Bear, Harry D.

Abstract Background NRG Oncology 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 the 36-Item Short Form Health Survey (SF-36) vitality scale. Assessments occurred before random assignment, 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 March 21, 2005 to May 25, 2009, 975 patients enrolled in this sub-study; 950 had follow-up data. APBI had 3-year cosmesis equivalent to WBI (95% CI = -0.0001 to -0.16; equivalence margin -0.22 to -0.22) in all patients. The APBI group without chemotherapy had less EOT fatigue (P = .011; mean score APBI 63 vs WBI 59); the 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 the 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. ClinicalTrials.gov NCT00103181.

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.

Abstract Chemotherapy resistant breast cancer is a major health challenge, resulting in high relapse rates and poor survival. Neoadjuvant chemotherapy (NACT) is a standard treatment for women with high-risk TNBC, HER2+, and locally advanced ER+ breast cancer. A completed course of NACT results in two possible outcomes: pathologic complete response (pCR) or residual disease. While pCR is a reliable clinical prognostic biomarker associated with excellent outcomes and prolonged survival, especially for TNBC and HER2+ cancers, patients with residual disease have a higher risk of recurrence. Patients with residual disease can be further stratified clinically using the Residual Cancer Burden (RCB) classification; however, patients with similar RCB classes may experience dramatically different clinical outcomes. Thus, additional precision biomarkers to stratify patients with residual disease after NACT are needed to identify patients at highest risk of recurrence, and to develop new therapeutic strategies to eradicate multidrug-resistant tumors. Supported by strong evidence in developmental, evolutionary and cancer biology, we found that K-RAS-SIAH pathway activation is a major tumor driver, and SIAH represents a key tumor vulnerability in breast cancer. Normal K-RAS/SIAH signaling pathway activation is indispensable for proper cell-cell communication, cell proliferation and tissue homeostasis in multicellular organisms. However, abnormal K-RAS/SIAH pathway activation is highly prevalent in high-risk and locally advanced breast cancer, and may confer chemo-resistance to these high-risk mammary tumors. Based on its evolutionary conservation and significance as the most downstream signaling module indispensable for K-RAS signal transduction, SIAHON/OFF expression is a reliable readout of K-RAS/EGFR/HER2 pathway activation/inactivation. We showed that SIAHON/OFF expression is a binary code in residual mammary tumors that can be used to stratify patients, augment RCB classification, forecast tumor relapse, and predict patient survival after 1st line NACT in a pilot retrospective study. Multidrug-resistant high-grade breast cancer is a genetically diverse, highly heterogeneous disease that challenges our ability to individualize and optimize precision therapy. Persistent K-RAS-SIAH-EGFR pathway activation endows TNBC with therapy resistance, and increases the risk of metastasis and early relapse. As such, we developed a K-RAS/SIAH-centered biomarker discovery program and a new anti-SIAH research initiative with the intended goal of designing novel and potentially life-saving anti-K-RAS targeted strategies to control and eradicate multidrug-resistant and intractable mammary tumors. Citation Format: Amy H. Tang, Lauren L. Siewertsz van Reesema, Vasilena P. Zheleva, Janet S. Winston, Rick J. Jansen, Emanuel F. Petricoin, Matthew P. Goetz, Matthew P. Goetz, Harry D. Bear, Richard A. Hoefer. Detect early tumor relapse in high-risk breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2145.

Abstract We have previously shown T-cell–mediated rejection of the neu-overexpressing mammary carcinoma cells (MMC) in wild-type FVB mice. However, following rejection of primary tumors, a fraction of animals experienced a recurrence of a neu antigen-negative variant (ANV) of MMC (tumor evasion model) after a long latency period. In the present study, we determined that T cells derived from wild-type FVB mice can specifically recognize MMC by secreting IFN-γ and can induce apoptosis of MMC in vitro. Neu transgenic (FVBN202) mice develop spontaneous tumors and cannot reject it (tumor tolerance model). To dissect the mechanisms associated with rejection or tolerance of MMC tumors, we compared transcriptional patterns within the tumor microenvironment of MMC undergoing rejection with those that resisted it either because of tumor evasion/antigen loss recurrence (ANV tumors) or because of intrinsic tolerance mechanisms displayed by the transgenic mice. Gene profiling confirmed that immune rejection is primarily mediated through activation of IFN-stimulated genes and T-cell effector mechanisms. The tumor evasion model showed combined activation of Th1 and Th2 with a deviation toward Th2 and humoral immune responses that failed to achieve rejection likely because of lack of target antigen. Interestingly, the tumor tolerance model instead displayed immune suppression pathways through activation of regulatory mechanisms that included in particular the overexpression of interleukin-10 (IL-10), IL-10 receptor, and suppressor of cytokine signaling (SOCS)-1 and SOCS-3. These data provide a road map for the identification of novel biomarkers of immune responsiveness in clinical trials. [Cancer Res 2008;68(7):2436–46]

Purpose To review the state of the science with respect to diagnostic imaging and locoregional therapy for patients with breast cancer receiving preoperative chemotherapy. Methods Published data relevant to clinical staging, monitoring of tumor response, and locoregional therapy for patients with breast cancer treated with preoperative chemotherapy were reviewed. Results High-quality data from prospective randomized trials are limited. Available data suggest that locoregional therapy decisions should be based on both the pretreatment clinical extent of disease and the pathologic extent of the disease after chemotherapy. Accordingly, physical examination and imaging studies that accurately define the initial extent of disease are required before treatment. Sentinel lymph node biopsy can be performed either before or after preoperative chemotherapy for patients with clinical N0 disease. The success of breast conservation after preoperative chemotherapy depends on careful patient selection and achieving negative surgical margins. Adjuvant breast radiation is indicated for all patients treated with breast conservation. For patients treated with mastectomy, chest-wall and regional nodal radiation should be considered for those who present with clinical stage III disease or have histologically positive lymph nodes after preoperative chemotherapy. Additional prospective studies are needed to determine the value of postmastectomy radiation for patients with stage II breast cancer who have negative lymph nodes after chemotherapy. Conclusion The increased use of preoperative chemotherapy has raised new questions concerning the optimal methods to stage and monitor disease response to treatment and how to optimize locoregional treatment. The available evidence suggests that a multidisciplinary approach improves outcomes.