Further Optimizing Care of Patients With Operable Hormone Receptor-Sensitive Breast Cancer.

Background: In node negative and 1-3 positive nodes breast cancer patients with hormone receptor positive (HR+), HER2-negative (HER2-) early-stage breast cancer the indication for chemotherapy is based on clinical and pathologic risk stratification (tumor size, nodal status, grading, quantitative ER, progesterone receptor and Ki67). For further decision-making, the EndoPredict test, which combines a molecular signature with the clinical risk factors tumor size and nodal status, stratifies patients into “low risk" or “high risk” groups. Level I-B- evidence demonstrates, that EndoPredict predicts the 10 year cumulative risk of relapse and metastases in patients with HR+/HER2- primary breast cancer with endocrine treatment. Aim: In the RESCUE-Trial we document distant metastasis-free survival (DMFS), disease free survival (DFS) and overall survival (OS) events in patients who had an EndoPredict test. The primary objective is to show that 10-year DMFS of patients tested as “low risk” by EndoPredict and treated with adjuvant endocrine therapy alone is >90 %. Secondary endpoints among others include DMFS, DFS, OS in patients with EPclin “low risk” versus “high risk”. Also the proportion of patients whose treatment was concordant and non-concordant with EndoPredict test results, will be analyzed for survival. The prognostic performance of classical prognostic factors (like tumor size, nodal status, grading, quantitative ER, progesterone receptor and Ki67 level) with respect to survival will also be assessed. Eligibility: Patient with HR+/HER2- primary invasive breast cancer stage I/II and T1 to T3 with 0 to 3 positive lymph nodes will be eligible, if they had an EndoPredict test within three months before inclusion. Methods: The EndoPredict test results, tumor board decision and anti-tumor therapy will be assessed. After one year, annually (for 10 years), patients will be evaluated for treatment compliance, recurrence, metastases, and survival. The primary endpoint will be analyzed by a Kaplan-Meyer estimate for which a one-sided lower 95 % confidence interval will be given. Several secondary endpoints will be assessed in three interim analyses after completion of the 1st, 3rd, 5th year and then finally after 10 years. Accrual: Start of accrual is planned for July 2018. At least 26 sites in Germany and one site in Switzerland will be active. Sponsor: The study is sponsored by the North-Eastern-German Society of Gynecological Oncology (NOGGO) e.V. Contact Information: For further information, contact NOGGO via studies@noggo.de or the leading physician Dr. Johannes Ettl via johannes.ettl@tum.de. Citation Format: Ettl J, Blohmer J-U, Denkert C, Keller M, Klein E, Kronenwett R, Neuser P, Paepke S, Schade-Brittinger C, Schnuppe K, Untch M, Wittenberg M, Kiechle M. RESCUE: Reaching for Evidence-baSed Chemotherapy Use in Endocrine sensitive breast cancer - A prospective health care study on risk assessment by the clinicomolecular test EndoPredict® and long-term patient outcome in early luminal breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-12-03.

Prognostic Significance of Metabolic Tumor Volume Measured by (18)F-FDG PET/CT in Operable Primary Breast Cancer.

e11047 Background: Blood levels of tumor markers are widely used to assess response/progression to breast cancer treatment and guide therapy change in the real world setting compared to clinical trials where treatment efficacy is assessed by imaging methods. Our aim was to describe management of ER+ advanced breast cancer and reasons for treatment change in postmenopausal patients (pt) with hormone sensitive advanced breast cancer in the Czech Republic. Methods: The study was a retrospective, multi-centre, observational study that collected data from postmenopausal pt with hormone sensitive advanced breast cancer that have been treated with minimum two hormonal agents according to approved SmPC. Data collection started in February 2011in 16 centres in the Czech republic. The target number of enrolled pt was 400. Standard descriptive statistical methods were used for data analysis. Confidence intervals are reported where applicable. Results: We present an interim analysis of the study based on 169 pt enrolled till 21st July 2011. 150 pt have evaluable data. Median age was 55 years. Median time from diagnosis of BC to metastatic dissemination is 44.0 months (mean time 62.5 months). BC was diagnosed in Stage I in 12.0%, Stage II 43.3%, Stage III 24.0% and Stage IV 20.7%. Rebiopsy was done in 27.0% of pt who developed metastases (M). 63,5% pt were diagnosed with bone M, 45,3% with lymph node and soft tissue M, 22,3% with lung M, only 9,5% with liver M. 65% pt were treated with hormonotherapy in the first line and 84,2% in the second line. The main reason for hormonotherapy change was the progression according to examination (63%), elevation of tumor markers (13%), progression of symptoms (8%) intolerance of the treatment (3%) and other reasons (13%). Conclusions: Pt treated in the first line with hormonotherapy in daily practice in the Czech Republic are mostly pt without organ M. Pt with organ M are treated first with chemotherapy. Increase of tumor markers is the reason for treatment change in 13% of pt, progression of symptoms in 8%.

Tumor-associated macrophages (TAMs) and abnormalities in cancer cells affect cancer progression and response to therapy. TAMs are a major component of the tumor microenvironment (TME) in breast cancer, with their invasion affecting clinical outcomes. Programmed death-ligand 1 (PD-L1), a target of immune checkpoint inhibitors, acts as a suppressive signal for the surrounding immune system; however, its expression and effect on TAMs and the clinical outcome in breast cancer are unknown. In this study, we used high-throughput multiple immunohistochemistry to spatially and quantitatively analyze TAMs. We subjected 81 breast cancer specimens to immunostaining for CD68, CD163, PD-1, PD-L1, CD20, and pan-CK. In both stromal and intratumoral areas, the triple-negative subtype had significantly more CD68/CD163, CD68/PD-L1, and CD163/PD-L1 double-positive cells than the estrogen receptor (ER)/progesterone receptor (PR) subtype. Interestingly, a higher number of CD68+/PD-L1+/CK-/CD163- TAMs in the intratumoral area was correlated with a favorable recurrence rate (p = 0.048). These findings indicated that the specific subpopulation and localization of TAMs in the TME affect clinical outcomes in breast cancer.

Additional age-related issues should be considered when managing breast cancer in young women.1 Among them, the potential consequences of anticancer treatments on ovarian function and fertility potential are of particular concern and need to be addressed as early as possible after diagnosis.2,3 Therefore, current guidelines strongly voice the need to provide proper oncofertility counseling with all patients of reproductive age with newly diagnosed cancer irrespective of its stage.2,3 This is a crucial step to discuss with all young women their disease and prognosis, the required treatments including their potential gonadotoxicity, the need for contraception during and after active systemic therapies, their future desire of conception, likelihood of pregnancy, its safety and outcomes as well as the available strategies to avoid the negative impact of the proposed treatment on ovarian function and fertility.

Need to Improve Communication in Breast Cancer Care

BackgroundDifferences in the incidence and outcome of breast cancer among Hispanic women compared with white women are well documented and are likely explained by ethnic differences in genetic composition, lifestyle, or environmental exposures.Methodolgy/Principal FindingsA population-based study was conducted in Galicia, Spain. A total of 510 women diagnosed with operable invasive breast cancer between 1997 and 2010 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics were collected. The different breast cancer tumor subtypes were compared on their clinico-pathological characteristics and risk factor profiles, particularly reproductive variables and breastfeeding. Among the 501 breast cancer patients (with known ER and PR receptors), 85% were ER+/PR+ and 15% were ER-&PR-. Among the 405 breast cancer with known ER, PR and HER2 status, 71% were ER+/PR+/HER2- (luminal A), 14% were ER+/PR+/HER2+ (luminal B), 10% were ER−/PR−/HER2- (triple negative breast cancer, TNBC), and 5% were ER−/PR−/HER2+ (non-luminal). A lifetime breastfeeding period equal to or longer than 7 months was less frequent in case patients with TNBC (OR = 0.25, 95% CI = 0.08–0.68) compared to luminal A breast cancers. Both a low (2 or fewer pregnancies) and a high (3–4 pregnancies) number of pregnancies combined with a long breastfeeding period were associated with reduced odds of TNBC compared with luminal A breast cancer, although the association seemed to be slightly more pronounced among women with a low number of pregnancies (OR = 0.09, 95% CI = 0.005–0.54).Conclusions/SignificanceIn case-case analyses with the luminal A cases as the reference group, we observed a lower proportion of TNBC among women who breastfed 7 or more months. The combination of longer breastfeeding duration and lower parity seemed to further reduce the odds of having a TNBC compared to a luminal A breast cancer.

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Background: Breast cancer is one of the most common diseases, second only to lung cancer as the leading cause of cancer death in women. In particular hormone sensitive metastatic breast cancer (MBC) and triple-negative breast cancer (TNBC) remains a therapeutic challenge as resistance develops in almost all patients. Despite aggressive treatment strategies, survival is poor due to the development of resistance, prompting the need for novel approaches. Here, we characterize the molecular mechanisms underlying epigenetic modifiers and in particular histone deacetylase inhibitors (HDACi) as priming modulators of immunotherapy, with a specific focus on TNBC and hormone resistant breast cancers. HDACi represent a new class of anticancer agents that can reverse hormone therapy resistance, resulting in prolonged anti-tumor responses in patients. In addition to their effects on estrogen receptor (ER) signaling, HDACi can also influence immune cell function, including but not limited to modulation of Foxp3+ regulatory T-cells (Tregs), tumor-infiltrating lymphocyte (TILs) composition, as well as induction of the co-inhibitory receptors PD-L1 and PD-1. Under normal conditions the PD-1/PD-L1 pathway down-regulates cytotoxic T-cell activity to maintain immune homeostasis. Cancer cells exploit this pathway in the tumor microenvironment to suppress cytotoxic T-cell activation, significantly diminishing the anti-tumor immune response. In breast cancer, PD-L1 expression is less frequent and mainly found in TNBC, HER2+, ER- and PR- tumors. Increased PD-L1 expression correlates with increased TILs and these criteria together are indicative of improved response rates in breast cancer patients. The PD-1/PD-L1 pathway represents one of the primary immunosuppressive drivers in multiple types of cancer. Thus, inhibiting PD-1/PD-L1 interactions may prevent T-cell suppression and reactivate immunosurveillance mechanisms necessary for tumor cell eradication. Methods and Results: Evaluation of basal PD-L1 expression in a range of human and mouse breast cancer cell lines by western blotting and real-time PCR identified TNBC and HER2+ cells as the highest expressing cells. Testing different epigenetic modifiers, we found that HDACi were able to up-regulate PD-L1 mRNA and protein in a time-dependent manner up to 72 hours. This was a direct transcriptional effect induced by HDACi and was confirmed even in tamoxifen resistant breast cancer cells, characterized by increased basal expression of PD-L1 as compared to the parental cells. To define the role of epigenetic priming in promoting immune cell activation, we co-cultured tumor cells and human peripheral blood mononuclear cell (PBMCs) and performed comprehensive immunophenotyping by flow cytometry. HDACi were able to up-regulate PD-L1 on tumor cells independent of PBMCs, while exhibiting a selective decrease in the frequency of immunosuppressive Tregs. Conclusion: Our data demonstrate that the combination of HDACi with immune checkpoint inhibitors represents a novel therapeutic anti-tumor strategy and warrants further clinical evaluation for the treatment of TNBC and hormone resistant breast cancer. Citation Format: Manuela Terranova Barberio, Scott Thomas, Niwa H. Ali, Jeenah Park, Michael D. Rosenblum, Alfredo Budillon, Pamela N. Munster. HDAC inhibitors modulate immune checkpoint blockade in breast cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B111.

Introduction: Breast cancer (BC) is the most common cancer in women worldwide and leading cause of cancer death. More than 70% of cancers are estrogen receptor alpha (ERα) positive. Despite effective therapeutic strategies for treating hormone receptor-positive (HR+) breast cancer, resistance to endocrine therapy that is either de novo or acquired still occurs. Understanding the molecular pathways that contribute to BC resistance will enable to develop new treatments for improving the efficacy of endocrine therapy. Studies have shown that estrogen receptor beta (ERβ) and its agonists inhibits the different types of cancers including BC. Herein, we investigated mechanism(s) for therapeutic efficacies of ERβ agonists in breast cancer. Methods: To investigate the mechanisms of ERβ agonists (S-Equol and LY500307), in the treatment of breast cancer, we used therapy sensitive (MCF7-Aro) and letrozole resistant (MCF7-Aro-LTLT) cells and ERβ knock down cell lines, generated by CRISPR-Cas9 technology. The wild type and ERβ knock down cells with or without treatment of ERβ agonists were analyzed, for cell proliferation, protein (Western), Gene expression array analysis, RNA-seq analysis, data-independent acquisition (DIA) mass spectrometry analyses and RNA (RT-qPCR) analysis. Xenograft and patient derived BC explants (PDEX) were used to test the antiproliferative activity of ERβ agonists. Results: Our results demonstrated that treatment with ERβ agonists, S-Equol and LY500307 inhibited the growth of both endocrine therapy sensitive and resistant breast cancer cells. Gene expression array analysis of LY500307 treated breast cancer cells showed the modulation of signaling molecules involved in cell death and cell cycle pathways. RNA-seq analysis showed that treatment with S-equol modulated the ERβ target genes involved in tumor progression and resistance to hormone therapies. Mass spectrometry based DIA analysis and Reactome pathway analysis revealed that S-equol treatment modulated the key proteins involved in DNA replication and cell cycle. Both ERβ agonists S-Equol and LY500307 inhibited the cell proliferation of parental cells whereas they could not elicits the inhibitory effect on the knock out cells. By using ERα positive PDX tumors, we have demonstrated that both the ERβ agonists inhibited the proliferation of human BC tumors. Our mechanistic studies confirmed that increased FOXO3 activation by S-equol in LTLT cells can reverse letrozole resistance. Our results showed that inhibiting FOXM1 by ERβ agonists significantly reduce the proliferation of letrozole-resistant cells. These changes were not observed in ERβ knockdown cells confirming the anti-proliferative role of ERβ in breast cancer progression. Conclusions: Collectively, our results suggest that ERβ agonists may offer a new targeted therapy for endocrine therapy resistant breast tumors. (Supported by BCRP 151884/DOD grant W81XWH-16-1-0294 and P30 CA-54174 NCI-Mays cancer center grant). Citation Format: Kumaraguruparan Ramasamy, Suryavathi Viswanadhapalli, M.A. Sureshkumar, Susan Weintraub, Ratna K. Vadlamudi, Rajeshwar R. Tekmal. Estrogen receptor β agonists reverses letrozole therapy resistance of breast cancer through FOXO3 and FOXM1 mediated actions [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4365.

A positive association between obesity and the risk of incident postmenopausal breast cancer has been consistently observed in epidemiologic studies. Although most studies of premenopausal women have not found a similar relationship between breast cancer and obesity, the prognosis for both pre- and postmenopausal breast cancer is substantially worse among obese than normal-weight individuals. Increasing evidence suggests that these associations may be mechanistically related to sex hormones, insulin, and certain adipokines. Insulin, for example, has important mitogenic/antiapoptotic activity in addition to its metabolic effects, and many breast tumors express high levels of the insulin receptor (IR)-A isoform. Further, the use of metformin, a diabetes medication that reduces insulin levels, has been epidemiologically associated with reduced breast cancer risk among patients with diabetes, and a recent observational study found a higher rate of pathologic complete responses among patients with diabetes and breast cancer who were using metformin. Formal clinical trials of metformin as adjuvant breast cancer therapy have been initiated and are ongoing. Similarly, the effect of lifestyle changes on breast cancer outcomes is actively being investigated. Several lifestyle intervention studies have demonstrated that weight loss, increased physical activity, and dietary changes are feasible in breast cancer populations, and that individuals who make lifestyle changes after breast cancer diagnosis experience several physical and psychologic benefits. In this article, the authors review the evidence linking obesity with breast cancer risk and outcomes and provide an overview of lifestyle intervention studies in patients with breast cancer.

Objective:Breast cancer (BC) in non-Caucasian females is understudied and its management is based on Caucasian data. 30 % of the West Midlands females are non-Caucasian. We aimed to elucidate the pathologic features, molecular profile, and outcome of non-Caucasian breast cancer. Methods:Breast cancers (BCs) of different ethnic origins diagnosed at a large Birmingham tertiary referral hospital between 2000 and 2016 were identified. Detailed clinical and histological data were collected and statistically analyzed. Results:Out of 7554 BC cases, 749 were of ethnic ancestry and median age of 51 years. These comprised 47 in-situ and 702 invasive carcinomas of presenting symptomatically in 86.2% of patients. 53.4% of the invasive carcinomas measured >20 mm. Cancers were predominantly of grade 3 (45%), and grade 2 (42.4%). Median NPI was 4.35. 65.1% of the ethnic carcinomas were of luminal subtype, 18.6% were Her2 positive and 16.2% triple-negative. Median overall survival was 62 months. Five and ten-year survival was 81.7% & 68.4% respectively. Ethnicity correlated with higher NPI (p <0.001), larger tumour size (p= 0.001) and larger number of positive axillary nodes (p=0.007). Negative correlations were found between age at diagnosis and both invasive tumour size & grade (p< 0.001) and between tumour grade and overall survival (p= 0.006). Conclusion:Compared with Caucasian breast cancer, non-Caucasian tumours presented predominantly symptomatically at younger age, were of larger size, higher grade with more unfavorable phenotypes and shorter survival. This is important in counselling, planning management and follow up of non-Caucasian patients.

Objective In Europe and America breast cancer commonly occurs in women of middle and old age, with a median age of about 57 years. Modified radical mastectomy now called standard radical mastectomy, has taken the place of traditional radical mastectomy. Patients with breast cancer at an early stage commonly receive BCT (breast conservative therapy). The TNM stage (especially the lymph node status) affects the prognosis, and adjuvant therapy can improve survival. In China, only a few reports have been published studying large numbers of breast cancer patients. This study was designed to analyze the clinical features, surgical pattern and treatment outcome of resectable breast cancer, as well as to explore the prognostic factors and the effect of adjuvant therapy, with a goal to improve the level of diagnosis and treatment.

Aromatase inhibitors (AIs) are currently the standard treatment for estrogen receptor positive breast cancer in postmenopausal women. Unfortunately, the majority of patients treated with AIs eventually develop resistance to these drugs. The mechanism by which AI resistance occurs is still not known, however, there is strong evidence that upregulation of the PI3K/Akt/mTOR pathway might play an important role. As such, mTOR inhibition is now under study in clinical trials as a breast cancer treatment. The newest mTOR inhibitor, Everolimus (Afinitor®), has been FDA approved for the treatment of metastatic breast cancer. We have previously reported the development of two AI-resistant breast cancer cell lines (MCF-7:5C and MCF-7:2A) which were clonally derived from parental MCF-7 cells following long term estrogen deprivation. Both MCF-7:5C and MCF-7:2A cells have been shown to overexpress members of the PI3K/Akt/mTOR pathway. In this study, we examined the therapeutic benefits of everolimus in AI-resistant MCF-7:5C and MCF-7:2A cells compared to endocrine sensitive MCF-7 breast cancer cells and normal breast epithelium MCF10A cells. Results from cell viability assay showed that everolimus markedly inhibited the proliferation of endocrine sensitive MCF-7 cells and AI-resistant MCF-7:5C and MCF-7:2A cells in a time-dependent and concentration-dependent manner with IC50s of 30 nM, 40 nM and 10 nM, respectively. Notably, the MCF-7:2A cells were the most sensitive to everolimus which caused a 70% reduction in proliferation at 24 hours whereas in MCF-7 and MCF-7:5C cells only 30% inhibition was observed at the same time point. The inhibitory effect of everolimus was due primarily to G1 arrest and was associated with significant downregulation of phospho-mTOR, phospho-p70S6K, phospho-Akt, GSK3β, cyclin D1 and p21. Colony formation assay in soft agar indicated that AI-resistant MCF-7:5C and MCF-7:2A cells formed significantly more colonies than MCF-7 cells and that treatment with everolimus notably reduced the size and number of colonies for all three cell lines. Finally, we found that exposure of AI-resistant MCF-7:5C and MCF-7:2A cells to a single dose of gamma-irradiation (6 Gy) significantly enhanced the anti-proliferative effect of everolimus on these cells. In summary, these studies showed that everolimus significantly inhibited the proliferation and tumorigenicity of AI-resistant breast cancer cells and that everolimus might be an effective treatment option for patients with AI-resistant breast cancer. Citation Format: Asona Lui, Joan Lewis-Wambi. Everolimus inhibits the proliferation of aromatase inhibitor-resistant breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5488. doi:10.1158/1538-7445.AM2014-5488

Young breast cancer (BC) patients carrying a germline BRCA pathogenic variant (mBRCA) have similar outcomes as non-carriers. However, the impact of the type of gene (BRCA1 vs. BRCA2) and hormone receptor status (positive [HR+] vs. negative [HR−]) on clinical behavior and outcomes of mBRCA BC remains largely unknown. This is an international, multicenter, hospital-based, retrospective cohort study that included mBRCA patients diagnosed, between January 2000 and December 2012, with stage I–III invasive early BC at age ≤40 years. From 30 centers worldwide, 1236 young mBRCA BC patients were included. Among 808 and 428 patients with mBRCA1 or mBRCA2, 191 (23.6%) and 356 (83.2%) had HR+tumors, respectively (P < 0.001). Median follow-up was 7.9 years. Second primary BC (P = 0.009) and non-BC malignancies (P = 0.02) were more frequent among mBRCA1 patients while distant recurrences were less frequent (P = 0.02). Irrespective of hormone receptor status, mBRCA1 patients had worse disease-free survival (DFS; adjusted HR = 0.76, 95% CI = 0.60–0.96), with no difference in distant recurrence-free interval (DRFI) and overall survival (OS). Patients with HR+ disease had more frequent distant recurrences (P < 0.001) and less frequent second primary malignancies (BC: P = 0.005; non-BC: P = 0.18). No differences in DFS and OS were observed according to hormone receptor status, with a tendency for worse DRFI (adjusted HR = 1.39, 95% CI = 0.94–2.05) in patients with HR+ BC. Type of mBRCA gene and hormone receptor status strongly impact BC clinical behavior and outcomes in mBRCA young patients. These results provide important information for patients’ counseling on treatment, prevention, and surveillance strategies.