Expert consensus recommendations on the daily clinical use of pembrolizumab for early triple-negative breast cancer.

e12521 Background: Triple-negative breast cancer (TNBC) accounts for 10–15% of all breast cancer cases and is associated with poor outcomes. Neoadjuvant chemotherapy is the standard treatment for early TNBC (eTNBC) to achieve a pathologic complete response which is associated with long-term clinical outcomes and to guide adjuvant treatment for residual disease after definitive surgery. Pembrolizumab, a programmed death 1 (PD-1) inhibitor, is approved for the peri-operative treatment of stage II and III TNBC. The Hong Kong Breast Cancer Foundation (HKBCF) convened a multi-disciplinary consensus consisting of surgeons, and clinical and medical oncologists to discuss the implementation of immunotherapy in the peri-operative setting and provide expert guidance on topics lacking definitive evidence from the KEYNOTE-522 study in daily clinical routine. Methods: The panel included 7 breast surgeons, 6 clinical oncologists, and 3 medical oncologists representing the academic, public, and private settings in Hong Kong. A modified Delphi panel was conducted, testing the panel on 7 different topics and 45 statements relating to the peri-operative treatment of eTNBC. Evidence was graded according to GRADE. Statements were initially voted by online form on a 6-point Likert scale, and the results were discussed during a consensus meeting. Consensus to accept was considered at a median ≥5 and an IQR ≤1.75 and consensus to reject at median ≤2 and an IQR ≤1.75. Results: Key findings are that the panel considered 1) the uncommon subtype “oestrogen receptor (ER)-low” does not formally meet the definition of TNBC but should be treated as TNBC; 2) pembrolizumab as a viable addition in the peri-operative setting; 3) guideline-recommended NAC for cT1c disease may be considered; but 4) this does not necessarily mean immunotherapy should be added, though it may be considered case-by-case. Furthermore, the panel 5) agreed that pembrolizumab prescription does not need to be guided by PD-L1 expression, and 6) that for patients with residual disease after NAC plus pembrolizumab, the addition of capecitabine to pembrolizumab is acceptable, however, 7) was divided about the addition of a PARPi to pembrolizumab for patients with a germline BRCA1/2 mutation (g BRCA1/2m) and residual disease — guided by the lack of routine g BRCA1/2m testing in Hong Kong. Finally, the panel 8) proposed to recommend adhering to the KEYNOTE-522 weekly paclitaxel regimen with a subclause to consider 3-weekly regimen as an alternative for specific technical or logistical challenges. Conclusions: The KEYNOTE-522 study has provided robust evidence on the efficacy and safety of peri-operative pembrolizumab in eTNBC patients. However, several clinical questions remain unanswered, and until further evidence is available, the HKBCF recommendations provide expert guidance on the use of pembrolizumab for eTNBC patients in daily clinical practice.

Multidisciplinary considerations in the treatment of triple-negative breast cancer.

PurposeIn recent years, many meta-analyses of triple-negative breast cancer (TNBC) treatment have been published; however, these studies still lack systematic summary. Therefore, the aim of this study is to summarize and evaluate the evidence level and efficacy of treatment for TNBC.Materials and MethodsRetrospective and prospective studies on treatment of TNBC were searched in the PubMed, Embase, and Cochrane Library databases. The literature search deadline was June 30, 2021. Two investigators independently screened the literature and extracted the data. In addition, the joint World Health Organization–United Nations Food and Agriculture Organization expert consultation was used to evaluate the validity of the evidence.ResultsA total of 28 meta-analyses were included in this study. The treatment interventions for TNBC mainly included surgery, chemotherapy (CT), radiotherapy, molecular targeted therapy, immunotherapy, zoledronic acid, and gonadotropin-releasing hormone (GnRH) analog. Platinum improves the pathological complete response (PCR) rate of patients treated with neoadjuvant chemotherapy (NACT), the objective remission rate (ORR) and overall survival (OS) in patients with metastatic triple-negative breast cancer. Capecitabine improves disease-free survival (DFS) and OS in patients treated with adjuvant CT. Bevacizumab was added to NACT to improve the PCR rate in patients. Immunotherapy improves the PCR rate in patients treated with NACT. The improvement in PCR rate in patients with high Ki67 expression treated with neoadjuvant therapy is highly suggestive. Other interventions had suggestive or weak evidence.ConclusionAmong the strategies for treating TNBC, platinum, bevacizumab, and immunotherapy can lead to better PCR rates as part of a NACT regimen. Capecitabine as adjuvant CT and platinum in the treatment of metastatic TNBC can benefit patients’ survival. However, the effectiveness of other interventions for TNBC is not yet clear. Further research is needed in the future to obtain more reliable clinical evidence.

Pathologic Complete Response in Triple Negative Breast Cancer of Black vs White Patients in the Post-Keynote 522 Era Melanie Sheen MD, Victoria Chung DO, Ruby Maini MD, Michael Duggan BS, Julia Levy BS Background Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) gene amplification. Women with TNBC have worse survival outcomes and increased rates of relapse and distant metastasis as compared to women with non-TNBC. Treatment of TNBC has recently been focused on neoadjuvant chemotherapy (NACT) with a goal of achieving a pathologic complete response (pCR) which is associated with longer event-free survival and overall survival. The KEYNOTE-522 trial was presented at the San Antonio Breast Cancer Symposium in December 2019 and found that patients who received pembrolizumab, an anti–programmed death 1 (PD-1) monoclonal antibody, plus NACT were more likely to achieve pCR than women who received placebo plus NACT. On July 26, 2021, the FDA approved the use of pembrolizumab in combination with NACT for high risk, early stage TNBC. KEYNOTE-522 did not collect race as a baseline demographic characteristic, and since TNBC disproportionately affects younger women and Black women, confirming the efficacy of achieving pCR in these groups is essential. Further investigation of the factors that may contribute to achieving pCR in women treated with pembrolizumab for TNBC is warranted. We set out to perform a retrospective analysis examining the rates of pCR in Black versus White patients with TNBC since the initial revelation of the KEYNOTE-522 data. Methods This retrospective chart review of a regional health care network included patients who had been diagnosed with Stage II/III TNBC, documented race as Black/African-American or White, and received treatment with pembrolizumab in the NACT setting. Exclusion criteria included ER-positivity, PR-positivity, HER2-positivity, or unknown receptor status, no pembrolizumab in the neoadjuvant setting, absence of documented race, and age < 18 years-old. Data was collected using Epic SlicerDicer program. Results 118 patients met inclusion criteria. 59 (50.0%) were Black/African American, 59 (50.0%) were white. There were 57 (48.3%) patients who had pCR status identified through pathology reports while the remaining 61 (51.7%) are still undergoing NACT awaiting surgery. 34 Black women and 17 white women have not had surgery yet. Of women who underwent surgery, 12 Black women achieved pCR compared to 15 White women. 13 Black women and 16 White women did not have pCR Discussion Analysis of the data demonstrates an equal number of Black and White women receiving NACT with pembrolizumab. Of those women, there was relatively equal number of pCR between Black and White women. This data shows no appreciable difference in outcomes of Black and White women in terms of response to therapy. Conclusion Given the known association of pCR with increased survival, pembrolizumab should be considered in the treatment regimen for both Black and White women with stage II/III TNBC. This retrospective study is limited by a small patient population. Continued data collection is underway and will be updated. Citation Format: Melanie Sheen, Victoria Chung, Ruby Maini, Michael Duggan, Julia Levy. Pathologic Complete Response in Triple Negative Breast Cancer of Black vs White Patients in the Post-Keynote 522 Era [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 P4-06-11.

Background: Combination immunotherapy (IO) and chemotherapy (CT) for triple-negative breast cancer (TNBC) improves overall survival (OS) over CT alone in both the neoadjuvant and metastatic setting. Large-scale real-world analysis of IO +/- CT for TNBC has been limited to date. We present prescribing patterns and OS of initial chemo-immunotherapy treatments in a large US population-based cohort of TNBC patients. Methods: Patients with TNBC diagnosed from 2018-2020 were identified in the National Cancer Database (NCDB), a US-wide oncology outcomes database. Those with undocumented staging and stage 0 disease were excluded. The primary outcome, OS, was evaluated by initial treatment: chemotherapy/IO (CT/IO), chemotherapy/no IO (CT), IO/no chemotherapy (IO), or no chemotherapy/no IO (NT), using cox proportional hazards models and Kaplan-Meier methods. The secondary objective was real world practice patterns. Categorical variables were compared between the groups using a Chi-square test. Age was compared using a Kruskal-Wallis test. Results: 58,128 new TNBC diagnoses were identified in NCDB between 2018-2020, with 6.7% de novo metastatic. IO use steadily increased over time (2018 = 19.5%, 2019 = 31.0%, 2020 = 49.5%). Academic research programs most commonly used IO. Most patients received CT (73.3%, n = 32,858), with 5.6% (n=3276) receiving CT/IO, 0.1% (n=66) receiving IO, and 20.5% (n=11,926) NT following initial diagnosis. CT +/- IO use was associated with younger age, whereas IO alone or NT was more common in older patients (median age: CT/IO = 55 years [y], CT = 58y, IO = 71y, NT = 72y; p< 0.001). Treatment with CT/IO or CT was most common among private insurers (57.6% and 53.3%, respectively) whereas Medicare was the most common payor for IO or NT (59.1% and 64.1%, respectively; p<0.001). Proportionally, stage I TNBC received less treatment (CT/IO 13.3%, CT 34.1%, IO 18.2%, NT 55.3%; p< 0.001) and single agent IO treatment was more common in stage IV TNBC (CT/IO 24.3%, CT 4.9%, IO 53.0%, NT 8.4%; p< 0.001). Pathologic complete response (pCR) rates after neoadjuvant chemotherapy (NACT; n = 27,900) differed by treatment group, with pCR most common following CT (CT/IO 27.6%, CT 29.6%, IO 16.7%, NT 1.8%; p<0.001). OS was similar among treatment groups in the full TNBC population, with median survival for NT at 36 months. Race differed significantly between treatment (p<0.001). Among White patients with TNBC (70.9%), 72.1% received CT/IO and 70.5% received CT. However, among Black patients with TNBC (11.9%), 19.4% received CT/IO and 23.6% received CT. OS was highest in the CT group, whereas the IO only group had the worst survival outcome – even worse than NT (hazard ratio (HR) CT 0.52, IO 2.22, NT 1.17; ref CT/IO, p< 0.001 each HR). Nonetheless, Black race was associated with worse OS than White race and the addition of IO to CT did not fully mitigate the OS racial gap (HR Black CT/IO 1.38, White CT 0.52, Black CT 0.65; ref White CT/IO, p< 0.001 each HR). Conclusions: This large NCDB cohort analysis of newly diagnosed TNBC cases revealed practice patterns for initial TNBC treatment varies widely. Furthermore, this analysis captured new TNBC diagnoses from 2018 to 2020 and describes significant off-label use of IO+/- CT in both the NACT (Keynote-522 FDA approval 2021) and metastatic (ImPassion130 FDA accelerated approval 2019) settings with some relation to the payor. In addition, single agent IO use was higher than expected for stage IV and resulted in worse OS, again raising concerns of off-label use of the tumor agnostic IO approvals (tumor mutation burden-high, microsatellite instability). Finally, racial discrepancies of use and efficacy of IO was present. Further studies and interventions are needed to address TNBC treatment disparities. Citation Format: Dionisia Quiroga, Julie A Stephens, Gilbert Bader, Mathew A Cherian, Ashley P Davenport, Kai CC Johnson, Sagar Sardesai, Daniel Stover, Robert Wesolowski, Nicole Williams, Nerea Lopetegui-Lia, Arya M Roy, Samilia Obeng-Gyasi, Bridget A Oppong, Sachin R Jhawar, Margaret E Gatti-Mays. Real-world first-line immunotherapy use and overall survival rates for triple-negative breast cancer: analyses from a 2018-2020 US population-based cohort [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-10-03.

BACKGROUND: Approximately 50% of TNBC pts treated with standard taxane/anthracycline-based NACT will have chemo-insensitive disease (CID) manifested as extensive residual disease (RCB-II or III) at the time of surgery. 40-80% of these pts will develop recurrence within 3 years of initial diagnosis. Recent advances in molecular profiling have identified subsets of TNBC with distinct, targetable molecular features. We developed a clinical trial to identify and characterize CID (ARTEMIS: A Randomized, TNBC Enrolling trial to confirm Molecular profiling Improves Survival). In the ARTEMIS trial, treatment naïve pts with localized TNBC undergo a pretreatment biopsy and then immediately start their initial phase of anthracycline-based chemotherapy so that the results of the molecular characterization are used in combination with response assessment (clinical exam/diagnostic imaging) to identify CID and inform the second phase of NACT, thus using a 'second hit' strategy in the middle of NACT to overcome drug resistance. The mesenchymal subtypes of TNBC have a high incidence of PI3K pathway activation. Preclinical models demonstrated response to PI3K inhibitors in this subtype. Metaplastic breast cancers make up ∼30% of tumors characterized as 'claudin-low/mesenchymal' by gene signature and are also associated with a high rate of PI3K activating molecular aberrations. A combination regimen of liposomal doxorubicin, bevacizumab and the mTOR inhibitors temsirolimus or everolimus (DAT or DAE) demonstrated response (including durable complete responses) in metastatic metaplastic breast cancer. PRIMARY OBJECTIVE: Determine the rate of pathologic complete response (pCR/RCB-0) or minimal residual disease (RCB-I) after 4 cycles of DAE for treatment of mesenchymal TNBC deemed to be CID through the ARTEMIS trial TRIAL DESIGN AND STATISTICAL METHODS: Only pts deemed to have mesenchymal CID on the ARTEMIS trial can enter this non-randomized phase II study. Realizing that pts without response to their initial cycles of chemotherapy have very low chance (5%) of achieving pCR with additional cycles of chemotherapy, it would be clinically meaningful to see pCR in this pt population improved to 20%. Counting pCR (RCB-0) or RCB-I as response, a two-stage Gehan-type design will be employed with 14 pts in the first stage. If at least one pt responds, 23 more pts will be added for a total of 37 pts. This design has a 49% chance of terminating after the first stage if the true response rate is 0.05, 23% chance if the true rate is 0.10, 10% if the true rate is 0.15 and 4% if the true rate is 0.20. If accrual continues to the second stage and a total of 37 pts are enrolled, the 95% confidence interval for a 0.20 response rate will extend from 0.10 to 0.35. BRIEF ELIGIBILITY CRITERIA: Inclusion: localized TNBC enrolled onto ARTEMIS trial, adequate organ, bone marrow and cardiac parameters Exclusion: metastatic disease, pregnant or lactating pts, medical illness that increases chance of moderate to severe toxicity CORRELATIVE SCIENCE: Correlate vimentin expression by IHC, mesenchymal signatures and PI3K pathway aberrations with response. Citation Format: Moulder S, Hess K, Rauch M, Astrada B, Litton J, Mittendorf E, Ueno N, Tripathy D, Lim B, Piwnica-Worms H, Thompson A, Symmans WF. NCT02456857: A phase II trial of liposomal doxorubicin, bevacizumab and everolimus (DAE) in patients (pts) with localized triple-negative breast cancer (TNBC) with tumors predicted insensitive to standard neoadjuvant chemotherapy (NACT) [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 OT2-01-22.

Background: Neoadjuvant chemotherapy (NAC) is standard of care for the majority of patients with clinical stage II-III triple negative breast cancer (TNBC) and is considered in high-risk patients with hormone receptor positive (HR+)/human epidermal growth factor receptor 2 (HER2) negative (-) tumors, with expected pathological complete response (pCR) rates of 40-60% and 10-12%, respectively. In HER2- patients with residual disease (RD) after NAC, there is limited data on rates of gain of HER2 amplification. The biological and clinical significance of this phenomenon is unknown and determining the best adjuvant therapy for these patients remains a challenge. We sought to determine the rate of HER2 gain in a cohort of consecutive patients with HER2- breast cancer (BC) treated with NAC. Methods: From 01/2021 to 12/2021, we identified patients with HER2- breast cancer treated with NAC followed by surgery at our institution. Patients who received neoadjuvant endocrine therapy were excluded. The rates of pCR (ypT0/is ypN0) and HER2 status pre- and post-NAC were assessed. Estrogen receptor (ER), progesterone receptor (PR) and HER2 status on surgery specimens were internally determined for all patients using ASCO/CAP 2020 guidelines. ER-low was defined as ER expression by immunohistochemistry (IHC) 1-10%. Results: We included 256 patients, 130 (51%) HR+/HER2- [13/130(10%) ER-low] and 126 (49%) TNBC. Median age was 48 years (range 25-82) and the majority presented with clinical T2 (57%) and N1 (59%). Of 130 patients with HR+/HER2-tumors, 120 (92%) received dose-dense (dd) doxorubicin/cyclophosphamide-paclitaxel (AC-T). Of 126 TNBC patients, 46 (37%) received ddAC followed by carboplatin in combination with paclitaxel +/- pembrolizumab. Centralized HER2 status assessment on the core biopsy was performed in 22% of samples. Overall, pCR was achieved in 40% of TNBC and 11% of HR+/HER2-. Among the 192 patients with RD, the rate of HER2 gain was 8/192 (4%), including 3% (2/76) of TNBC and 5% (6/116) of HR+/HER2- patients. 7 of the 8 patients (88%) converted from IHC 1+ or 2+ fluorescence in situ hybridization (FISH) not amplified on core biopsy to IHC 2+ FISH amplified on the surgical specimen. In only 1 case, the HER2 status converted from IHC2+ FISH not amplified to IHC3+. 3/8 patients had multifocal disease. All 6 patients with HR+/HER2- BC and HER2 gain had high (>90%) ER expression (Table 1). All but one patient with HER2 gain received adjuvant anti-HER2 therapy. After a median follow-up of 10 months, no recurrence events occurred in this group.12 of the remaining 184 patients experienced a recurrence [11 distant recurrences (8 and 3, in the TNBC and HR+/HER2- groups, respectively), and there was 1 local event (localized chest wall recurrence) in the HR+/HER2- group]. Conclusions: At a single center, we found that in patients with HER2- BC treated with NAC, HER2 gain in patients with RD was uncommon and occurred more frequently in those with HR+ tumors. Analysis of a larger cohort is ongoing to corroborate these results. It is remains to be determined if this phenomenon represents a true HER2 status conversion or tumor heterogeneity. Table 1: Clinico-pathological characteristics of patients with HER2 gain on residual disease Citation Format: Emanuela Ferraro, Sonya Chew Minmin, Anton Safonov, Andrea V. Barrio, Shanu Modi, Andrew D Seidman, Hanna Y Wen, Edi Brogi, Mark E. Robson, Chau T Dang. Gain of HER2 Amplification in Patients with HR+/HER2- and Triple Negative Early Breast Cancer Treated with Neoadjuvant Chemotherapy [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 P4-02-14.

Breast cancer is one of the most common malignant tumors in women in the world, and its incidence is increasing year by year, which seriously threatens the physical and mental health of women. Triple negative breast cancer (TNBC) is a special molecular type of breast cancer in which estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2 are negative. Compared with other molecular types of breast cancer, triple-negative breast cancer (TNBC) has high aggressiveness and metastasis, high recurrence rate, lack of effective therapeutic targets, and usually poor clinical treatment effect. Chemotherapy was the main therapeutic means used in the past. With the advent of the immune era, immunotherapy has made a lot of progress in the treatment of triple-negative breast cancer (TNBC), bringing new therapeutic hope for the treatment of triple-negative breast cancer. This review combines the results of cutting-edge medical research, mainly summarizes the research progress of immunotherapy, and summarizes the main treatment methods of triple-negative breast cancer (TNBC) immunotherapy, including immune checkpoint inhibitors, tumor vaccines, adoptive immunotherapy and the application of traditional Chinese and western medicine. It provides a new idea for the treatment of triple negative breast cancer (TNBC).

Background: Neoadjuvant chemotherapy (NACT) is the standard early-stage triple-negative breast cancer (TNBC) treatment. Achieving pathological complete response (pCR) is considered an essential prognostic factor with favorable long-term outcomes. Younger patients have with poorer prognosis in breast cancer. To date, few studies are comparing the prognosis of AYA and older women (≥40) with breast cancer subtypes, specifically Triple-negative breast cancer (TNBC), as AYAs had higher proportions of this subtype. Method: Retrospective review was performed on female patients who received NACT at a King Hussien Cancer Center from January 2014 to June 2020. Data were collected from patients’ electronic medical records. TNBC was histopathologically confirmed. Logistic regression analysis of predictors of pathologic complete response (pCR). Survival curves were estimated with the Kaplan-Meier method. Multivariate analysis for EFS was performed using Cox’s proportional hazards regression model, covariates included age at diagnosis (AYA vs. ≥40), tumor size, nodal status LVI and pCR Result: We analyzed 211 women with stage I-III TNBC, including 62 (29.4%) women aged 18 to 39 years (AYA) and 149 (70.6%) ≥40 years. 138 (68.3%) were node positive, and 71 (34.8%) were T3/4 disease. Median follow-up was 28.1 months, median number of ER visit during NAC is 1 (0-11), 23 (10.9 %) patients had admission during neoadjuvant chemotherapy, most commonly due to febrile neutropenia 13 (56.9%). 37 (17.5%) patients did not complete NAC, due to disease progression in 22 (10.4%), and toxicity in 15 (7.1%) patients. 195 (92.4%) patients had surgery, including 75 (35.5%) had breast-conserving surgery (BCS). 166 (76.3%) patients had objective response, and 64 (30.3%) had pCR. 170 (80.6%) received adjuvant radiotherapy, and 38 (18%) received adjuvant capecitabine. No significant differences between the AYA and the ≥40 group in terms of clinicopathological, toxicity, pCR rate, and the rate of BCS. In univariate analysis, the LVI, nodal status, pCR, and age group were significant predictors of DFS. In multivariate analysis, only PCR and age are the only independent predictor of DFS. The median DFS was worse in the AYA population 47.8 (31.21-64.39) months vs. NR in ≥40 (p-value 0.013). In patients who achieved pCR, the estimated 5-years DFS for the AYA group was 56.1% versus 86.8% for the ≥40 group, (p-value 0.71). In patients with residual disease, PFS for AYA was 34.2 (95%CI 11.5-57) months vs. 59.5 months in the ≥40 group, (p 0.009). Conclusion: Although there is no difference in pCR between the AYA age group patient treated with NACT for TNBC and the older age group, the DFS is significantly worse in the AYA than the ≥40 age group in patients with residual disease. As well, DFS is numerically worse in the AYA age vs. the ≥40 age group in patients who achieved pCR. Citation Format: Faris Tamimi, Baha’ Sharaf, Suhaib Khater, Suhaib Al-Sawajneh, Malek Horani, Khalid M. Elrabii, Anas Zayed, Hikmat Abdel-Razeq. Neoadjuvant B27 protocol in Triple-Negative Breast Cancer: Evaluation response rate, pathological complete response rates,toxicity,and the prognosis of Adolescent and Young Adult (AYA) age group compared to older population [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 P4-06-06.

Rationale and purpose: Triple negative breast cancers (TNBCs), characterized by lack of hormone receptors' expression in absence of HER2 amplification, partially overlap with the basal-like subtype, with frequent occurrence in BRCA1 mutation carriers (BRCA1+). TNBCs are often associated with earlier onset, interval cancer diagnosis, larger size and aggressive clinical course with peak risk of recurrence at 1-3 years and increased mortality rate in the first 5 years. Thus, when screening women at high risk of breast cancer, special attention should be paid to patient outcome for TNBCs in comparison with non-TNBCs. Our aim was to compare TNBCs and non-TNBCs diagnosed during a prospective, non-randomized, multimodality screening study – including clinical breast examination (CBE), mammography, ultrasound (US) and magnetic resonance imaging (MRI) – on women at familial/genetic high risk of breast cancer conducted in 18 centres from June 2000 to March 2008 (ISS-HIBCRIT-1; Sardanelli F et al, Invest Radiol 2011). Methods: Comparisons were performed using Mann-Whitney U, Fisher exact and χ2 tests. Results: Among the 44 patients diagnosed with invasive cancers, 14 (31%) were TNBCs and 30 (69%) non-TNBCs, the former being 13 invasive ductal (IDC) and 1 atypical medullary carcinoma, the latter also including 15/30 lobular subtypes and/or DCIS component (p=0.005). Of the 14 TNBCs, 10 (71%) were found in BRCA1+, 2 (14%) in BRCA2+ and 2 (14%) in BRCA-untested women with strong family history of breast/ovarian cancer; the same data for 30 non-TNBCs were 9 (30%), 6 (20%) and 15 (50%) respectively (p=0.028). We had only three interval cancers, all TNBCs. The median age at diagnosis was 49 years (range 36-62) for TNBCs and 53 years (range 35-72) for non-TNBCs (p=n.s). TNBCs presented a higher rate (11/14, 79%) of pathological grade 3 IDCs compared with non-TNBCs (8/30, 27%) (p=0.002). The mean tumor size was 1.6 cm for TNBCs and 1.2 cm for non-TNBCs (p=n.s). Nodal status was negative in 12/14 (86%) TNBCs and in only 16/30 (53%) non-TNBCs (p=0.038). MRI similarly outperformed CBE, mammography and US in both TNBCs and non-TNBCs. Clinical course and survival could be monitored for 40/44 patients (91%), 13 TNBCs and 27 non-TNBCs, with a follow-up of 5.8 and 6.3 years (p=n.s) respectively. The rate of disease-free patients for over 5 years was 8/13 (62%; mean disease-free interval 7.0 years, range 5.0-8.0) for TNBCs and 17/27 (63%; mean 7.2 years, range 5.2-9.9) for non-TNBCs. Death due to BC occurred for 2/13 TNBC (15%, at 3.5 and 4.2 years) and 3/27 non-TNBC patients (11%; at 2.0, 4.9 and 5.7 years). The rate of locoregional relapse was 1/13 (8%, at 4.4 years) and 5/27 (19%; mean time of 5.0 years, range 2.4-7.0) respectively. Distant recurrence was reported for only 2 non-TNBC patients. Conclusion: TNBCs showed stronger association with BRCA1+ status, lower rate of lobular subtypes or DCIS component, and less frequent nodal involvement. Despite a more frequent pathological grade 3 and the tendency to be diagnosed as interval cancers, under the current treatment protocols TNBCs showed relapse and BC-related death rates and over-5-year disease-free intervals similar to those of non-TNBCs. These data provide outcome evidence supporting the value of entering women at high risk of TNBC (in particular BRCA1+) in intensive screening programs including MRI. Citation Format: Franca Podo, Filippo Santoro, Siranoush Manoukian, Clelia de Giacomi, Laura Cortesi, Lorenzo Preda, Stefano Corcione, Francesco Sardanelli. High-risk patients found affected with breast cancer during a multimodality screening program: Triple negative versus non-triple negative breast cancers. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B13.

lncRNA MIR503HG inhibits cell proliferation and promotes apoptosis in TNBC cells via the miR-224-5p/HOXA9 axis

Introduction. The standard treatment for non-metastatic triple-negative breast cancer (TNBC) is neoadjuvant chemotherapy (NAC) and nearly 50% exhibit pathological complete response (pCR). However, patients with residual disease after NAC are at increased risk for recurrence and death. Prior studies examining the transcriptome of TNBC pre/post-NAC have examined a limited number of genes (<500) in heterogeneous subgroups of TNBC (e.g. LAR and non-LAR). We explored the transcriptome of androgen-receptor (AR) negative (non-LAR) TNBC subtype both pre/post NAC to identify pathways associated with NAC response. Methods. Tumors obtained pre/post NAC from TNBC patients enrolled in the Breast Cancer Genome Guided therapy study (BEAUTY) underwent RNA sequencing and reverse-phase protein array (RPPA). EdgeR was applied for differentially expressed (DE) analysis and regression methods for RPPA. Digital deconvolution method (CIBERSORTx) and TNBC single-cell data were used to obtain cell types. Pathway analysis was carried out using 2972 gene sets and gene set variation analysis (GSVA). Functional enrichment analysis was conducted with significant genes. Results. Of the 44 TNBC patients, 32 patients were excluded from the analysis cohort due to: LAR tumor (6 pts.), non-LAR tumor with pCR (23 pts.), and cell type issues with RNA-seq data (3 pt.). Paired RNA-Seq data were available for 12 TNBC patients (4 with progression <2 years [EP]) and 8 who were progression-free > 4 years [NP]) and paired RPPA data were available for 9 of these 12 patients. Differentially expressed genes, proteins and cell types between EP and NP in post-NAC. We identified 489 genes differentially expressed (DE) between EP and NP (logFC=|2|, FDR < 0.05). Analysis of cytobands from these 489 genes showed an enrichment of genes on chromosome 6p22.1-2 and 17q25.3 regions (enrichment ratio >5; p-value <10E-4). Critical genes identified in the AR- network (p-value < 10E-3) were IL1RN, SLAMF9, KRT81, BHLHE22, B3GALT5, PCP4, TREM1, AQP9, NRTN, and COL2A1.In addition, preliminary results from RPPA data of post-NAC tumors showed astrocytic phosphoprotein (PEA-15), involved in apoptosis, proliferation, glucose metabolism, as well as cell proliferation and Y box binding (YB1) proteins (involved in metastases), were more DE in EP than NP (p < 0.05). CIBERSORTx was applied to estimate the proportions of different cell types in post-NAC tumors. Cancer-associated fibroblasts iCAFs were low and myCAFs are high in EP vs NP. It is known that the cross-talk between CAFs and tumor cells may induce tumor resistance to chemotherapy. Differentially expressed pathways in post and pre-NAC EP tumors. Using genome-wide expression data from the paired 12 tumors and the GSVA method, we obtained individual pathway scores for 2972 pathways. One hundred ninety pathways were downregulated and 61 pathways were upregulated (p-value <= 0.05) in the post-NAC residual disease of EP relative to NP. We further examined these 190 pathways in the paired EPs and found 71% of those pathways were upregulated in the pre-NAC. These 190 downregulated pathways were enriched with FOXO, TGF-beta, PI3k, FGFR1, insulin and others. The 61 upregulated pathways in post-NAC EP tumors were enriched with mismatch repair, purine, tubulin, telomere, polymerase and gap-junction related pathways; 77% of those 61 pathways were downregulated in pre-NAC. Conclusions. Using a comprehensive “omics” approach, we have identified novel cancer and drug response pathways associated with recurrence in AR-TNBC disease. Further work to evaluate these as markers of outcome and potential drug targets is warranted. Citation Format: Krishna R Kalari, Vera J Suman, Xiaojia Tang, Jason P Sinnwell, Kevin J Thompson, Peter T Vedell, Jodi M Carter, Sarah A McLaughlin, Alvaro Moreno Aspitia, Donald W Northfelt, Richard J Gray, Richard Weinshilboum, Liewei Wang, Judy C Boughey, Matthew Goetz. Multi-omics data shows downregulation of mismatch repair, purin and tublin pathways in AR-negative triple-negative chemotherapy-resistant tumors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-01-05.

Neoadjuvant chemotherapy is the foundation treatment for triple-negative breast cancer (TNBC) and frequently results in pathological complete response (pCR). However, there are large differences in clinical response and survival after neoadjuvant chemotherapy of TNBC patients. The aim was to identify genes whose expression significantly associates with the efficacy of neoadjuvant chemotherapy in patients with TNBC. Transcriptomes of 46 formalin-fixed paraffin-embedded (FFPE) tumor samples from TNBC patients were analyzed by RNA-seq by comparing 26 TNBCs with pCR versus 20 TNBCs with pathological partial remission (pPR). Subsequently, we narrowed down the list of genes to those that strongly correlated with drug sensitivity of 63 breast cancer cell lines based on Dependency Map Consortium data re-analysis. Furthermore, the list of genes was limited to those presenting specific expression in breast tumor cells as revealed in three large published single-cell RNA-seq breast cancer datasets. Finally, we analyzed which of the selected genes were significantly associated with overall survival (OS) in TNBC TCGA dataset. A total of 105 genes were significantly differentially expressed in comparison between pPR versus pCR. As revealed by PLSR analysis in breast cancer cell lines, out of 105 deregulated genes, 42 were associated with sensitivity to docetaxel, doxorubicin, paclitaxel, and/or cyclophosphamide. We found that 24 out of 42 sensitivity-associated genes displayed intermediate or strong expression in breast malignant cells using single-cell RNAseq re-analysis. Finally, 10 out of 24 genes were significantly associated with overall survival in TNBC TCGA dataset. Our RNA-seq-based findings suggest that there might be transcriptomic signature consisted of 24 genes specifically expressed in tumor malignant cells for predicting neoadjuvant response in FFPE samples from TNBC patients prior to treatment initiation. Additionally, nine out of 24 genes were potential survival predictors in TNBC. This group of 24 genes should be further investigated for its potential to be translated into a predictive test(s).

Background: Patients with triple-negative breast cancer (TNBC) have a high unmet therapeutic need with a generally poor prognosis. Initial data from two randomised, phase III trials of capecitabine (C) in early breast cancer (EBC), ABCSG-24 and FinXX, are promising. ABCSG-24 demonstrated significant improvements in pathological complete response (pCR) rate with the incorporation of C into a neoadjuvant regimen of epirubicin (E) plus docetaxel (D) (24.3% vs 16.0%; p=0.02) [Steger G, et al. ECCO-ESMO 2009; Abst 4BA]. FinXX revealed significant improvements in 3-year recurrence-free survival (RFS) with the addition of C to a sequential taxane-anthracycline adjuvant regimen (92.5% vs 88.9% control; hazard ratio [HR] 0.66, 95% CI 0.47-0.94; p=0.020) [Joensuu H, et al. Lancet Oncol 2009]. We review subgroup analyses from these two studies in patients with TNBC to assess the potential benefit of C in this patient subgroup. Methods: Patients with operable breast cancer except T4d, ± nodal involvement were randomised in the ABCSG-24 study to 6x ED every 21 days (dl: E 75mg/m2 and D 75mg/m2, d2: pegfilgrastim 6mg) ± C (1,000mg/m2 b.i.d., d1-14). Patients with medium-to high risk EBC were randomised in the FinXX study to 3x D≥3x CycEF (D 80mg/m2 d1→cyclophosphamide [Cyc] 600mg/m2 d1, E 75mg/m2 d1, F 600mg/m2 d1, every 21 days) or 3x CD≥3x CycEC (C 900mg/m2 bid d1-15 + D 60mg/m2 d1→Cyc 600mg/m2 d1, E 75mg/m2 d1, C 900mg/m2 b.i.d., d1-15, every 21 days). Results: Patients with TNBC in the ABCSG-24 study (n=122) had a significantly greater chance of achieving a pCR than non-TNBC (n=348) (odds ratio [OR] 5.29, 95% CI: 3.22-8.68, P<0.0001), irrespective of the regimen. In the total study population, the highest pCR rates were achieved in patients with TNBC receiving EDC therapy (47.5% vs 31.2% with ED; p=NS). Patients with TNBC in the FinXX study (n=202) had significantly shorter RFS than patients without TNBC (n=1,294) (81.7% vs 92.2%, HR 0.43, 95% CI 0.29-0.63; P<0.001). Within the TNBC subgroup, 3-year RFS was significantly longer in the C-containing arm (n=93) than in the control arm (n=109) (87.7% vs 76.6%, respectively; HR 0.43, 95% CI 0.21-0.90; p=0.024). RFS did not differ significantly in the C arm among patients with TNBC or non-TNBC (HR 0.74, 95% CI: 0.38-1.41; p=0.357). Conclusions: Initial data for C in EBC are promising with the ABCSG-24 and FinXX randomised, phase III trials demonstrating significant improvements in pCR and RFS, respectively, with the addition of C to standard (neo)adjuvant regimens. Exploratory subgroup analyses from these studies show additional benefit of C therapy in patients with TNBC, who are typically recognised as a group with poorer prognosis. An ongoing randomised, phase III study conducted by the CIBOMA collaborative group is prospectively investigating C maintenance therapy after adjuvant anthracycline/taxane in patients with TNBC. This is the first study of C to specifically target patients with early TNBC and interim safety data are expected in 2010. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD01-03.

Introduction The treatment landscape of early triple-negative breast cancer (TNBC) has recently expanded after the Food and Drug Administration (FDA) approval of pembrolizumab in combination with neoadjuvant chemotherapy. The addition of this immune checkpoint inhibitor (ICI) has shown significantly increased pathological complete response (pCR) rate and event-free survival (EFS) in the KEYNOTE-522 phase III trial. Several additional studies are ongoing with the goal of further improving the outcomes and achieving an optimal integration of ICIs in the treatment of TNBC. Areas covered The article examines pCR and survival rates in TNBC. It appraises clinical trials investigating neoadjuvant ICIs for TNBC and the improvement of pCR rates (biomarker-driven escalation of treatment, optimization of chemotherapy backbone, and addition of locoregional treatments or innovative agents). Insights into the role of pCR as a surrogate endpoint and the possibility of enhancing pCR rates for women affected by early TNBC are offered. Expert opinion The pharmacopoeia of early TNBC is growing and becoming more heterogeneous with the advent of ICIs; to enhance the clinical benefit of patients, it is necessary to develop response endpoints that consider the mechanism of action of experimental drugs, to optimize patient selection through validated biomarkers, and to compare the most promising treatment strategies in randomized clinical trials.