Hormone Receptor Positive BC Research Articles

Abstract PS13-07: Systemic therapy in geriatric patients with triple negative breast cancer: a National Cancer Database analysis

Abstract Background Breast cancer (BC) incidence increases with age and is the leading cause of new cancer diagnosis among women in the United States. Although the median age of diagnosis is 63 years (yrs.), over a third of patients diagnosed, and about half of BC mortality in Western societies are in patients over 70 yrs. old. Overall, outcomes for early-stage BC have improved. Despite the lower incidence of triple negative BC (TNBC) (12%-15%) the 5-year survival is 8% to 16% lower than in hormone receptor-positive BC. With the improved life expectancy in the US and the increased incidence of BC as patients age, it is of vital importance to know how to treat BC in the elderly. Unfortunately, optimal management of BC among the elderly has not been adequately studied due to underrepresentation in clinical trials. Furthermore, there is limited information of the potential toxicity and real benefit of chemotherapy in older patients. Methods This is a retrospective analysis of data collected from the National Cancer Database (NCDB), a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society, during the years 2004 to 2019. All women ≥65yrs with early stage TNBC (stages I-III) were included in the analysis. Patients were categorized into three treatment groups – those who did not receive chemotherapy (No-CT), those who received chemotherapy (CT), and those who received chemotherapy and immunotherapy (CTIO). After adjusting for multiple variables including race, insurance, Charleson-Deyo score, stage at diagnosis, and receipt of loco-regional therapy, using the log rank P value, the age cutoff over which the survival rates were not significantly different between two treatment groups (No-CT and CT/CTIO) was identified. The main outcome of this study was all-cause mortality Results A total of 11,416 women with TNBC were included in the analysis. Of these, 4105 (36.0%) received No-CT, while 7311 (64.0%) received CT/CTIO. Log rank P values showed that above 81 years, there was no survival benefit between No-CT and CT/CTIO. A further analysis categorized patients into two groups – those between 65-80yrs and those ≥81 yrs. old. Cox proportional regression analysis showed that among patients between 65-80 yrs. all-cause mortality was significantly lower among patients in the CT/CTIO group compared to those in the No-CT group (hazard ratio [HR], 0.52; CI: 0.45-0.60). However, among patients ≥81yrs old, there was no significant difference in all-cause mortality between the treatment groups (hazard ratio [HR], 0.84; CI: 0.67-1.05). Conclusions: Among patients who were >81yrs old with early-stage TNBC, those who received treatment with CT/CTIO did not have an overall survival benefit as compared to those who received No-CT. Limitations of this study includes the small number of patients >81yr old who received chemotherapy which could explain why we were not able to identify a statistically significant benefit of CT/CTIO. Another limitation is that we were not able to assess breast cancer specific mortality. However, this analysis highlights the importance of individualizing treatment recommendations in older patients, who may not garner the same benefit of treatment as younger patients. Additional studies are required to clarify contributing factors and to help optimize the management of geriatric patients with TNBC. Table 1. Patient characteristics based on treatment. Citation Format: Yolcar Chamorro, Muni Rubens, Mukesh Roy, Naomi Dempsey, Reshma Mahtani, Manmeet Ahluwalia, Lauren Carcas, Ana Sandoval-Leon. Systemic therapy in geriatric patients with triple negative breast cancer: a National Cancer Database analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS13-07.

Abstract 6440: Novel N-myristoyltransferase immunohistochemistry-based predictive and prognostic tests for breast cancer

Abstract Breast cancer (BC) is the most common cancer worldwide, surpassing lung cancer incidence for the first time in 2020, and is the most common cancer diagnosed in American women. Despite the relative success of endocrine therapies in treating hormone receptor-positive (HR+) BC, de novo and developed resistances to these therapies (endocrine resistance) are still significant concerns. Furthermore, triple-negative breast cancer has a poor prognosis and remains one of the most challenging cancers to treat. We have discovered that the expression and localization of N-myristoyltransferase 2 (NMT2) could be prognostic and predictive markers for metastatic BC. We determined the expression patterns of NMT2 by immunohistochemical (IHC) analyses on primary tumor samples from treatment naïve BC patients. This retrospective study was blinded, and the tumor tissues in duplicate were stained with NMT2 monoclonal/polyclonal antibodies on an autostainer (Leica Bond). Stained slides were scored, and an "H" score representing the intensity and percent positive cells was given to each sample. In a combined cohort of BC represented by ER+, Triple Positive, and Triple Negative (n= 598) cases, we determined the expression and localization of NMT2. The localization pattern of NMT2 turned out to be a significant prognostic and predictive molecular signature. The nuclear localization serves as both prognostic and predictive markers. In a cohort of 447 ER+ BC cases that included 18 triple positive cases, the majority of the cases showed negative staining for nuclear NMT2 (n=394) and positive nuclear staining with differential expression in 53 cases. Whereas, in a cohort of 151 TNBC cases, nuclear NMT2 staining was positive in most cases (n= 116) and negative in 20 cases (undetermined; n= 15). The most important finding was the dichotomy of the nuclear NMT2 staining in predicting treatment response and prognosis. Both high cytoplasmic H score (>180) and positive nuclear staining (>0) predicted significant association with worse clinical outcomes for OS (HR = 1.72, P = .0284, 95% CI 1.06 to 2.81 for cytoplasmic NMT2 and HR = 1.74, P = 0.0006, CI 1.27 to 2.39 for the nuclear NMT2). Nuclear NMT2 status alone predicted a significant association with worse clinical outcomes to RFS (HR = 1.56, P = 0.0027, CI 1.17 to 2.09). The data from our study indicate that NMT2 could be a potential marker for predicting the likelihood of recurrence of BC and become part of routine first-line prognostic and predictive tests. Citation Format: Anuraag Shrivastav, Dean Reddick, Abinash Meher, Shailly Varma Shrivastav, Sahil Mittal, Vijayakrishna K. Gadi, Leigh Murphy. Novel N-myristoyltransferase immunohistochemistry-based predictive and prognostic tests for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6440.

Effects of Sacituzumab on Breast Cancer: Target Therapy

Triple-negative breast cancer (TNBC) is considered one of the most aggressive forms of BC, which increases the risk of cancer-associated death. Despite the availability of specifically targeted medications for treating TNBC with HER2-positive or hormone receptor-positive cancers, chemotherapy is still the mainstay of treatment. Sacituzumab, an antibody-drug conjugate (ADC), targets tumor-associated calcium signal transducer 2 (Trop-2)-expressing cells and presents biologically active metabolites of irinotecan hydrochloride (SN-38). This review evaluates the effectiveness and safety of Sacituzumab in treating metastatic or previously treated TNBC in patients. According to the National Center for Biotechnology Information website, another epithelial metastasis has been included in data on clinical trials and sacituzumab. Sacituzumab has hopeful antitumor effects on patients with metastatic TNBC treated with at least two treatment lines, according to a clinical trial that is in phase I/II. Sacituzumab has a controllable adverse effect, with neutropenia, nausea, and diarrhea being the most frequent negative side effects. As a result of these promising early efficacy data, Sacituzumab’s activity may develop in TNBC, as well as various other epithelial tumors, such as hormone receptor-positive BC.

Abstract P3-06-01: Unleashing NK- and CD8 T cells by combining monalizumab (anti-NKG2A) and trastuzumab for metastatic HER2+ breast cancer: first results MIMOSA trial

Abstract Background Although treatment options and survival of HER2+ metastatic breast cancer (MBC) patients have greatly improved, the majority of MBC-patients still die of this disease. The relatively high levels of TILs observed in this BC subtype provide a rationale for immunomodulatory strategies, however, PD1-blockade has only shown modest response rates in this setting. While PD-1 blockade mainly acts on T cells, monalizumab targets the inhibitory immune checkpoint NKG2A which interacts with HLA-E on tumor cells, thereby unleashing NK- as well as CD8 T cells. We hypothesize that monalizumab can promote antibody-dependent cell-mediated cytotoxicity (ADCC) which is critical for trastuzumab efficacy. Clinical activity was shown in patients with head and neck cancer when monalizumab was combined with cetuximab (anti-EGFR). Here, we present the first results of the MIMOSA-trial investigating the efficacy of the novel combination monalizumab and trastuzumab in patients with HER2+ MBC. Methods In the phase II MIMOSA-trial (NTC04307329), HER2+ MBC patients were treated biweekly with 4mg/kg trastuzumab and 750mg monalizumab. Key eligibility criteria were progressive disease despite anti-HER2 therapy, had received a minimum of one and a maximum of three lines of palliative chemotherapy, had measurable disease according to RECIST1.1, and a serum LDH-level below 500U/L. Primary endpoint was objective response rate according to RECIST1.1. Secondary endpoints included clinical benefit rate (complete response CR, partial response PR or stable disease SD for at least 6 months) according to RECIST1.1, progression-free survival, overall survival and safety. Dose-limiting toxicities were continuously monitored throughout the trial and evaluated using a pre-defined Pocock-type boundary rule. Following a Simon’s two-stage design, 11 patients were included in stage I of the trial. If two or more responders were observed, further exploration is warranted in stage II. Results Between January 2021 and April 2022, eleven women of which ten are currently evaluable were enrolled in the trial. Patients received a median of two lines of prior treatment for MBC, of which 6 out of 11 patients were treated with trastuzumab emtansine (T-DM1). The majority of patients had hormone receptor positive BC (72% of the patients) and had low levels of tumor-infiltrating lymphocytes (TILs) with a median of 1% (ranging from 1% to 20%). Patients received a median of four cycles of trastuzumab and monalizumab. Treatment was well tolerated with no dose-limiting toxicities. No objective responses were observed in the first ten out of eleven evaluable patients. Therefore, MIMOSA stage I did not meet its primary endpoint, leading to discontinuation of the trial. Conclusions The novel combination of trastuzumab and monalizumab did not induce objective responses in heavily pre-treated HER2+ MBC patients. Citation Format: Veerle Geurts, Leonie Voorwerk, Karolina Sikorska, Roberto Salgado, Koen van de Vijver, Marloes van Dongen, Inge Kemper, Ingrid A. Mandjes, Martine Heuver-mes, John Haanen, Gabe S. Sonke, Hugo Horlings, Marleen Kok. Unleashing NK- and CD8 T cells by combining monalizumab (anti-NKG2A) and trastuzumab for metastatic HER2+ breast cancer: first results MIMOSA trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-06-01.

Involvement of Mitochondrial Mechanisms and Cyclooxygenase-2 Activation in the Effect of Desethylamiodarone on 4T1 Triple-Negative Breast Cancer Line.

Novel compounds significantly interfering with the mitochondrial energy production may have therapeutic value in triple-negative breast cancer (TNBC). This criterion is clearly fulfilled by desethylamiodarone (DEA), which is a major metabolite of amiodarone, a widely used antiarrhythmic drug, since the DEA previously demonstrated anti-neoplastic, anti-metastasizing, and direct mitochondrial effects in B16F10 melanoma cells. Additionally, the more than fifty years of clinical experience with amiodarone should answer most of the safety concerns about DEA. Accordingly, in the present study, we investigated DEA’s potential in TNBC by using a TN and a hormone receptor positive (HR+) BC cell line. DEA reduced the viability, colony formation, and invasive growth of the 4T1 cell line and led to a higher extent of the MCF-7 cell line. It lowered mitochondrial transmembrane potential and induced mitochondrial fragmentation. On the other hand, DEA failed to significantly affect various parameters of the cellular energy metabolism as determined by a Seahorse live cell respirometer. Cyclooxygenase 2 (COX-2), which was upregulated by DEA in the TNBC cell line only, accounted for most of 4T1’s DEA resistance, which was counteracted by the selective COX-2 inhibitor celecoxib. All these data indicate that DEA may have potentiality in the therapy of TNBC.

SY23-4 Combination therapy with immune checkpoint inhibitor and targeted agents in metastatic TNBC and HR-positive breast cancer

In recent years, immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1) pathway have been developed for various cancer types. The IMpassion 130 study demonstrated the efficacy and safety of atezolizumab, a programmed cell death ligand-1 (PD-L1) antibody, plus nab-paclitaxel for patients with PD-L1-positive triple-negative breast cancer (TNBC). However, IMpassion 131 study did not demonstrate the efficacy of atezolizumab plus paclitaxel for patients with PD-L1-positive TNBC. Now the discussion of optimal combination strategy is getting more interesting and challenging. On the other hand, hormone receptor-positive BC and PD-L1-negative TNBC are less sensitive than PD-L1-positive TNBC to immune checkpoint inhibitors. Novel combinations of multiple classes of drugs are under evaluation. Anti-VEGF antibody or in combination with PD-1 antibody is evaluated in various cancer types, and the strategy is also promising in hormone receptor-positive BC and PD-L1-negative TNBC. Combination therapy of CDK4/6 inhibitor and PD-1/L-1 antibody is also a potential strategy in hormone receptor(HR)-positive, HER2-negative metastatic BC. We discuss future perspective of immunotherapy in combination with targeted agents in metastatic TNBC and also HR-positive breast cancer.

20P Is evaluation of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutational status on circulating tumour DNA (ctDNA) by liquid biopsy ready for prime-time? A systematic review and an individual patient meta-analysis

PIK3CA represents one of the most mutated genes, both in hormone receptor-positive BC and HER2-positive ones. Several clinical trials demonstrated that the detection of PIK3CA mutations in ctDNA could represent a predictive biomarker of PI3K-inhibitor treatment response. BELLE-2, BELLE-3, and SOLAR-1 trials prospectively showed a significant progression-free survival benefit in ctDNA PIK3CA-mutant patients, suggesting PIK3CA mutation detection in ctDNA could represent a PI3K-Is predictive biomarker.

Abstract PS10-38: Real Would Evidence (RWE) of neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) in patients with HER2 positive early or locally advanced breast cancer treated Single institutional experience

Abstract Introduction Adding pertuzumab(P) on trastuzumab(H) with cytotoxic chemotherapy increased pathologic complete response (pCR) of early or locally advanced HER2 positive breast cancer (EBC) with neoadjuvant chemotherapy. Since 63.6% of pCR rate has been reported from TRYPHAENA trial, TCHP regimen has been used as a standard of neoadjuvant treatment regimen for patients with HER2 positive EBC. However, this regimen has profound toxicities in terms of myelosuppression, neurotoxicity, and etc. Furthermore we still need more information on clinical outcomes and toxicities with this regimen. Therefore, we report real world experience of EBC patients treated with neoadjuvant TCHP followed by curative surgery. Methods We retrospectively reviewed electronic medical record of EBC patients who received neoadjuvant TCHP. Information which we gathered included patients’ and tumor characteristics at the time of diagnosis, details of neoadjuvant chemotherapy, pathologic assessment of tumor response to neoadjuvant TCHP and recurrence free survival after curative surgery. pCR was defined as absence of residual invasive cancer on pathologic evaluation of the resected breast specimen and all sampled regional lymph nodes (ypT0/isN0). Results Between February 2016 and August 2019, 447 patients were treated with neoadjuvant TCHP followed by curative surgery. Median age at BC diagnosis was 56. In clinical stage, stage II was 54.6% and 45.4% of stage III and hormone receptor (HR) positive BC was 48.3%. Most commonly reported adverse event(AE) was mucositis (84%) followed by diarrhea (77%). In terms of Grade 3 AE, anorexia(6%), diarrhea(2%) were frequently observed and 9(2%) of febrile neutropenia occurred despite of prophylactic use of peg-filgrastim. Forty percent of patients experienced dose reduction due to AEs. Of 447 patients, 29% of patients underwent total mastectomy and 71% of breast conserving surgery. In terms of clinical outcome, pCR rate was 64%; 77% of HR negative BCs and 50% of HR positive BCs. Among baseline characteristics, high nuclear grade, high histologic grade, HR stats affected to pCR status (Ps<.005, respectively). Survival analysis presented that median follow up duration was 21months and invasive BC recurrences were observed in 23 patients. Estimated 3year recurrence free survival of patients with pCR was 95% and 87% of whom without pCR (P=.022). Conclusion Our clinical experience with neoadjuvant TCHP was compatible with the efficacy and safety data from TRYPHAENA trial. To concrete the result of BC recurrence after neoadjuvant TCHP, further survival analysis would be warranted. Key words: neoadjuvant chemotherapy, HER2+ breast cancer, pertuzumab, pathologic complete response Citation Format: Ji-Yeon Kim, Seok Jin Nam, Seok Won Kim, Jonghan Yu, Byung Joo Chae, Se Kyung Lee, Jai Min Ryu, Jin Seok Ahn, Young-Hyuck Im, Yeon Hee Park. Real Would Evidence (RWE) of neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) in patients with HER2 positive early or locally advanced breast cancer treated Single institutional experience [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-38.

Abstract CT075: Fasting-mimicking diet and hormone therapy modulates metabolic factors to promote breast cancer regression and reduce side effects

Abstract Breast cancer (BC) is the most common malignancy with 1.7 million new diagnoses/year and is responsible for more than 450,000 yearly deaths worldwide. Two thirds of BC express the estrogen receptor (ER) and/or progesterone receptor and are referred to as hormone receptor-positive (HR+) BC. Endocrine therapy (ET) is usually active in these tumors, although drug resistance and side effects limit its benefit. Growth factor signaling through the PI3K/AKT/mammalian target of rapamycin (mTOR) and MAP kinase axes enhances ER activity and is a key mechanism underlying endocrine resistance. Water-only fasting (fasting) or plant-based, low-calorie, carbohydrate- and protein-restricted fasting-mimicking diets (FMDs) reduce circulating growth factors, such as insulin and IGF1 Therefore, we hypothesized that these dietary interventions could be used to enhance the activity of ET and delay the occurrence of resistance. For our in vitro experiments we used the HR+ BC cell lines, MCF7, T47D, and ZR-75-1, as well as metastases-derived organoids from patients with HR+ BC. Our in vivo experiments in mouse xenografts of human BC cell lines, were conducted in six-to-eight-week old female NOD SCID or athymic Nude-FoxN1 mice treated with ET w/ or w/o 48-72 hours of fasting/FMD. We monitored tumor growth and mouse survival and collected tumor masses and blood to detect circulating levels of several growth factors, adipokines and cytokines. In vivo add back experiments with fasting-reduced factors were done with IGF1, insulin and leptin. Circulating growth factors and adipo-cytokines were also detected in blood samples from 36 patients with HR+ BC, who were enrolled in either one of two clinical trials (NCT03595540 and NCT03340935) assessing safety and feasibility of periodic FMD in cancer patients. Patient nutritional status and response to treatment were also monitored in our clinical trials.We found that in HR+ BC models, periodic fasting or FMD enhanced tamoxifen and fulvestrant activity by lowering circulating IGF1, insulin, and leptin levels and by blocking AKT-mTOR signaling via EGR1 and PTEN upregulation. When fulvestrant was combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic FMD cycles promoted long-lasting tumour regressions and reverted acquired resistance to this regime. Moreover, both fasting and FMD prevented tamoxifen-induced endometrial hyperplasia. In HR+ BC patients receiving ET, FMD cycles caused metabolic changes analogous to those observed in mice, including reduced leptin and IGF1 levels, which were found to remain low for extended periods. In mice, these long-lasting effects were associated with carryover anticancer activity. Overall, our results provide the rationale for conducting further clinical studies of fasting-based dietary strategies as an adjuvant to ET w/ or w/o CDK4/6 inhibitors in patients with HR+ BC. Citation Format: Irene Caffa, Vanessa Spagnolo, Pamela Becherini, Francesca Valdemarin, Claudio Vernieri, Min Wei, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Lorenzo Ferrando, Luca Mastracci, Michele Cilli, Francesco Piacente, Anna Laura Cremonini, Mario Passalacqua, Valerio Vellone, Gabriele Zoppoli, Michele Cea, Giulia Salvadori, Salvatore Cortellino, Hans Clevers, Filippo De Braud, Alessandro Provenzani, Valter D. Longo, Alessio Nencioni. Fasting-mimicking diet and hormone therapy modulates metabolic factors to promote breast cancer regression and reduce side effects [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 CT075.

140O Veliparib plus carboplatin-paclitaxel in patients with HER2-negative advanced/metastatic gBRCA-associated breast cancer: Results in hormone receptor-positive and triple-negative breast cancer subgroups from the phase III BROCADE3 trial

In BROCADE3 (NCT02163694), addition of the PARP1/2 inhibitor veliparib (Vel) to carboplatin-paclitaxel (C-P) significantly prolonged progression-free survival (PFS) in patients (pts) with HER2-negative locally advanced/metastatic gBRCA-associated breast cancer (BC; hazard ratio=0.71 [95% CI 0.57, 0.88], P=.002). Here we report efficacy and safety in hormone receptor-positive (HR+) and triple-negative BC (TNBC) subgroups separately.

Oral Capecitabine-Vinorelbine is Associated with Longer Overall Survival When Compared to Single-Agent Capecitabine in Patients with Hormone Receptor-Positive Advanced Breast Cancer.

Background: Single-agent capecitabine (C) is a moderately effective chemotherapeutic compound in the treatment of patients with HER2-negative metastatic breast cancer (mBC). The capecitabine-vinorelbine (CV) combination is also used due to a good tolerability profile, but no studies have demonstrated its superiority over single-agent C. Methods: We conducted a retrospective analysis to compare overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and incidence of adverse events (AEs) in patients with HER2-negative mBC treated with CV vs. single-agent C. Results: Out of 290 patients included in this study, 127 (43.8%) received single-agent C, while 163 (56.2%) patients were treated with CV. Median PFS was similar in patients treated with single-agent C or CV, while CV was associated with significantly longer OS in patients with hormone receptor-positive (HR+) BC. This OS advantage was confirmed at multivariable analysis also after propensity score-based matching of patients according to relevant clinical or tumor characteristics. When compared with single-agent C, CV was associated with higher incidence of G3/G4 and any-grade nausea/vomiting, diarrhea and increased transaminases. Conclusions: While prospective studies are needed to confirm our findings, the potential OS advantage of CV over single-agent C in HR+ mBC patients must be weighed against a significantly higher incidence of AEs.

Cadmium Exposure and Risk of Breast Cancer by Histological and Tumor Receptor Subtype in White Caucasian Women: A Hospital-Based Case-Control Study.

As the majority of experimental studies suggest cadmium being metalloestrogen, we examined cadmium/breast cancer (BC) association by histological and tumor receptor subtype in 509 invasive BC patients and 1170 controls. Urinary cadmium was determined by atomic absorption spectrometry, and categorized using tertiles of its distribution in the controls: <0.18, 0.18–0.33, >0.33 kg × 10−9/kg × 10−3 creatinine. Relative to the lowest category of urinary cadmium adjusted odds ratio (OR) of ductal BC was 1.18 (95% confidence interval (CI): 0.89–1.58) in the intermediate and 1.53 (95% CI: 1.15–2.04) in the highest category. There was a significant association for hormone receptor-positive ductal BC: ORs per category increase were 1.34 (95% CI: 1.14–1.59) for estrogen receptor-positive (ER+), 1.33 (95% CI: 1.09–1.61) for progesterone receptor-positive (PR+) and 1.35 (95% CI: 1.11–1.65) for ER+/PR+ BC. We found a significant association between cadmium and human epidermal growth factor receptor 2-negative (HER2−) ductal BC. The strongest association with cadmium was for ER+/PR+/HER2− ductal BC. The associations between cadmium and lobular BC with hormone receptor-positive and HER2− were positive but insignificant. There was no evidence that the associations with cadmium differed for cancers with different tumor histology (p-heterogeneity > 0.05). This study provides evidence that urinary cadmium is associated with the risk of hormone receptor-positive and HER2− breast cancer independent of tumor histology.

Cumulative benefit of multiple agents and drug classes for adjuvant therapy (adj rx) of HER2+ early breast cancer (EBC).

e12037 Background: Disease-free survival (DFS) in patients with EBC has improved over time. Trials of systemic agents for adj rx of HER2+ BC, including chemotherapies (CT), endocrine, and HER2-targeted agents have reported improved DFS. This review is a high-level overview describing DFS improvements in adj rx HER2+ BC. Methods: Therapeutic agents listed in NCCN guidelines for adj rx HER2+ BC were evaluated for relative and absolute improvements in DFS. Information was derived from US product labels and publications. Hazard ratios, 95% CI, p-values, and DFS differences at 2 and 5 years (if available) are reported. Results: At 2−3 years, adj rx of HER2+ BC with CT and HER2 treatments reported DFS improvements of 4−5% and 0.9−11.3%, respectively. For hormone receptor positive (HR+) BC, unselected by HER2 status, extended adj letrozole had a 1.9% DFS improvement at 2 years; in HR+ HER2+ BC, extended adj neratinib had 4.5% DFS at 2 years. Conclusions: Relative and absolute improvements in DFS in the adj rx BC setting have been largely incremental and cumulative. Absolute improvements in DFS were 0.9−11.3% with CT, HER2 agents, and AIs. In the subset of HR+ / HER2-positive patients, neratinib showed higher DFS improvement compared to non-steroidal AIs. Similar hazard ratios did not always correspond to similar DFS improvements, possibly reflecting differences in baseline risks in the study populations. [Table: see text]

Abstract 2547: Discovery and characterization of late-stage breast cancer estrogen receptor alpha 1 bound long non-coding RNAs

Abstract Breast cancer (BC) is the second most common newly diagnosed cancer and the second leading cause of cancer death among women in the United States. Despite the proven benefits of adjuvant endocrine therapy in women with hormone receptor positive BC, relapses still occur even after initial treatment with endocrine therapy for 5 years, referred to as late-stage relapse. Long non-coding RNAs (lncRNAs) have been shown to be dysregulated in breast cancer. Recent studies have also shown lncRNAs to function by interfacing with corresponding RNA binding proteins to play critical regulatory roles of diverse cellular processes. Therefore, we hypothesize that lncRNAs may interact with ER to regulate genes promoting late-stage relapse. To address this, we aimed to identify lncRNAs bound to the estrogen receptor alpha 1 protein (ESR1) that promote late-stage relapse breast cancer. We first used transcriptome sequencing to identify altered expression levels of lncRNAs between 72 primary tumors and 24 late-stage relapse breast cancer patients. We detected 1192 altered lncRNAs when comparing the metastatic to the primary samples (FDR &amp;lt;0.05). Next, to identify ESR1 bound lncRNAs associated with late-stage BC, we conducted RNA Immunoprecipitation Sequencing of all transcripts bound to ESR1 as compared to an IgG control in the ER+ T47D cell line. We identified 217 lncRNAs bound to ESR1 of which 50 were up-regulated in late-stage BC, termed Late-Stage Relapse BC ESR1-bound lncRNAs (LASERs). Next, we focused on characterizing the most up-regulated differentially expressed lncRNA, LASER1. We found that LASER1 has increased expression in ER+ breast cancer cell lines. Further, elevated expression of LASER1 was also detected in MCF7 long-term estrogen deprived cells lines that have amplified ER+, suggesting an ER dependent mechanism. Preliminary functional studies indicate LASER1 to promote proliferation and invasion in BC cell lines. Ongoing studies will decipher how LASERs interact with ESR1 to promote late-stage relapse. Overall, this is the first study to discover ESR1 bound lncRNAs that may be contributing to late-stage relapse in BC patients. Citation Format: Jessica Monique Silva-Fisher, Abdallah M. Eteleeb, Torsten Nielsen, Charles M. Perou, Jorge S. Reis-Filho, Mathew J. Ellis, Elaine R. Mardis, Christopher A. Maher. Discovery and characterization of late-stage breast cancer estrogen receptor alpha 1 bound long non-coding RNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2547. doi:10.1158/1538-7445.AM2017-2547

Abstract 5881: Identification of resistance mechanisms to IGF-IR targeting in triple negative breast cancer

Abstract The triple negative subtypes of breast cancer (TNBC) are associated with poor prognosis. Unlike HER2+ and hormone receptor-positive BC, TNBC do not respond to targeted therapy and chemotherapy remains the primary treatment option. There is therefore an unmet need to develop effective therapy for TNBC. The insulin-like growth factor 1 (IGF-I) axis plays a critical role in BC progression by conveying survival and growth signals. Our laboratory reported on the production of a soluble fusion protein comprised of the extracellular domain of human IGF-IR fused to the Fc portion of human IgG (the IGF-Trap). The IGF-Trap reduces the bioavailability of circulating and locally produced IGF-I, thereby limiting tumor growth. When human TNBC MDA-MB-231 cells were xenotransplanted into nude mice and treated with the IGF-Trap, we observed variability in the response as it ranged from complete tumor regression to disease stabilization and tumor progression in some mice. This suggested that MDA-MB-231 cells are heterogeneous in respect to their sensitivity to IGF-IR signaling blockade. The aim of the present study was to identify resistance mechanisms that allow the cells to progress in the face of IGF-IR signaling blockade by the IGF-Trap. We first analyzed the tyrosine kinase receptor profile of these cells and confirmed by PCR that in addition to IGF-IR, they express epidermal growth factor receptor (EGFR), c-Met, and fibroblast growth factor receptor 1 (FGFR1). They also produce IGF-I, EGF and relatively high level of FGF1 that could provide potential autocrine signaling to compensate for IGF signaling blockade. Using limiting dilution cloning, we isolated MDA-MB-231 cells with a range of IGF-IR expression levels, as confirmed by qPCR and Western blotting. We found that clones with higher basal IGF-IR activation levels, independently of expression levels had increased sensitivity to IGF-Trap treatment in the presence of serum, identifying them as IGF-addicted clonal subpopulations. Furthermore, an IGF-Trap resistant population selected from MDA-MB-231 cells by prolonged exposure to the IGF-Trap had an increased proliferation rate in the presence of the IGF-Trap as compared to unselected cells, as assessed by MTT and showed higher p-EGFR and p-ERK levels, suggesting that prolonged IGF-Trap treatment enriched an IGF-I-independent population with increased aggressiveness. Collectively these results showed that MDA-MB-231 cells are heterogeneous in respect to IGF-IR expression levels and that IGF-Trap sensitivity correlated with constitutive IGF-IR activation levels. Moreover, IGF-Trap resistance in these cells was associated with increased EGFR signaling and proliferation. Further interrogation of the gene expression profile of these cells will define a “resistance signature” with potential relevance to personalized treatment with IGF-targeting drugs. Supported by the CIHR and Mitacs. Citation Format: Jennifer Tsui, George Vaniotis, Maria Celia Fernandez, Pnina Brodt. Identification of resistance mechanisms to IGF-IR targeting in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5881. doi:10.1158/1538-7445.AM2017-5881

Abstract P3-03-15: Synergistic suppression of triple negative breast cancer with the combination of PI3K inhibitor (alpelisib, BYL719) and CDK inhibitor (ribociclib, LEE011)

Abstract INTRODUCTION. Triple negative breast cancer (TNBC) is an aggressive form of BC that lacks effective targeted therapy. It is a biologically heterogeneous disease with several molecular subtypes: basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M), mesenchymal-stem-like (MSL), immune-modulatory (IM) and unclassified (UNC). The PI3K/AKT/mTOR pathway affects cell proliferation, survival, and apoptosis through growth receptor interaction with downstream targets such as AKT and mTOR. TNBC frequently has activation of this pathway by mutation and other means across several subtypes. Recently the PI3K inhibitor alpelisib (BYL719) has been found to have efficacy in a combination study in ER positive metastatic BC (MBC) with a Phase 3 trial in progress. Ribociclib (LEE011) is a CDK inhibitor targeting cyclin D1/CDK4 and cyclin D3/CDK6 that recently met its primary endpoint in a phase 3 trial in a combination study in hormone receptor positive BC. As with all BC, TNBC has intact or mutant RB which affects susceptibility to CDK inhibitor. We hypothesize that targeting both PI3K with alpelisib and CDK with ribociclib may provide enhanced suppression of TNBC. MATERIALS AND METHODS. HCC38 and MDA468 are TNBC subtype BL1; MDA468 is RB1 and PTEN mutant. HCC1187 is IM. BT549 is M, mutant RB1 and PTEN. Hs578T, MDA157, and MDA231 are MSL. Cells were treated with alpelisib and ribociclib alone with 2-fold increase in concentrations, or the combination, for 72h and assessed by MTT assay. Western blot was performed using probes for pAkt (T308 and S473), Akt, pS6K1, S6K1, pS6, S6, and β-actin. RESULTS. Synergy in growth inhibition was seen combining alpelisib and ribociclib as reflected by combination indices &amp;lt;1 (Table). At least 3 subtypes, BL1, M, and MSL have cell lines that have synergy; however, the MSL subtype MDA157 is antagonistic and not RB1 mutant. In the 2 responsive MSL lines Hs578T and MDA231 ribociclib alone has no effect or increases phosphorylation of Akt by Western blot, but in combination with the PI3K inhibitor alpelisib, there is enhanced inhibition of phosphorylation of Akt with enhanced inhibition of the phosphorylation of the end target S6. Chou-Talalay Combination Indices for Treatment with Alpelisib plus RibociclibCell Line (subtype)Combination Index Values with Different Combinations of Increasing Effective Proportional Doses of BYL719 and LEE011 ABCDERB mutant MDA468 (BL1)&amp;gt;1001.2551.1941.2780.970BT549 (M)0.9890.9940.9570.8390.726RB intact HCC38 (BL1)0.2320.3670.6890.6800.519HCC1187 (IM)&amp;gt;100&amp;gt;100&amp;gt;100&amp;gt;100&amp;gt;100Hs578T (MSL)0.2040.2580.4000.4940.594MDA231 (MSL)1.5810.9400.7210.4650.308MDA157 (MSL)7.022051&amp;gt;100&amp;gt;100 Conclusion. Our study demonstrates that alpelisib plus ribociclib can synergistically enhance suppression of BC across multiple subtypes of TNBC. Cancer cells within the same subtype may not demonstrate a synergistic response, depending on RB status. Nevertheless, if RB mutant cells are susceptible to ribociclib then synergy can be seen even in these cancer cells. Antagonism can be seen independent of RB status in the same subtype. These findings point to a potential role for combination therapy with alpelisib and ribociclib in the treatment of TNBC. Citation Format: Yuan Y, Mortimer J, Xing Q, Yan J, Wen W, Han E, Yim JH. Synergistic suppression of triple negative breast cancer with the combination of PI3K inhibitor (alpelisib, BYL719) and CDK inhibitor (ribociclib, LEE011) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-03-15.

Abstract P1-12-08: The incidence and outcomes of brain metastases in HER2-positive metastatic breast cancer with the advent of modern anti-HER2 therapies

Abstract Background: Human epidermal growth factor receptor 2 (HER2) is over-expressed in approximately 20 - 30% of breast cancers. HER2-positive breast cancers frequently metastasize to the brain. In recent years, many new drugs have been approved for HER2-positive metastatic breast cancer (MBC). In the metastatic setting, trastuzumab was approved in 2000, lapatinib 2007, and pertuzumab and ado-trastuzumab emtansine in 2012. We sought to describe the incidence, time course, and prognostic factors of BM in patients (pts) with HER2+ MBC during the time when dramatic changes in systemic therapy occurred. Patients/methods: The study included pts with HER2-positive MBC treated at two academic hospitals: Dana Farber Cancer Institute (DFCI) (2000-2007 [DFCI-T1], 2008-2011 [DFCI-T2]) and University of North Carolina (UNC) (2012-2014). We examined the incidence of BM (at diagnosis [dx] and within 1-2 years of MBC dx). We combined the two cohorts to examine outcomes – time to BM, survival following MBC, and survival following BM – using the Kaplan Meier method and Cox regression modeling. Results: We identified 185 (DFCI n=128, 97 diagnosed 2000-2007 and 31 diagnosed 2008-2011; UNC n=57, all diagnosed 2012-2014) pts with HER2-positive MBC. Through a median of 4 years follow-up after the MBC dx (min 2, max 11), 118 had died and 67 were censored. The median age at MBC dx was 52 (min 25, max 88), 149 (82%) were Caucasian, 88 (48%) had hormone receptor (HR) positive BC, and 67 (37%) had de-novo (i.e., non-recurrent) MBC. BM was present at the MBC dx for 8% of pts in DFCI-T1, 16 % of pts in DFCI-T2, and 16% of pts at UNC. Within 1 year of the MBC dx, BM was present in 21% of DFCI-T1, 29% in DFCI-T2, 23% of UNC pts. Within 2 years of the MBC dx, 67 (36%) pts had developed BM, of which one third (22) were diagnosed at initial MBC presentation. In unadjusted analyses, there were no differences in time to BM dx by age (p=0.2), race (p=0.1) or HR status (p=0.1). The median survival following the development of BM for all pts was 1.5 years. A multivariable model predicting survival after the MBC dx, found factors associated with shorter survival included having (vs. not having) BM at the initial MBC dx, having received (vs. not having received) adjuvant HER2-directed therapy prior to the MBC dx, and having recurrent (vs. de novo) MBC (P≤0.02 for all). Age, HR status, race and time period of MBC dx were not significant in the multivariable model. Conclusions: Among pts diagnosed in the modern era, after new therapies became available, BM remains a common problem for pts with HER2-positive MBC. While no obvious trends in the incidence of HER2-positive MBC are suggested, conclusions regarding incidence trends should be considered hypothesis-generating until larger, population-based data become available. Nevertheless, a dx of BM early in the course of MBC treatment and prior receipt of adjuvant trastuzumab appeared to confer a more aggressive disease course. Coordinated, prospective collection of the incidence and outcomes of BM among pts with HER2-positive MBC, studies of pts who develop BM &amp;gt;2 years after their MBC dx, and clinical trials of treatment strategies for pts with trastuzumab-resistant BM are needed. Citation Format: Strulov Shachar S, Deal AM, Vaz-Luis I, Dees EC, Carey LA, Hassett MJ, Garrett AL, Benbow JM, Hughes ME, Mounsey L, Lin N, Anders CK. The incidence and outcomes of brain metastases in HER2-positive metastatic breast cancer with the advent of modern anti-HER2 therapies [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-12-08.

Association of Genome-Wide Association Study (GWAS) Identified SNPs and Risk of Breast Cancer in an Indian Population

To date, no studies have investigated the association of the GWAS-identified SNPs with BC risk in Indian population. We investigated the association of 30 previously reported and replicated BC susceptibility SNPs in 1,204 cases and 1,212 controls from a hospital based case-control study conducted at the Tata Memorial Hospital, Mumbai. As a measure of total susceptibility burden, the polygenic risk score (PRS) for each individual was defined by the weighted sum of genotypes from 21 independent SNPs with weights derived from previously published estimates of association odds-ratios. Logistic regression models were used to assess risk associated with individual SNPs and overall PRS, and stratified by menopausal and receptor status. A total of 11 SNPs from eight genomic regions (FGFR2, 9q31.2, MAP3K, CCND1, ZM1Z1, RAD51L11, ESR1 and UST) showed statistically significant (p-value ≤ 0.05) evidence of association, either overall or when stratified by menopausal status or hormone receptor status. BC SNPs previously identified in Caucasian population showed evidence of replication in the Indian population mainly with respect to risk of postmenopausal and hormone receptor positive BC.

Abstract P1-14-14: Impact of body mass index (BMI) and neo-adjuvant chemotherapy (NAC) dosing on pathologic complete response (pCR) in operable breast cancer (bc)

Abstract Introduction: pCR following NAC is associated with improved long term outcomes. Though obesity is associated with chemo-resistance, its impact on pCR is less clear, likely because most studies were unable to account for NAC dose adjustments. An association between taxane dose reduction and BMI has previously been shown in European populations. However, most patients (pts) with increased BMI had doses capped at BSA of 2. We studied the impact of BMI on NAC dosing when treatment is based on actual weight and whether dosing adjustments preferentially impact pCR rate. Methods: Pts prospectively enrolled in the University of Iowa Breast Molecular Epidemiologic Resource from 2010-14 with invasive bc who received at least one cycle of NAC were eligible. Pts were stratified by BMI category: normal (BMI ≤25) or overweight-obese (BMI &amp;gt;25). Planned total dose was calculated based on both dosing and number of cycles. Dose reduction was defined as any decrease in total intended dose. pCR was defined as no residual invasive disease in breast and lymph nodes. To investigate the relationship between BMI, dose reductions, and pCR, chi-square tests and logistic regression models were used. Results: 87 pts were eligible. 22 (26%), 25 (29%) and 51 (59%) of pts had HER2 positive, triple negative and hormone receptor positive bc (HER- or +), respectively. 62 (71%) pts had Stage I-II bc. All pts received a combination of taxanes with other agents (Cytoxan, 5FU, Carboplatin, Gemcitabine) with or without an anthracycline (Adriamycin or Epirubicin) or anti HER 2 therapy (Pertuzumab, Traztuzumab or Lapatinib) and were initially dosed based upon actual body weight. Taxanes were planned at treatment initiation in all pts. Anthracyclines were given to 71 (82%) pts. pCR was achieved in 28 (32%) pts. Association between BMI and NAC dosing are shown in - Table 1: Association between NAC dosing and BMI category NormalOverweight-ObesepN3651 NoYesNoYes Taxane dose reduction30(83%)6(17%)29(57%)22(43%)&amp;lt;0.01Non taxane dose reduction28(78%)8(22%)40(78%)11(22%)0.94 . Relative to normal weight pts, overweight-obese pts were more likely not to achieve a pCR (OR 2.09, CI 0.84-5.21, p=0.11) and have residual disease in the breast alone (OR 2.92, CI 1.18-7.24, p=0.02). Overweight-obese pts with taxane reductions, relative to overweight-obese pts without taxane reductions, were at elevated odds of not achieving a pCR (OR 2.03, CI 0.53-7.73) -. Table 2: Impact of taxance dose reduction on pCR by BMI category NormalOverweight-Obese No pCRpCRNo pCRpCRTaxane reductionNo19(63%)11(37%)20(69%)9(31%) Yes2(33%)4(67%)18(82%)4(28%) Interaction between BMI and taxane dose reduction on pCR trended towards significance (p=0.10), a trend not seen for non-taxane drugs. The most common adverse event resulting in taxane dose reduction was neuropathy (10/28 pts). Conclusion: Overweight-obese women experienced significantly higher rates of taxane dose reductions during NAC for bc with initial full-weight dosing. BMI status may modify the effects of taxane dose reduction on the likelihood of not achieving a pCR, Further investigation of this outcome in a larger cohort is warranted. Citation Format: Raman R, Mott SL, Schroeder MC, Thomas A. Impact of body mass index (BMI) and neo-adjuvant chemotherapy (NAC) dosing on pathologic complete response (pCR) in operable breast cancer (bc). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-14.

Фулвестрант в эндокринной терапии рецидивирующего и метастатического рака молочной железы

Hormone therapy of recurrent and metastatic breast cancer has a wide range of drugs possessing different medical effects. However, the main problem is the sequence of endocrine therapy of hormone receptor-positive metastatic BC in the absence of visceral crisis, nowadays. The recommendations of the different professional communities do not contain visible preference in favor of the choice of any specific endocrine therapy or specific treatment sequence. According to the information we have received, at present the optimal treatment path, in the absence of resistance to endocrine therapy and visceral crisis, will be the following: line 1 - fulvestrant 500 mg; line 2 - AIs (for example anastrozole); line 3 - tamoxifen. The choice of the therapy must be based on the characteristics of not only the tumor, but also the patient. One should take into account the age of the patient, the duration of the interval without disease symptoms after adjuvant chemotherapy, the type of the damage and the involvement of internal organs in the process, the presence of concomitant diseases, toxic manifestations of chemotherapy regimens, the price and availability of the drugs.