.4%, and 55.3%, respectively), and the greatest number of T central memory cells (T CM ) compared to IL-2, IL-21 and IL-2/21 (45.8% vs. 11.1%, 7.7%, and 12.1%, respectively). IL-21 and IL-2/21-expanded T cells preferentially differentiated into T naïve cells (T N ) vs. those expanded in IL-2, IL-7/15 and IL-7/15/21 (27.6% and 23.2% vs. 1.7%, 4.5%, and 10.4%, respectively), and demonstrated the highest IFN-γ levels in vitro. In vivo adoptive immunotherapy (AIT) experiments demonstrated anti-tumor efficacy was equally effective using IL-2, IL-21, IL-2/21, IL-7/15 and IL-7/15/21-cultured lymphocytes vs. control or cyclophosphamide alone, even at lower doses or with greater initial size of tumor prior to treatment.

Adoptive T cell immunotherapy is a promising approach to cancer treatment that currently has limited clinical applications. DNA methyltransferase inhibitors (DNAMTi) have known potential to affect the immune system through multiple mechanisms that could enhance the cytotoxic T cell responses, including: upregulation of tumor antigen expression, increased MHC class I expression, and blunting of myeloid derived suppressor cells (MDSCs) expansion. In this study, we have investigated the effect of combining the DNAMTi, decitabine, with adoptive T cell immunotherapy in the murine 4T1 mammary carcinoma model. We found that expression of neu, MHC class I molecules, and several murine cancer testis antigens (CTA) was increased by decitabine treatment of 4T1 cells in vitro. Decitabine also increased expression of multiple CTA in two human breast cancer cell lines. Decitabine-treated 4T1 cells stimulated greater IFN-gamma release from tumor-sensitized lymphocytes, implying increased immunogenicity. Expansion of CD11b + Gr1 + MDSC in 4T1 tumor-bearing mice was significantly diminished by decitabine treatment. Decitabine treatment improved the efficacy of adoptive T cell immunotherapy in mice with established 4T1 tumors, with greater inhibition of tumor growth and an increased cure rate. Decitabine may have a role in combination with existing and emerging immunotherapies for breast cancer.

Two major barriers to cancer immunotherapy include tumor-induced immune suppression mediated by myeloid-derived suppressor cells and poor immunogenicity of the tumor-expressing self-antigens. To overcome these barriers, we reprogrammed tumor-immune cell cross-talk by combined use of decitabine and adoptive immunotherapy, containing tumor-sensitized T cells and CD25(+) NKT cells. Decitabine functioned to induce the expression of highly immunogenic cancer testis antigens in the tumor, while also reducing the frequency of myeloid-derived suppressor cells and the presence of CD25(+) NKT cells rendered T cells, resistant to remaining myeloid-derived suppressor cells. This combinatorial therapy significantly prolonged survival of animals bearing metastatic tumor cells. Adoptive immunotherapy also induced tumor immunoediting, resulting in tumor escape and associated disease-related mortality. To identify a tumor target that is incapable of escape from the immune response, we used dormant tumor cells. We used Adriamycin chemotherapy or radiation therapy, which simultaneously induce tumor cell death and tumor dormancy. Resultant dormant cells became refractory to additional doses of Adriamycin or radiation therapy, but they remained sensitive to tumor-reactive immune cells. Importantly, we discovered that dormant tumor cells contained indolent cells that expressed low levels of Ki67 and quiescent cells that were Ki67 negative. Whereas the former were prone to tumor immunoediting and escape, the latter did not demonstrate immunoediting. Our results suggest that immunotherapy could be highly effective against quiescent dormant tumor cells. The challenge is to develop combinatorial therapies that could establish a quiescent type of tumor dormancy, which would be the best target for immunotherapy., (© The Author(s).)

Background: Interest in immunotherapy for breast cancer is rapidly emerging, and applicable animal models that mimic human cancer are urgently needed for preclinical studies. This study aimed to improve a technique for orthotopic inoculation of syngeneic breast cancer cells to be used as a preclinical animal model for immunotherapy., Materials and Methods: We used our previously reported murine model of orthotopic cancer cell inoculation under direct vision and compared the efficiency of tumorigenesis with tumor cells suspended in either phosphate-buffered saline or Matrigel containing varying numbers of cells. As a model for immune rejection, murine BALB/c-derived 4T1-luc2 breast cancer cells were inoculated orthotopically into both BALB/c and C57BL/6 mice., Results: Matrigel-suspended cells formed larger tumors with higher efficiency than phosphate-buffered saline-suspended cells. The maximum volume of Matrigel that could be inoculated without spillage was 20 μL and 30 μL in the #2 and #4 mammary fat pads, respectively. Tumor take rates increased as the injected cell number increased. In this immune rejection model, there were no significant differences in tumor weight between the strains up to day 7, after which tumor weight decreased in C57BL/6 mice. Bioluminescence in C57BL/6 mice was also significantly less than that in BALB/c mice and increased up to day 7, then swiftly decreased thereafter., Conclusions: This improved technique of innoculating murine breast cancer cells using bioluminescence technology may be useful in evaluating the efficacy of tumor regression mediated by immune responses, as shown by an allogeneic response in C57BL/6 mice., Competing Interests: There are no potential conflicts of interest to disclose., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Medicaid expansion under the Affordable Care Act facilitates access to care among vulnerable populations, but 21 states have not yet expanded the program. Medicaid expansions may provide increased access to care for cancer survivors, a growing population with chronic conditions. We compare access to health care services among cancer survivors living in non-expansion states to those living in expansion states, prior to Medicaid expansion under the Affordable Care Act., Methods: We use the 2012 and 2013 Behavioral Risk Factor Surveillance System to estimate multiple logistic regression models to compare inability to see a doctor because of cost, having a personal doctor, and receiving an annual checkup in the past year between cancer survivors who lived in non-expansion states and survivors who lived in expansion states., Results: Cancer survivors in non-expansion states had statistically significantly lower odds of having a personal doctor (adjusted odds ratio [AOR] 0.76, 95 % confidence interval [CI] 0.63-0.92, p < 0.05) and higher odds of being unable to see a doctor because of cost (AOR 1.14, 95 % CI 0.98-1.31, p < 0.10). Statistically significant differences were not found for annual checkups., Conclusions: Prior to the passage of the Affordable Care Act, cancer survivors living in expansion states had better access to care than survivors living in non-expansion states. Failure to expand Medicaid could potentially leave many cancer survivors with limited access to routine care., Implications for Cancer Survivors: Existing disparities in access to care are likely to widen between cancer survivors in Medicaid non-expansion and expansion states.

Unlabelled: Our objective was to determine whether early change in standardized uptake values (SUVs) of 3'deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) using PET with CT could predict pathologic complete response (pCR) of primary breast cancer to neoadjuvant chemotherapy (NAC). The key secondary objective was to correlate SUV with the proliferation marker Ki-67 at baseline and after NAC., Methods: This prospective, multicenter phase II study did not specify the therapeutic regimen, thus, NAC varied among centers. All evaluable patients underwent (18)F-FLT PET/CT at baseline (FLT1) and after 1 cycle of NAC (FLT2); 43 patients were imaged at FLT1, FLT2, and after NAC completion (FLT3). The percentage change in maximum SUV (%ΔSUVmax) between FLT1 and FLT2 and FLT3 was calculated for the primary tumors. The predictive value of ΔSUVmax for pCR was determined using receiver-operating-characteristic curve analysis. The correlation between SUVmax and Ki-67 was also assessed., Results: Fifty-one of 90 recruited patients (median age, 54 y; stage IIA-IIIC) met the eligibility criteria for the primary objective analysis, with an additional 22 patients totaling 73 patients for secondary analyses. A pCR in the primary breast cancer was achieved in 9 of 51 patients. NAC resulted in a significant reduction in %SUVmax (mean Δ, 39%; 95% confidence interval, 31-46). There was a marginal difference in %ΔSUVmax&#95;FLT1-FLT2 between pCR and no-pCR patient groups (Wilcoxon 1-sided P = 0.050). The area under the curve for ΔSUVmax in the prediction of pCR was 0.68 (90% confidence interval, 0.50-0.83; Delong 1-sided P = 0.05), with slightly better predictive value for percentage mean SUV (P = 0.02) and similar prediction for peak SUV (P = 0.04). There was a weak correlation with pretherapy SUVmax and Ki-67 (r = 0.29, P = 0.04), but the correlation between SUVmax and Ki-67 after completion of NAC was stronger (r = 0.68, P < 0.0001)., Conclusion: (18)F-FLT PET imaging of breast cancer after 1 cycle of NAC weakly predicted pCR in the setting of variable NAC regimens. Posttherapy (18)F-FLT uptake correlated with Ki-67 on surgical specimens. These results suggest some efficacy of (18)F-FLT as an indicator of early therapeutic response of breast cancer to NAC and support future multicenter studies to test (18)F-FLT PET in a more uniformly treated patient population., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: NSABP B-40 was a 3 × 2 factorial trial testing whether adding capecitabine or gemcitabine to docetaxel followed by doxorubicin plus cyclophosphamide neoadjuvant chemotherapy would improve outcomes in women with operable, HER2-negative breast cancer and whether adding neoadjuvant plus adjuvant bevacizumab to neoadjuvant chemotherapy regimens would also improve outcomes. As reported previously, addition of neoadjuvant bevacizumab increased the proportion of patients achieving a pathological complete response, which was the primary endpoint. We present secondary patient outcomes, including disease-free survival, a specified endpoint by protocol, and data for distant recurrence-free interval, and overall survival, which were not prespecified endpoints but were collected prospectively., Methods: In this randomised controlled trial (NSABP B-40), we enrolled women aged 18 years or older, with operable, HER2-non-amplified invasive adenocarcinoma of the breast, 2 cm or greater in diameter by palpation, clinical stage T1c-3, cN0, cN1, or cN2a, without metastatic disease and diagnosed by core needle biopsy. Patients received one of three docetaxel-based neoadjuvant regimens for four cycles: docetaxel alone (100 mg/m(2)) with addition of capecitabine (825 mg/m(2) oral twice daily days 1-14, 75 mg/m(2) docetaxel) or with addition of gemcitabine (1000 mg/m(2) days 1 and 8 intravenously, 75 mg/m(2) docetaxel), all followed by neoadjuvant doxorubicin and cyclophosphamide (60 mg/m(2) and 600 mg/m(2) intravenously) every 3 weeks for four cycles. Those randomly assigned to bevacizumab groups were to receive bevacizumab (15 mg/kg, every 3 weeks for six cycles) with neoadjuvant chemotherapy and postoperatively for ten doses. Randomisation was done (1:1:1:1:1:1) via a biased-coin minimisation procedure to balance the characteristics with respect to clinical nodal status, clinical tumour size, hormone receptor status, and age. Intent-to-treat analyses were done for disease-free survival and overall survival. This study is registered with ClinicalTrials.gov, number NCT00408408., Findings: Between Jan 5, 2007, and June 30, 2010, 1206 patients were enrolled in the study. Follow-up data were collected from Oct 31, 2007 to March 27, 2014, and were available for overall survival in 1186 patients, disease-free survival in 1184, and distant recurrence-free interval in 1181. Neither capecitabine nor gemcitabine increased disease-free survival or overall survival. Median follow-up was 4·7 years (IQR 4·0-5·2). The addition of bevacizumab significantly increased overall survival (hazard ratio 0·65 [95% CI 0·49-0·88]; p=0·004) but did not significantly increase disease-free survival (0·80 [0·63-1·01]; p=0·06). Four deaths occurred on treatment due to vascular disorder (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), sudden death (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), infective endocarditis (docetaxel plus bevacizumab followed by doxorubicin plus cyclophosphamide and bevacizumab group), and visceral arterial ischaemia (docetaxel followed by doxorubicin plus cyclophosphamide group). The most common grade 3-4 adverse events in the bevacizumab group were neutropenia (grade 3, 99 [17%]; grade 4, 37 [6%]), hand-foot syndrome (grade 3, 63 [11%]), and hypertension (grade 3, 60 [10%]; grade 4, two [<1%]) and in the non-bevacizumab group were neutropenia (grade 3, 98 [16%]; grade 4, 36 [6%]), fatigue (grade 3, 53 [9%]), and hand-foot syndrome (grade 3, 43 [7%])., Interpretation: The addition of gemcitabine or capecitabine to neoadjuvant docetaxel plus doxorubicin plus cyclophosphamide does not seem to provide any benefit to patients with operable breast cancer, and should not change clinical practice in the short term. The improved overall survival with bevacizumab contradicts the findings of other studies of bevacizumab in breast cancer and may indicate the need for additional investigation of this agent., Funding: National Institutes of Health, Genentech, Roche Laboratories, Lilly Research Laboratories, and Precision Therapeutics., (Copyright © 2015 Elsevier Ltd. All rights reserved.)