Operable Triple-negative Breast Cancer Research Articles

Intensive chemotherapy versus standard chemotherapy among patients with high risk, operable, triple negative breast cancer based on integrated mRNA-lncRNA signature (BCTOP-T-A01): randomised, multicentre, phase 3 trial

ObjectiveTo evaluate the feasibility of using a multigene signature to tailor individualised adjuvant therapy for patients with operable triple negative breast cancer.DesignRandomised, multicentre, open label, phase 3 trial.Setting7 cancer centres...

Impact of Presenting Stage on Overall Survival in Patients Treated with Neoadjuvant Chemotherapy for Triple Negative Breast Cancer.

For operable triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC), clinical prognostication and postoperative decision-making relies exclusively on whether a pathologic complete response (pCR) is achieved or not. We evaluated whether extent of disease at presentation further influenced overall survival (OS) among patients with pCR or with residual disease (RD) following NAC. Patients with stage I-III TNBC who underwent NAC were identified from the National Cancer Database from 2010 to 2019. Overall survival was assessed by disease extent using the Kaplan-Meier method and Cox proportional hazards regression for univariate and multivariable analysis. A total of 35,598 patients met inclusion criteria, and 11,967 achieved pCR. Ten-year OS was 88.5% and varied by cT and cN categoryat presentation. Best 10-year OS was seen in patients with cT1-2, cN0 (90.9%) and was worst in those with cT3-4, cN2-3 disease (72.0%). A total of 23,631 patients had RD. Ten-year OS was 60.1% and varied by cT and cN categoryat presentation. Best 10-year OS was seen in patients with cT1-2, cN0 (73.0%) and was worst in those with cT3-4, cN2-3 disease (36.3%). Notably, OS was significantly poorer for patients with cT3-4, cN2-3 diseaseat diagnosis and pCR versus those with cT1-2 cN0 and RD (aHR 1.30, 95% confidence interval 1.03-1.63, p = 0.03). Among patients with TNBC, extent of disease at presentation was prognostic for OS independently of response to NAC. Patients with advanced stage at presentation had poorer OS even in the context of pCR. Further investigation is needed to evaluate whether additional adjuvant therapy strategies should be considered for these patients.

Adjuvant chemotherapy guided by an integrated mRNA–lncRNA signature in triple-negative breast cancer (BCTOP-T-A01): A randomized, open-label, multicenter phase 3 trial.

525 Background: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with variable clinical outcomes. We have previously classified patients with TNBC into high- and low-risk groups based on a multigene signature. In this study, we aimed to evaluate the feasibility of utilizing a multigene signature to tailor individualized adjuvant therapy for patients with operable TNBC. Methods: This multicenter, open-label, randomized, phase 3 trial was conducted at 7 cancer centers in China. We included female patients aged 18-70 years with early TNBC after definitive surgery (histologically confirmed axillary lymph node-positive or lymph node-negative with tumor diameter >10 mm). After categorization using the integrated signature, high-risk patients were randomized (1:1) to receive an intensive adjuvant treatment comprising four cycles of docetaxel, epirubicin, and cyclophosphamide followed by four cycles of gemcitabine and cisplatin (TEC-GP; arm A), or the standard four cycles of epirubicin and cyclophosphamide followed by four cycles of docetaxel (EC-T; arm B). Low-risk patients received the same adjuvant chemotherapy as arm B (arm C). The primary endpoint was disease-free survival (DFS) in the intention-to-treat analysis of arm A versus arm B. Results: Between January 2016 and July 2023, 504 patients (336 high-risk and 168 low-risk; median age, 52 years; 488 with T1-2 tumors; 263 with node-positive disease) were recruited. At a median follow-up of 45.1 months, the 3-year DFS rates were 90.9% for patients in arm A and 80.6% for patients in arm B (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.28 to 0.95; P = 0.030). Intensive chemotherapy improved DFS relative to standard therapy irrespective of tumor size and nodal status. The 3-year RFS was 92.6% in arm A and 83.2% in arm B (HR, 0.50; 95% CI, 0.25 to 0.98; P = 0.039). The groups did not differ in OS (HR, 0.58; 95% CI, 0.22 to 1.54; P = 0.267; 3-year OS, 98.2% vs 91.3%). Upon receiving the same chemotherapy regimen, patients in arm C had significantly higher DFS (HR, 0.57; 95% CI, 0.33-0.98; P = 0.038; 3-year DFS, 90.1% vs 80.6%), RFS (HR, 0.42; 95% CI, 0.22-0.81; P = 0.007; 3-year RFS, 94.5% vs 83.2%) and OS (HR, 0.14; 95% CI, 0.03-0.61; P = 0.002; 3-year OS, 100% vs 91.3%) compared to patients in arm B. The incidence of grade 3 to 4 treatment-related adverse. events for arms A, B and C, respectively, were thrombocytopenia (14.1%, 2.5%, 1.8%), febrile neutropenia (9.9%, 4.3%, 4.9%), anemia (5.8%, 1.9%, 1.8%), nausea (7.0%, 3.7%, 4.9%), vomiting (8.3%, 4.3%, 4.9%) and myalgia (2.6%, 5.6%, 5.5%). There were no treatment-related deaths. Conclusions: The multigene signature showed potential for tailoring adjuvant chemotherapy for patients with operable TNBC. Intensive regimens incorporating GP into anthracycline/taxane-based therapy improves survival with manageable toxicity. Clinical trial information: NCT02641847 .

Tolerance and safety of adjuvant metronomic capecitabine in Indian patients with non-metastatic triple negative breast cancer (TNBC): An institutional experience.

e12530 Background: Triple-negative breast cancer (TNBC) subtype has a high risk of recurrence and overall poorer survival after standard treatment. SYSUCC-001 study presented in ASCO 2020 reported an increased disease-free survival after one year of metronomic capecitabine in operable TNBC patients after completion of local therapy. As per our clinical experience in metastatic breast cancer, many Indian patients are not able to tolerate capecitabine for longer duration. Hence, we wanted to assess the tolerance and safety of one year of daily dosing of capecitabine in our patients with Non-Metastatic TNBC. Methods: We performed a retrospective analysis of non-metastatic TNBC patients receiving adjuvant capecitabine 650 mg /m2 twice daily continuously for one year who took treatment from June 2020 to August 2022. The data extracted included patient socio-demographics, capecitabine information, side effects, and capecitabine treatment changes (dose reductions and dose interruptions). Statistical analysis was conducted using SPSS, version 24. Results: We analyzed 90 patients, out of which majority (62%) were stage II. Median age of the cohort was 48 years. Germline data was available for 64 patients, out which 8 patients were BRCA 1 positive and 8 patients had a variant of undetermined significance. Median duration of capecitabine in our patients was 230 days (IQR: 10 - 360). Twenty-six (28.8%) patients underwent dose reduction and 15 (16.6%) had reported grade 3 toxicity. Mean dose of capecitabine received was 535 mg / m2 twice daily. Treatment was interrupted due to toxicity in 20 (22%) of patients. The most common capecitabine-induced toxicity was hand foot syndrome, which was also the most common reason for dose reduction and treatment interruption. Dihydropyrimidine dehydrogenase (DPD) mutation status was known for 38 patients out of which only one (2.6%) was found to have DPD deficiency. Incidence of grade 3 toxicity was observed to be less in patients with age less than 50 years, ECOG performance status 0-1 and absence of comorbidities. Two-year disease free survival (DFS) and overall survival (OS) was estimated to be 79.3% and 80% respectively. Most common site of metastases was reported to be brain followed by lung. Conclusions: Continuous metronomic dosing of adjuvant capecitabine for 1 year is fairly well tolerated in Indian patients with non-metastatic TNBC, but may still require dose reduction in some patients due to toxicity.

Abstract PO5-03-11: Ultra-low dose nivolumab added to dose-dense, cisplatin-based neoadjuvant chemotherapy in locally advanced, borderline operable triple negative breast cancer: A matched case-control study

Abstract Background In India, the majority of patients with triple negative breast cancer(TNBC) present with locally advanced and often inoperable disease due to lack of screening, awareness, and social stigma. This makes pathological complete response(pCR) after neoadjuvant chemotherapy(NAC) less likely, leading to early recurrence and poor survival outcomes. Immune checkpoint inhibitors(ICI) in addition to platinum agents have improved both pCR and disease-free survival(DFS). However, these are accessible only to a very small proportion(< 3%) of patients in LMICs due to exorbitant costs. The activity and cost-effectiveness of low dose ICI has been demonstrated in head and neck. The efficacy of low dose ICI in the neoadjuvant setting for TNBC has not been studied. We examined our outcomes with ultra-low dose nivolumab(< 0.6 mg/kg every 2 weeks) added to NAC for locally advanced and borderline operable TNBC. Methods A retrospective analysis of 132 patients with TNBC who received NAC with the ddDCEP regimen(Docetaxel 75mg/m2 and Cyclophosphamide 600 mg/m2 alternating with Epirubicin 90mg/m2 and Cisplatin 60mg/m2 every 2 weeks for 8 cycles) or ddDCEP plus low dose nivolumab(< 0.6mg/kg/2 weeks) and underwent mastectomy at our centre between 2018-2023 was carried out. 105 and 27 patients received ddDCEP alone and ddDCEP + low dose nivolumab respectively. Using rigorous exact matching, 26 matched pairs(52 patients) were obtained based on tumour grade and AJCC TNM stage. pCR in the surgical specimen was the principal outcome assessed. Survival data, adverse events and cost were also analysed. Results The median age of cases and controls was 42 and 40 years respectively. Tumour histology was ductal carcinoma most patients. Across both groups the stage distribution was the same with nearly 85% stage III(IA 3.8%;IIB 7.7%; IIIA 23.1%;IIIB 43.2%;IIIC 19.2%). 92% of cases and 85% of controls had node positive disease. 62% of cases and 46% of controls had T4 disease. At a median follow up of 9 months, there were no recurrences or deaths among the cases. The most common immune mediated adverse event was hypothyroidism seen in 11.5% of cases. The rates of grade 3/4 anaemia, thrombocytopenia and febrile neutropenia were approximately 38%, 10% and 3.8% across cases and controls respectively. The median dose of nivolumab was 0.27mg/kg/2weeks as opposed to the approved dose of 3mg/kg/2weeks for most indications. The range of doses varied from 0.07 to 0.58mg/kg/2weeks. In the overall cohort, the addition of nivolumab did not have any apparent effect on the pCR rates which were identical at 42.3% in both cases and controls. However, there was a positive correlation between the total dose of nivolumab/kg(body weight) and the likelihood of pCR(coefficient 0.34; p-value 0.046). Patients who received higher than the median dose of nivolumab had a significantly higher likelihood of attaining pCR than those who received lower doses (69.2% pCR vs.15.4%;p-value 0.015). The cost of nivolumab at 0.6 mg/kg for 4 doses is approximately USD2000 compared to USD34400 for 8 doses of pembrolizumab in the neoadjuvant component of the KEYNOTE-522 regimen. Conclusion In this cohort with locally advanced/inoperable TNBC, the addition of ultra-low dose nivolumab did not improve pCR overall compared to a matched control set who did not receive ICI. However, in the subset of patients who received between 0.27-0.58 mg/kg/2weeks, the pCR rates were significantly higher at 69%. This presents a promising and cost-effective approach for TNBC management in LMICs. This effect needs verification in larger phase II/III trials. Table. Citation Format: Zachariah Thomas, Josh Georgy, Ashish Singh, Anjana Joel, Divya Thumaty, Ajoy John, Jerryes Wisely, Grace Rebekah, Elanthenral Sigamani, Anish Cherian, Deepak Abraham, Paul Jacob, Rajesh Balakrishnan, Patricia Solomon, Selvamani Backianathan, Raju Chacko. Ultra-low dose nivolumab added to dose-dense, cisplatin-based neoadjuvant chemotherapy in locally advanced, borderline operable triple negative breast cancer: A matched case-control study [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 PO5-03-11.

Abstract PO2-17-12: Phase I Trial of alpha-lactalbumin vaccine in high risk operable triple negative breast cancer (TNBC) and patients at high genetic risk for TNBC

Abstract Background: Triple-negative breast cancer (TNBC) has a poor prognosis and may be associated with germline mutations. α-Lactalbumin (aLA) is expressed in lactating breasts but not at other times or in other tissues. Expression of aLA is found in 70% of TNBC (PMID: 27322324) so could be an immunologic target for TNBC based on the “retired protein hypothesis” (PMID: 31926646). In pre-clinical studies, vaccination with aLA provided protection from development of autochthonous tumors in transgenic murine models of breast cancer and inhibited growth of established 4T1 transplantable breast tumors in BALB/c mice (PMID: 20512124). Methods: To determine the safety and immunogenicity of aLA, patients with early stage TNBC are being entered in a Phase I trial of aLA with GMP-grade zymosan adjuvant in Montanide ISA 51 VG vehicle. Subjects receive 3 vaccinations given once every 2 weeks. Events of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2 are considered dose-limiting toxicities (DLTs). Results: CTCAE toxicity by dose level is summarized below. All DLTs were injection site reactions, with ulceration and need for incisional drainage representing the grade 3 events. Seven (7) of 10 patients assayed to date have met protocol specified definitions of an immune response based on ELISpot assays to determine frequencies of T cells producing IFNγ and IL-17 in response to recombinant aLA. Assays for an additional 6 patients will be available in September 2023. Conclusion: Dose level ≤ 2 appears to be the maximum tolerated dose. Based on immune response, additional intermediate dose levels may be studied. An additional cohort of patients receiving concurrent anti-PD1 treatment is being accrued. Accrual of patients with BRCA1/2 or PALB2 mutations planning to undergo prophylactic mastectomy is beginning in order to define the toxicity and immunologic effects in this group and to determine whether inflammatory changes from occult lactational foci will be produced. Funding Source: Department of Defense (W81XWH-17-1-0592 and W81XWH-17-1-0593) Table 1 Worst Toxicity by Dose Level Citation Format: Justin Johnson, Emily Rhoades, Holly Levengood, Halle Moore, Megan Kruse, Erin Roesch, Jame Abraham, Brenna Elliott, Rachel Swartz, Holly Pederson, Elena Haury, Azka Ali, Tiffany Onger, Andrew Sciallis, Zahraa Al-Hilli, Wei Wei, Thaddeus Stappenbeck, George Budd. Phase I Trial of alpha-lactalbumin vaccine in high risk operable triple negative breast cancer (TNBC) and patients at high genetic risk for TNBC [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 PO2-17-12.

Abstract PO1-16-09: Does T1c-2N0-1M0 triple negative breast cancer derive a benefit from neoadjuvant chemotherapy?

Abstract Objective: Although neoadjuvant chemotherapy (NCT) is a standard approach for operable triple negative breast cancer (TNBC), the potential risks brought by it should also be noticed. Is the expanding indication of NCT to T1cN0M0 population appropriate? We conducted an investigation to compare the long-term survival of small tumor TNBC between NCT and adjuvant chemotherapy (ACT). Methods: For this propensity-matched analysis, we used data from SEER database. We enrolled 1183 cases with NCT and 2550 cases with ACT who are AJCC clinical T1c-T2 N0-N1, diagnosed with TNBC, from 2016 to 2017. The propensity score matching was utilized to minimize baseline characteristics bias. Based on the Cox proportional hazard regression model, we calculated hazard ratios (HR) with 95% confidence intervals (CIs). Results: Multivariate analysis in matched patients showed that NCT had no significant survival benefit compared with ACT in T1c-2N0-1M0 TNBC patients. Stratified analyses by T stage and N stage demonstrated NCT mainly presented a survival advantage in patients with N1 stage. Further investigation found that NCT didn’t improve BCSS (HR=0.472; 95% CI: 0.135-1.647; p=0.239) and OS (HR=0.392; 95% CI: 0.147-1.047; p=0.062) for patients with T1cN0M0 TNBC; however, for patients with T2N1M0 TNBC, it was associated with improved OS (HR=1.951; 95% CI: 1.003-3.797; p=0.049). Conclusion: In our study, we did not find any profit brought by NCT in the stage I and stage IIa cohorts, but even more unfavorable outcomes appeared in the T1cN0M0 cohort. Therefore, whether the candidates of NCT should be extended to T1cN0M0 still need to be cautious. Treatment effect on breast cancer-specific survival (BCSS) and overall survival (OS) by subgroup. Citation Format: Jie Zhang, Yushuai Yu, Weiwei Chen, Wenfen Fu, Ruiliang Chen, Jialu Yi, Chuangui Song. Does T1c-2N0-1M0 triple negative breast cancer derive a benefit from neoadjuvant chemotherapy? [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 PO1-16-09.

Abstract GS01-03: Adding atezolizumab to adjuvant chemotherapy for stage II and III triple-negative breast cancer is unlikely to improve efficacy: interim analysis of the ALEXANDRA/IMpassion030 phase 3 trial

Abstract Background: Early stage triple negative breast cancer (TNBC) is associated with a high risk of distant relapse. ALEXANDRA/IMpassion030 is a global, prospective, randomized, open-label, phase 3 trial that investigated the efficacy, safety and pharmacokinetic profile of adjuvant atezolizumab plus standard anthracycline/taxane chemotherapy (arm A) versus chemotherapy alone (arm B) in early-stage TNBC. Methods: ALEXANDRA/IMpassion030 (NCT03498716) aimed to randomize (1:1) 2300 patients with operable stage II-III TNBC, confirmed by central pathology review. Patients were stratified by type of surgery (breast conserving versus mastectomy), nodal status (0 versus 1-3 versus >=4 nodes), and centrally assessed PD-L1 status (IC 0 vs >=1% ). Adjuvant chemotherapy consisted of weekly paclitaxel 80 mg/m2 for 12 weeks followed by dose dense anthracycline (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2) and cyclophosphamide 600 mg/m2 for 4 doses every 2 weeks given concomitantly with atezolizumab 840 mg every 2 weeks followed by maintenance atezolizumab 1200 mg every 3 weeks until completion of 1 year of atezolizumab (Arm A) or the same chemotherapy regimen (T-EC/AC) alone (Arm B). The primary endpoint was invasive disease-free survival (iDFS); secondary endpoints included, iDFS in the PD-L1 positive and lymph node-positive subpopulations, overall survival, safety, patient functioning and health related quality of life (HRQoL). On the 14th of November 2022, following an IDMC recommendation, the study accrual was temporarily stopped. In February 2023, the protocol was amended in order for the IDMC to perform an early interim analysis of efficacy and futility, at approximately 62% of the planned (390) iDFS events. The futility boundary was set to a Hazard Ratio (HR) > 1. Results: The IDMC recommendations of 15th March 2023 reported that the primary endpoint crossed the futility boundary, accrual to the study was permanently stopped and the experimental treatment was discontinued. Between August 2018 and November 2022, the study enrolled 2199 patients, with 1101 randomised to the atezolizumab arm (A) and 1098 to the control arm (B). At a median follow-up of 25.3 months, 239 (10.9%) iDFS events were observed in the 2199 enrolled patients; 127 versus 112 iDFS events were observed (61.3% of 390) in the A versus B arms respectively, HR 1.12, (95% confidence interval, CI, 0.87, 1.45). In the PD-L1 positive subgroup, (1567/2199 patients, 71.3%), 77 versus 73 iDFS events were observed in the A versus B arms respectively, HR 1.03, (95% CI 0.75, 1.42). Among patients with lymph node positive tumors (1066/2199 patients, 48.5%), 86 versus 66 iDFS events were observed in the A versus B arm respectively, HR 1.41, (95% CI 1.02, 1.96). Incidence of adverse events grade >=3 was 58.01% versus 48.15% in the A versus B arms, including death in 1.01% (11) and 0.55% (6) of patients, respectively. Conclusions: Crossing the pre-specified futility boundary of HR > 1 provides evidence that adjuvant atezolizumab is very unlikely to improve invasive disease-free survival when added to adjuvant anthracycline and taxane based chemotherapy in patients with stage II-III triple-negative breast cancer. With longer treatment exposure in the atezolizumab arm (A), adverse events were more frequent but consistent with the atezolizumab safety profile. No new or unexpected safety issue was identified. Citation Format: Michail Ignatiadis, Andrew Bailey, Heather McArthur, Sarra El-Abed, Evandro de Azambuja, Otto Metzger, Steve Chui, Max Dieterich, Thomas Perretti, Guenther Steger, Jacek Jassem, Soo Chin Lee, Michaela Higgins, José Zarbá, Marcus Schmidt, Henry Gomez, Angel Guerrero-Zotano, Luca Moscetti, Joanne Win Yang Chiu, Carter DuFrane, Vanessa Honvault, Rosa Altarcheh, Luciana Molinero, Andrew Ellingson, Elisabetta Munzone, Noa Efrat Ben-Baruch, Emilio Bajetta, Shinji Ohno, Seock-Ah Im, Gustavo Werutsky, Einav Gal-Yam, Xavier Gonzalez-Farré, Ling-Ming Tseng, William Jacot, Oleg Gluz, Zhimin Shao, Yaroslav Shparyk, Ivan Sinielnikov, Zimina Anastasia, Aleksandr Vasiliev, Esther Shearer-Kang, Eric Winer, Diogo Martins-Branco, Shona Fielding, David Cameron, Giuseppe Viale, Shigehira Saji, Richard Gelber, Martine Piccart. Adding atezolizumab to adjuvant chemotherapy for stage II and III triple-negative breast cancer is unlikely to improve efficacy: interim analysis of the ALEXANDRA/IMpassion030 phase 3 trial [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 GS01-03.

Abstract PO1-28-09: Rethinking the value of pathologic complete response rate for the survival outcomes of early triple-negative breast cancer treated with neoadjuvant chemotherapy: a systematic review and network meta-analysis

Abstract Background: Neoadjuvant chemotherapy (NACT) has been more frequently used in breast cancer, but it’s controversial whether NACT or adjuvant chemotherapy (ACT) is more effective in improving survival outcomes for triple-negative breast cancer (TNBC) patients. Recent studies also proposed pathologic complete response (pCR) could not be a robust surrogate for survival outcomes in certain types of breast cancer. To address these questions, a general meta-analysis and a network meta-analysis (NMA) were conducted to compare the survival outcomes of patients with pCR, non-pCR after NACT and ACT. The cut-off pCR rate was also declared to indicate when NACT produces equivalent survival outcomes to ACT (Registration: PROSPERO CRD42022336732). Methods: Databases including PubMed, Embase, Web of science and Cochrane library were searched up to June 2023 to investigate studies comparing NACT and ACT, as well as randomized controlled trials (RCTs) comparing different regimens in NACT or ACT settings in early operable TNBC patients. Heterogeneity was assessed using χ² based Q-test and I², combined with hazard ratios (HRs) with 95% confidence intervals (CI) computed for overall survival (OS), and disease-free survival (DFS, or event-free survival). The NMA with a Bayesian framework was conducted using both random and fixed effect model. The Weighted Least Square method and the Least Absolutely Deviation method were used to determine the cut-off pCR rates of OS and DFS. Results: A total of 35 studies involving 21 RCTs and 34143 TNBC patients were included. The general meta-analysis comprised 14 cohort studies. Eight high-quality cohort studies with propensity score matching and 21 RCTs were included in NMA. The pooled pCR rate for NACT was 42.2% (95% CI 37.8%-46.8%). Overall, the NACT cohort showed significantly worse OS and DFS than ACT cohort (HR=1.67, 95% CI 1.22-2.31; HR=1.37, 95% CI 1.14-1.64). However, patients with pCR after NACT showed improved OS than ACT (HR=0.58, 95% CI 0.50-0.66), while the patients without pCR after NACT had pooper OS than ACT (HR=2.03, 95% CI 1.88-2.19). As for DFS, there was no statistically difference between pCR after NACT and ACT groups (HR=1.04, 95% CI 0.63-1.73), while patients without pCR after NACT had significantly worse DFS than ACT (HR=2.65, 95% CI 1.98-3.55). From the NMA, the OS and DFS were better when combining modern target therapy such as Bevacizumab, PARPi, and PD-1/PD-L1 inhibitor (Figure 1), but not achieving pCR completely negated the benefits of newer drugs. Adding adjuvant capecitabine to patients not achieving pCR seemed to favor the OS. It was predicted that when the pCR rates were 64.7% and 46.9% (Figure 2), respectively, the OS and DFS of patients treated with NACT would be the same as those of patients treated with ACT. Conclusions: Higher pCR rate after NACT was associated with improved OS compared with ACT in TNBC patients. However, failure to achieve pCR after NACT resulted in worse survival outcomes than ACT. NACT had similar survival outcomes with ACT only when the pCR rate was at least 46.9%. The development of effective NACT regimens is beneficial for breast cancer patients. Figure 1. Forest plot of the Hazard Ratio for OS and DFS in TNBC patients pCR: pathological complete response; Bev: Bevacizumab; Pt: platinum; NACT: neoadjuvant chemotherapy; ACT: adjuvant chemotherapy; vel: veliparib; PDi:PD1/PDL1 inhibitor; X: capecitabine Figure 2. The cut-off value of pCR when NACT and ACT have the same Hazard Ratio based on OS and DFS. pCR: pathological complete response; Bev: Bevacizumab; Pt: platinum; NACT: neoadjuvant chemotherapy; ACT: adjuvant chemotherapy Citation Format: Xiaoying Qiao, Shu Wang, Taobo Hu, Baosheng Liang. Rethinking the value of pathologic complete response rate for the survival outcomes of early triple-negative breast cancer treated with neoadjuvant chemotherapy: a systematic review and network meta-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 PO1-28-09.

Abstract PO5-03-05: Rethinking the value of pathologic complete response rate for the survival outcomes of early triple-negative breast cancer treated with neoadjuvant chemotherapy: a systematic review and network meta-analysis

Abstract Background: Neoadjuvant chemotherapy (NACT) has been more frequently used in breast cancer, but it’s controversial whether NACT or adjuvant chemotherapy (ACT) is more effective in improving survival outcomes for triple-negative breast cancer (TNBC) patients. Recent studies also proposed pathologic complete response (pCR) could not be a robust surrogate for survival outcomes in certain types of breast cancer. To address these questions, a general meta-analysis and a network meta-analysis (NMA) were conducted to compare the survival outcomes of patients with pCR, non-pCR after NACT and ACT. The cut-off pCR rate was also declared to indicate when NACT produces equivalent survival outcomes to ACT (Registration: PROSPERO CRD42022336732). Methods: Databases including PubMed, Embase, Web of science and Cochrane library were searched up to June 2023 to investigate studies comparing NACT and ACT, as well as randomized controlled trials (RCTs) comparing different regimens in NACT or ACT settingsin early operable TNBC patients. Heterogeneity was assessed using χ² based Q-test and I², combined with hazard ratios (HRs) with 95% confidence intervals (CI) computed for overall survival (OS), and disease-free survival (DFS, or event-free survival). The NMA with a Bayesian framework was conducted using both random and fixed effect model. The Weighted Least Square method and the Least Absolutely Deviation method were used to determine the cut-off pCR rates of OS and DFS. Results: A total of 35 studies involving 21 RCTs and 34143 TNBC patients were included. The general meta-analysis comprised 14 cohort studies. Eight high-quality cohort studies with propensity score matching and 21 RCTs were included in NMA. The pooled pCR rate for NACT was 42.2% (95% CI 37.8%-46.8%). Overall, the NACT cohort showed significantly worse OS and DFS than ACT cohort (HR=1.67, 95% CI 1.22-2.31; HR=1.37, 95% CI 1.14-1.64). However, patients with pCR after NACT showed improved OS than ACT (HR=0.58, 95% CI 0.50-0.66), while the patients without pCR after NACT had pooper OS than ACT (HR=2.03, 95% CI 1.88-2.19). As for DFS, there was no statistically difference between pCR after NACT and ACT groups (HR=1.04, 95% CI 0.63-1.73), while patients without pCR after NACT had significantly worse DFS than ACT (HR=2.65, 95% CI 1.98-3.55). From the NMA, the OS and DFS were better when combining modern target therapy such as Bevacizumab, PARPi, and PD-1/PD-L1 inhibitor, but not achieving pCR completely negated the benefits of newer drugs. Adding adjuvant capecitabine to patients not achieving pCR seemed to favor the OS. It was predicted that when the pCR rates were 64.7% and 44.6%, respectively, the OS and DFS of patients treated with NACT would be the same as those of patients treated with ACT. Conclusions: Higher pCR rate after NACT was associated with improved OS compared with ACT in TNBC patients. However, failure to achieve pCR after NACT resulted in worse survival outcomes than ACT. NACT had similar survival outcomes with ACT only when the pCR rate was at least 44.6%. The development of effective NACT regimens is beneficial for breast cancer patients. Citation Format: Xiaoying Qiao, Taobo Hu, Baosheng Liang, Shu Wang. Rethinking the value of pathologic complete response rate for the survival outcomes of early triple-negative breast cancer treated with neoadjuvant chemotherapy: a systematic review and network meta-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 PO5-03-05.

Automated mitotic spindle hotspot counts are highly associated with clinical outcomes in systemically untreated early-stage triple-negative breast cancer

Operable triple-negative breast cancer (TNBC) has a higher risk of recurrence and death compared to other subtypes. Tumor size and nodal status are the primary clinical factors used to guide systemic treatment, while biomarkers of proliferation have not demonstrated value. Recent studies suggest that subsets of TNBC have a favorable prognosis, even without systemic therapy. We evaluated the association of fully automated mitotic spindle hotspot (AMSH) counts with recurrence-free (RFS) and overall survival (OS) in two separate cohorts of patients with early-stage TNBC who did not receive systemic therapy. AMSH counts were obtained from areas with the highest mitotic density in digitized whole slide images processed with a convolutional neural network trained to detect mitoses. In 140 patients from the Mayo Clinic TNBC cohort, AMSH counts were significantly associated with RFS and OS in a multivariable model controlling for nodal status, tumor size, and tumor-infiltrating lymphocytes (TILs) (p < 0.0001). For every 10-point increase in AMSH counts, there was a 16% increase in the risk of an RFS event (HR 1.16, 95% CI 1.08–1.25), and a 7% increase in the risk of death (HR 1.07, 95% CI 1.00–1.14). We corroborated these findings in a separate cohort of systemically untreated TNBC patients from Radboud UMC in the Netherlands. Our findings suggest that AMSH counts offer valuable prognostic information in patients with early-stage TNBC who did not receive systemic therapy, independent of tumor size, nodal status, and TILs. If further validated, AMSH counts could help inform future systemic therapy de-escalation strategies.

Comprehensive Analysis Identifies Variability in PI3K Pathway Alterations in Triple-Negative Breast Cancer Subtypes.

The PI3K pathway is frequently altered in triple-negative breast cancer (TNBC). Limited cell line and human data suggest that TNBC tumors characterized as mesenchymal (M) and luminal androgen receptor (LAR) subtypes have increased incidence of alterations in the PI3K pathway. The impact of PI3K pathway alterations across TNBC subtypes is poorly understood. Pretreatment tumor was evaluated from operable TNBC patients enrolled on a clinical trial of neoadjuvant therapy (NAT; A Robust TNBC Evaluation fraMework to Improve Survival [ClinicalTrials.gov identifier: NCT02276443]). Tumors were characterized into seven TNBC subtypes per Pietenpol criteria (basal-like 1, basal-like 2, immunomodulatory, M, mesenchymal stem-like, LAR, and unstable). Using whole-exome sequencing, RNA sequencing, and immunohistochemistry for PTEN, alterations were identified in 32 genes known to activate the PI3K pathway. Alterations in each subtype were associated with pathologic response to NAT. In evaluated patients (N = 177), there was a significant difference in the incidence of PI3K pathway alterations across TNBC subtypes (P < .01). The highest incidence of alterations was seen in LAR (81%), BL2 (79%), and M (62%) subtypes. The odds ratio for pathologic complete response (pCR) in the presence of PIK3CA mutation, PTEN mutation, and/or PTEN loss was highest in the LAR subtype and lowest in the M subtype, but these findings did not reach statistical significance. Presence of PIK3CA mutation was associated with pCR in the LAR subtype (P = .02). PI3K pathway alteration can affect response to NAT in TNBC, and targeted agents may improve outcomes, particularly in patients with M and LAR TNBC.

Association of androgen receptor and tumour-infiltrating lymphocytes with bone recurrence in triple-negative breast cancer

BackgroundAs compared to endocrine responsive breast cancer bone is less frequent site of distant recurrence in triple-negative breast cancer (TNBC). A biomarker which predicts bone recurrence would allow a more personalized treatment approach with adjuvant bisphosphonates in TNBC. Here we hypothesised that tumour expression of androgen receptor (AR) is associated with bone recurrence in TNBC. Materials and methodsPatients with operable TNBC who were treated at the Institute of Oncology Ljubljana between 2005 and 2015 and developed distant recurrence were included into our study. Nuclear expression of AR in the tissue of primary tumours was determined immunohistochemically by using the Androgen Receptor (SP107) Rabbit Monoclonal Antibody. We applied a logistic regression model to test the association between expression of AR and development of bone metastases. The model was adjusted for selected known prognostic factors and possible confounders in TNBC, including the level of the stromal tumour-infiltrating lymphocytes (sTILs). ResultsAt recurrence 45 (45 %) out of 100 patients presented with bone metastases. Additionally, seven (7 %) developed bone metastases metachronously. AR was expressed in primary tumours of 35 (35 %) women and 19 (54.3 %) developed bone recurrence. In 25 (25 %) patients sTILs were absent. Neither the proportion of AR positive cancer cells (OR = 1.00; 95 % CI 0.96–1.03; p = 1.00) nor the intensity of AR positive reaction (OR = 0.71; 95 % CI 0.02–21.4; p = 1.00) were significantly associated with bone recurrence. However, women with at least mild level of the sTILs were at significantly lower risk for bone recurrence as compared to those without any sTILs (OR = 0.01; 95 % CI < 0.01–0.08; p = 0.01). ConclusionsExpression of AR is not significantly associated with the development of bone metastases in TNBC. However, patients with absent sTILs in their primary tumours are highly susceptible for recurrence in the bone and might particularly benefit from adjuvant bisphosphonates.

The Immunomodulatory Effects of Dexamethasone on Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer.

The immunomodulatory impact of corticosteroids and concurrent chemotherapy is poorly understood within triple-negative breast cancer (TNBC). On a biochemical level, steroids have been linked to the signaling of chemotherapy-resistant pathways. However, on a clinical level, steroids play an essential role in chemotherapy tolerance through the prevention of chemotherapy-induced nausea and vomiting (CINV) and hypersensitivity reactions. Given these conflicting roles, we wanted to evaluate this interplay more rigorously in the context of early-stage TNBC. We performed a retrospective analysis of patients with operable TNBC who received neoadjuvant chemotherapy (NAC) between January 2012 and November 2018, with the primary goal of examining the dose-dependent relationship between pathological complete response (pCR) rates and corticosteroid use. Secondary endpoints included the impact of steroid dosing on overall survival (OS) and recurrence-free survival (RFS), along with a breakdown in pCR rates based on steroid doses provided during each chemotherapy phase. Further adjusted analyses were performed based on patient age, diabetic status, and anatomical stage. Finally, we explored the relationship between tumor-infiltrating lymphocytes (TILs) seen on tissue samples at baseline and dexamethasone doses in terms of pCR rates. In total, of the 174 patients screened within this study period, 116 met full eligibility criteria. Of these eligible patients, all were female, with a median age of 51.5years (27.0 to 74.0) and a mean body mass index (BMI) of 29.7 [standard deviation (SD) 7.04]. The majority were nondiabetic (80.2%). For cancer stage, 69.8% (n = 81) had stage 2 breast cancer. We found no statistically significant association between pCR rates and dexamethasone use, both in terms of the total dose (p = 0.55) and mean dose per NAC cycle (p = 0.74). Similarly, no difference was noted when adjusting for diabetic status, metformin use, or age at diagnosis, regardless of the total steroid dose provided (p = 0.72) or mean dose per cycle (p = 0.49). No meaningful changes to pCR rate were seen with higher mean or higher total steroid doses during the paclitaxel (T) phase (adjusted p = 0.16 and p = 0.76, respectively) or doxorubicin and cyclophosphamide (AC) phase (adjusted p = 0.83 and p = 0.77, respectively). Furthermore, we found no clinically significant association between dexamethasone dose and either RFS (p = 0.45) or OS (p = 0.89). Of the 56 patients who had available pre-treatment biopsy tissue samples, 27 achieved pCR, with higher TILs at baseline being associated with higher pCR rates, regardless of the mean dexamethasone dose used. Our findings demonstrate that dexamethasone has no clinically significant impact on pCR, RFS, or OS when given concurrently with NAC in patients with curative TNBC, regardless of diabetic status.

Abstract 3035: Phase I trial of alpha-lactalbumin vaccine in high-risk operable triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) has a poor prognosis and may be associated with germline mutations. α-lactalbumin (aLA) is expressed in lactating breasts but not at other times or in other tissues. Expression of aLA is found in 70% of TNBC (PMID: 27322324) so could be an immunologic target for TNBC based on the “retired protein hypothesis” (PMID: 31926646). In pre-clinical studies vaccination with aLA inhibited growth of established breast tumors and provided protection from development of autochthonous tumors in transgenic murine models of breast cancer and against 4T1 transplantable breast cancer in BALB/c mice (PMID: 20512124). Methods: To determine the safety and immunogenicity of aLA, patients with early stage TNBC are being entered in a Phase I trial of aLA with GMP-grade zymosan adjuvant in Montanide ISA 51 VG vehicle. Subjects receive 3 vaccinations given once every 2 weeks. Events of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥2 are considered dose-limiting toxicities (DLTs). Results: CTCAE toxicity by dose level is summarized below. All DLTs were injection site reactions, with ulceration and need for incisional drainage representing the grade 3 events. ELISpot assays to determine frequencies of T-cells producing IFN-γ and IL-17 in response to recombinant aLA and ELISA assays of antibody response to aLA will be available in December 2022. Conclusion: Dose level 2 appears to be the maximum tolerated dose. Accrual to dose levels 1 and 2 will be expanded to further define toxicity and immunologic effects. Accrual of patients with BRCA1 or PALB2 mutations planning to undergo prophylactic mastectomy is beginning in order to define the toxicity and immunologic effects in this group and to determine whether inflammatory changes from occult lactational foci will be produced. Funding Source: Department of Defense (W81XWH-17-1-0592 and W81XWH-17-1-0593) Worst Toxicity by Dose Level Dose Level aLAC (mcg) dose Zymosan (mcg) dose n Patients n Grade 0 n Grade 1 n Grade 2 n Grade 3 1 10 10 3 3 2 100 10 3 3 3 500 10 3 2 1 Original 2 100 100 1 1 Citation Format: George Thomas Budd, Justin M. Johnson, Emily Rhoades, Halle Moore, Holly Levengood, Megan Kruse, Erin Roesch, Jame Abraham, Brenna Elliott, Elena Haury, Rachel Swartz, Holly Pederson, Zahraa Al Hilli, Vincent Tuohy. Phase I trial of alpha-lactalbumin vaccine in high-risk operable triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3035.

Abstract OT2-10-02: Phase I trial of an alpha-lactalbumin vaccine in patients with operable triple-negative breast cancer (TNBC)

Abstract Background: Triple-negative breast cancer (TNBC) is the subtype of breast cancer with the worst prognosis and is the subtype most often associated with germline mutations of BRCA1 as well as other genes. Alpha-lactalbumin (aLA) is a milk protein expressed in lactating breasts but not at other times or in other normal tissues. Expression of aLA is found in approximately 70% of TNBC (Cancers PMID: 27322324) so is an attractive immunologic target for TNBC based on the “retired protein hypothesis” (Semin Immunol PMID: 31926646). Pre-clinical studies have shown that vaccination with aLA inhibits the growth of established breast tumors and provides potent protection from development of autochthonous tumors in transgenic murine models of breast cancer and against 4T1 transplantable breast cancer in BALB/c mice (Nat Med PMID: 20512124). Specific Aims: We are conducting a Phase I trial of vaccination with an aLA vaccine in patients with early stage TNBC to demonstrate the safety of this approach and to document the ability to produce a relevant immunologic response to aLA. Trial Design: Patients are being entered into a Phase I trial of alpha-lactalbumin with GMP-grade zymosan adjuvant in Montanide ISA 51 VG vehicle. Subjects receive a total of 3 vaccinations administered once every 2 weeks. Toxic events of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or greater are considered dose-limiting. Dose levels being tested in the current protocol are alpha-lactalbumin/zymosan 0.01/0.01, 0.1/0.01, 0.5/0.01, 0.5/0.03, and 0.5 mg/0.06 mg. Patients are being monitored for toxicity until 84 days after the first vaccination or resolution of toxicity, whichever is later. Blood is being drawn prior to therapy and 14, 28, and 56 days after the first vaccination to assess cellular response using enzyme-linked immunosorbent spot (ELISpot) assays of interferon-gamma and interleukin-17 production in response to aLA. Humoral response to aLA vaccination is being assessed by enzyme-linked immunosorbent assay (ELISA). Eligibility Criteria: Patients with ER-negative, PR-negative, HER2-negative breast cancer of pathologic stage II-III or who had residual disease after standard pre-operative systemic therapy. Participants must be within 3 years of initiation of treatment and have no evidence of recurrence. Dose Selection: Doses are being escalated using a 3+3 trial design to determine the maximum tolerated dose, the lowest immunologic dose and the optimal immunologic dose Present Accrual and Target Accrual: Dependent on toxicity, 18-30 patients will be treated. Future Plans and Contact Information: After identification of the maximum tolerated dose and expansion of the dose levels associated with effective tumor immunity we plan to enroll 2 additional cohorts of patients: 1) patients who have completed pre-operative chemo-immunotherapy and are receiving pembrolizumab as standard of care therapy, and 2) patients without cancer planning to undergo prophylactic bilateral mastectomy. Interested parties may contact Dr. Budd at buddg@ccf.org. Funding Source: Department of Defense (W81XWH-17-1-0592 and W81XWH-17-1-0593) Citation Format: George Budd, Justin M. Johnson, Emily Rhoades, Halle Moore, Megan L. Kruse, Erin Roesch, Jame Abraham, Brenna Elliott, Elena Haury, Vincent K. Tuohy. Phase I trial of an alpha-lactalbumin vaccine in patients with operable triple-negative breast cancer (TNBC) [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 OT2-10-02.

High Expression of NRF2 and Low Expression of KEAP1 Predict Worse Survival in Patients With Operable Triple-Negative Breast Cancer

High Expression of NRF2 and Low Expression of KEAP1 Predict Worse Survival in Patients With Operable Triple-Negative Breast Cancer

141MO Pathological response and early survival data according to TNBCtype4 classifier in operable triple-negative breast cancer (TNBC) treated with neoadjuvant carboplatin and docetaxel

141MO Pathological response and early survival data according to TNBCtype4 classifier in operable triple-negative breast cancer (TNBC) treated with neoadjuvant carboplatin and docetaxel

An Integrative Clinical Model for the Prediction of Pathological Complete Response in Patients with Operable Stage II and Stage III Triple-Negative Breast Cancer Receiving Neoadjuvant Chemotherapy

Simple SummaryNeoadjuvant chemotherapy (NAC) is widely used to treat stage II and III primary, operable triple-negative breast cancer (TNBC). The response to NAC critically affects the subsequent treatment plan, including not only curative surgical planning but also adjuvant therapy. There is no standard prediction model that accurately predicts NAC response. Therefore, the development of an easy-to-apply and cost-effective clinical prediction model for NAC treatment response would improve clinical practice. We propose an integrative clinical prediction model for the prediction of pathologically complete response in patients with operable stage II and stage III TNBC receiving NAC based on findings from tumor ultrasound and blood tests. All included parameters were readily available during and before NAC. This clinical prediction model could provide a reference to guide clinicians’ decisions in planning a patient’s NAC treatment as early as after the first cycle of NAC.Triple-negative breast cancer (TNBC) is treated with neoadjuvant chemotherapy (NAC). The response to NAC, particularly the probability of a complete pathological response (pCR), guides the surgical approach and adjuvant therapy. We developed a prediction model using a nomogram integrating blood tests and pre-treatment ultrasound findings for predicting pCR in patients with stage II or III operable TNBC receiving NAC. Clinical data before and after the first cycle of NAC collected from patients between 2012 and 2019 were analyzed using univariate and multivariate analyses to identify correlations with pCR. The coefficients of the significant parameters were calculated using logistic regression, and a nomogram was developed based on the logistic model to predict the probability of pCR. Eighty-eight patients were included. Five parameters correlated with the probability of pCR, including the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte (PLR) ratio, percentage change in PLR, presence of echogenic halo, and tumor height-to-width ratio. The discrimination performance of the nomogram was indicated by an area under the curve of 87.7%, and internal validation showed that the chi-square value of the Hosmer–Lemeshow test was 7.67 (p = 0.363). Thus, the integrative prediction model using clinical data can predict the probability of pCR in patients with TNBC receiving NAC.

Phase I trial of an alpha-lactalbumin vaccine in patients with moderate- to high-risk operable triple-negative breast cancer (TNBC).

TPS1125 Background: Triple-negative breast cancer (TNBC) is the subtype of breast cancer with the worst prognosis and is the subtype most often associated with germline mutations of BRCA1 and certain other genes. Alpha-lactalbumin (aLA) is a milk protein that is expressed in lactating breasts but not at other times or in other normal tissues. Expression of aLA is found in approximately 70% of TNBC (Cancers PMID: 27322324) so is an attractive immunologic target for TNBC based on the “retired protein hypothesis” (Semin Immunol PMID: 31926646). Pre-clinical studies have shown that vaccination with aLA provides treatment of established and, more potently, protection from development of autochthonous tumors in transgenic murine models of breast cancer and against 4T1 transplantable breast cancer in BALB/c mice (Nat Med PMID: 20512124). We are conducting a Phase I trial in patients with early stage TNBC to demonstrate the safety of this approach and to document the ability to produce a meaningful immunologic response to aLA. Methods: Patients with ER-negative, PR-negative, HER2-negative breast cancer of pathologic stage I-III or who had residual disease after standard pre-operative systemic therapy are being entered into a Phase I trial of alpha-lactalbumin with a GMP-grade zymosan adjuvant in Montanide ISA 51 VG vehicle. Participants must be within 3 years of initiation of treatment and have no evidence of recurrence. Patients receive a total of 3 vaccinations administered once every 2 weeks with doses escalated using a 3+3 trial design. Toxic events of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or greater are considered dose-limiting. Dose levels being tested are alpha-lactalbumin/zymosan 0.01 mg/0.01 mg, 0.1 mg/0.1 mg, and 1 mg/1 mg. Patients are being monitored for toxicity until 84 days after the first vaccination or resolution of toxicity, whichever is later. Blood is being drawn prior to therapy and 14, 28, and 56 days after the first vaccination to assess cellular response using enzyme-linked immunosorbent spot (ELISpot) assays of interferon-gamma and interleukin-17 production in response to aLA. Humoral response to aLA vaccination is being assessed by enzyme-linked immunosorbent assay (ELISA). After identification of the Maximum Tolerated Dose we will expand the dose levels associated with effective tumor immunity and enroll a cohort of patients without cancer planning to undergo prophylactic bilateral mastectomy. Funding Source: Department of Defense (W81XWH-17-1-0592 and W81XWH-17-1-0593). Clinical trial information: NCT04674306.