Carboplatin In Triple-negative Breast Cancer Research Articles

The preliminary efficacy and safety results of neoadjuvant phase 2 study of penpulimab combined with taxanes and carboplatin in triple-negative breast cancer (neoTAPPL).

e12617 Background: The KEYNOTE-522 trial demonstrated the addition of pembrolizumab to anthracycline-taxane-platinum chemotherapy improves pathologic complete response (pCR) and event free survival (EFS) in triple-negative breast cancer (TNBC). Penpulimab is a newly developed PD-1 monoclonal antibody with complete elimination of FcgR binding and ADCC/ADCP. This study aims to assess the efficacy of the anthracycline free neoadjuvant regimen of penpulimab plus carboplatin and taxanes in TNBC. Methods: In this open-label, phase 2 study, patients with untreated, histologically confirmed TNBC in stage II-III were enrolled. Patients received 6 cycles of neoadjuvant therapy with penpulimab (200 mg, d1, q3w) plus taxanes (docetaxel 75 mg/m2 or nab-paclitaxel 260 mg/m2, d1, q3w) and carboplatin (AUC=6, d1, q3w). Patients who either completed or discontinued the neoadjuvant treatment would undergo breast surgery. Adjuvant chemotherapy and immunotherapy were at the discretion of the treating physician, and radiation therapy was per standard of care. The primary endpoint was the rate of pCR based on the definition of ypT0/Tis ypN0. Secondary endpoints included residual cancer burden (RCB), EFS, overall survival (OS), adverse events (AE), and immune response biomarkers. Based on the Simon’s Two-Stage design, if >7 of 16 patients achieved pCR, the enrollment would proceed to full accrual of 46 patients as planned. If >23 of 46 patients achieved pCR, we would deem the study to have met the primary endpoint. Results: Nine out of 16 pts achieved pCR in the first stage, reaching the threshold for the second stage. From Nov 2022 to Jan 2024, 22 patients were enrolled, among which 17 patients received neoadjuvant treatment and underwent breast surgery. The median age was 51 years (range, 32-69). 13 (76.5%) patients had stage II breast cancer at diagnosis. 10 of the 17 patients achieved pCR (58.8%; 95% CI, 32.9-81.6), and 12 patients achieved RCB 0-I (70.6%; 95% CI, 44.0%-89.7%). Subgroup analysis showed the pCR rate of patients who were diagnosed initially to be lymph node negative was 75.0% (6/8), higher than that of patients who were lymph node positive (44.4%; 4/9). The ORR and DCR were 82.4% (95% CI, 56.6%-96.2%) and 88.2% (95% CI, 63.6%-98.5%), respectively. Treatment-emergent adverse events (TEAEs) of any grade occurred in all 17 pts, in which 10 (58.8%) were grade ≥3. The most common grade ≥3 TEAEs were neutropenia (47.1%), leukopenia (41.2%), anemia (23.5%), and thrombocytopenia (17.6%). 6 patients (35.3%) experienced immune related adverse events (irAEs), all of which were grade 1 hypothyroidism. Conclusions: The preliminary results demonstrated that penpulimab plus carboplatin and taxanes as neoadjuvant therapy for early-stage TNBC showed promising antitumor efficacy and manageable safety profile. The study is still ongoing. Clinical trial information: ChiCTR2300071925.

Exogenous Metabolic Modulators Improve Response to Carboplatin in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) lacks targeted therapies, leaving cytotoxic chemotherapy as the current standard treatment. However, chemotherapy resistance remains a major clinical challenge. Increased insulin-like growth factor 1 signaling can potently blunt chemotherapy response, and lysosomal processes including the nutrient scavenging pathway autophagy can enable cancer cells to evade chemotherapy-mediated cell death. Thus, we tested whether inhibition of insulin receptor/insulin-like growth factor 1 receptor with the drug BMS-754807 and/or lysosomal disruption with hydroxychloroquine (HCQ) could sensitize TNBC cells to the chemotherapy drug carboplatin. Using in vitro studies in multiple TNBC cell lines, in concert with in vivo studies employing a murine syngeneic orthotopic transplant model of TNBC, we show that BMS-754807 and HCQ each sensitized TNBC cells and tumors to carboplatin and reveal that exogenous metabolic modulators may work synergistically with carboplatin as indicated by Bliss analysis. Additionally, we demonstrate the lack of overt in vivo toxicity with our combination regimens and, therefore, propose that metabolic targeting of TNBC may be a safe and effective strategy to increase sensitivity to chemotherapy. Thus, we conclude that the use of exogenous metabolic modulators, such as BMS-754807 or HCQ, in combination with chemotherapy warrants additional study as a strategy to improve therapeutic responses in women with TNBC.

Comparative study of weekly and three-weekly neoadjuvant carboplatin in triple-negative breast cancer: retrospective analysis in real-world settings.

Tri-weekly carboplatin is an established neoadjuvant treatment for triple-negative breast cancer, enhancing pathological complete response (pCR) and overall survival. This study explores if weekly carboplatin provides lower toxicity and comparable pCR rates. A retrospective multicenter study (January 2021 to March 2023) compares outcomes of weekly and tri-weekly carboplatin. Among 104 participants, 60% received weekly and 40% tri-weekly treatments. Weekly administration had fewer discontinuations (56.5 vs. 70.7%, p=0.154). Both schedules exhibited similar overall toxicity (p=0.087), with slightly higher grade 3-4 toxicity in the tri-weekly group (56.1 vs. 48.4%, p=0.126). Hematological toxicity was comparable, but the weekly group experienced more diarrhea (p=0.432) and asthenia (p=0.012). Weekly treatment correlated with more frequent breast-conserving surgeries (p=0.004). pCR rates were 50% with weekly and 61% with tri-weekly regimens (p=0.186). Weekly carboplatin exhibited comparable toxicity, a trend toward fewer interruptions, and similar pCR rates. Prospective studies are essential for validating these findings.

Decitabine induces IRF7-mediated immune responses in p53-mutated triple-negative breast cancer: a clinical and translational study.

p53 is mutated in half of cancer cases. However, no p53-targeting drugs have been approved. Here, we reposition decitabine for triple-negative breast cancer (TNBC), a subtype with frequent p53 mutations and extremely poor prognosis. In a retrospective study on tissue microarrays with 132 TNBC cases, DNMT1 overexpression was associated with p53 mutations (P = 0.037) and poor overall survival (OS) (P = 0.010). In a prospective DEciTabinE and Carboplatin in TNBC (DETECT) trial (NCT03295552), decitabine with carboplatin produced an objective response rate (ORR) of 42% in 12 patients with stage IV TNBC. Among the 9 trialed patients with available TP53 sequencing results, the 6 patients with p53 mutations had higher ORR (3/6 vs. 0/3) and better OS (16.0 vs. 4.0 months) than the patients with wild-type p53. In a mechanistic study, isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher DNMT1 expression and decitabine sensitivity than the cell line with wild-type p53. In the DETECT trial, decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line (upregulation by 16-fold) and the most responsive patient with TNBC. Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.

Neoadjuvant carboplatin in triple-negative breast cancer: results from NACATRINE, a randomized phase II clinical trial

BackgroundNeoadjuvant chemotherapy (NACT) is the mainstay of treatment of stages II and III triple-negative breast cancer (TNBC). This study aims to evaluate if the addition of carboplatin to NACT is associated with an increase in the pathological complete response (pCR) rates in TNBC.MethodsWe conducted an open-label phase II randomized clinical trial in a single center in Brazil. Patients with stage II and III TNBC were randomized to receive standard NACT with or without carboplatin. All the patients received doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) both intravenously (i.v.) q21 days for four cycles. Patients were then randomized for additional treatment with weekly (wk) paclitaxel (80 mg/m2 i.v., for 12 cycles) plus wk carboplatin AUC 1.5 (experimental arm) or without wk carboplatin (control arm). Randomization was stratified according to gBRCA status, age, and AJCC 8th edition clinical stage (II vs. III). The primary endpoint was the pathologic complete response (pCR) rate. Secondary endpoints included recurrence-free survival and overall survival.ResultsBetween 2017 and 2021, 146 patients were randomized, 73 on each arm. The median age was 45 years. Most patients (66.4%) had locally advanced stage III disease, 67.1% had T3/T4 tumors, and 56.2% had clinically positive axillary lymph nodes. Germline BRCA status was available for all patients, and 19.9% had pathogenic BRCA1/2 variants. The pCR rate (ypT0ypN0) was numerically increased by 13.7%, being 43.8% (31 of 73 patients) in the experimental and 30.1% (22 of 73 patients) in the control arm, not meeting the prespecified goal of increasing the pCR in 15% (p-value = 0.08). Survival outcomes are immature.ConclusionThe addition of carboplatin to standard NACT in stages II and III TNBC was associated with a non-statistically significant numerical increase in the pCR rate. Follow-up for survival outcomes and translational research initiatives are ongoing.

MO18-2 A phase II trial of neoadjuvant apatinib combined with nab-paclitaxel and carboplatin in triple-negative breast cancer

Pathological complete response (pCR) is essential for improvements of prognosis in triple-negative breast cancer (TNBC). We evaluated the efficacy of apatinib combined with nab-paclitaxel and carboplatin in patients in this phase II clinical trial.

MIR4435-2HG Is a Potential Pan-Cancer Biomarker for Diagnosis and Prognosis.

The lncRNA MIR4435-2 host gene (MIR4435-2HG) is located on human chromosome 2q13, and its expression is up-regulated in 18 tumors. MIR4435-2HG participates in 6 signaling pathways to promote tumorigenesis, including the TGF-β signaling pathway, Wnt/β-catenin signaling pathway, MDM2/p53 signaling pathway, PI3K/AKT signaling pathway, Hippo signaling pathway, and MAPK/ERK signaling pathway. MIR4435-2HG competitively binds with 20 miRNAs to form a complex ceRNA network, thereby regulating the expression of downstream target genes. The high expression of MIR4435-2HG is also closely related to the clinicopathological characteristics and poor prognosis of a variety of tumors. Also, the high expression of MIR4435-2HG in peripheral blood or serum has the value of predicting the risk of 9 tumors. In addition, MIR4435-2HG participates in the mechanism of action of three cancer drugs, including resveratrol for the treatment of lung cancer, cisplatin for non-small cell lung cancer and colon cancer, and carboplatin for triple-negative breast cancer. This article systematically summarizes the diagnostic and prognostic value of MIR4435-2HG in a variety of tumors and outlines the ceRNA network and signaling pathways related to MIR4435-2HG, which will provide potential directions for future MIR4435-2HG research.

One therapeutic approach for triple-negative breast cancer: Checkpoint kinase 1 inhibitor AZD7762 combination with neoadjuvant carboplatin

Carboplatin treatment is associated with potential benefits in practice in the neoadjuvant chemotherapy for Triple-negative breast cancer (TNBC) patients. In order to enhance its anti-tumor effects, new concepts for successful combination therapy are needed. Here, we interestingly found that the combination treatment of carboplatin with the Chk1 inhibitor AZD7762 synergistically inhibits TNBC cell growth in multiple TNBC cell lines in vitro. Mechanistically, we proved that prolonged carboplatin-treated induce cell mitotic arrest, and cells would fail to initiate the G2-M transition following the inhibition of the Chk1 pathway, leading to accumulation of DNA lesions. With this drug-in-combination treatment, the incidence of mitotic catastrophes including spindle multipolarity and cytokinesis failure is remarkably enhanced, which subsequently drives tumor cells multinucleation, polyploidization and apoptosis. Thus, our findings not only propose Chk1 as a therapeutic target for combination therapy with DNA-damaging agents such as carboplatin in TNBC, but also highlight that the induction of mitotic catastrophe could be considered as an alternative strategy for TNBC therapy.

Abstract 1066: Pre-clinical combination of a PARP inhibitor, talazoparib, and carboplatin in triple-negative breast cancer

Abstract Background: PARP inhibitors, such as talazoparib, demonstrated an improvement in progression-free survival as monotherapy in germline BRCA1/2-mutated (BRCA-MUT) HER2-negative locally advanced/metastatic breast cancer patients. BRCA-MUT tumors constitute 15-20% of triple-negative breast cancers (TNBCs). TNBCs are an aggressive subtype and lack overexpression of hormone receptors and HER2. Here, we evaluate the impact of the combination of talazoparib and a chemotherapeutic agent, carboplatin, to better understand which TNBCs will benefit from this combination, and the manner in which different sequencing strategies can impact primary tumor growth and distant metastasis development. Methods: We performed a 10-day chemosensitivity assay using 7 BRCA-MUT and BRCA wild-type TNBC cell lines. We tested 9 concentrations of talazoparib (Pfizer), and carboplatin (Selleckchem) each. Post-treatment, we used automated high-content imaging with Operetta (Perkin Elmer). We calculated IC50 values for talazoparib alone, CI (Combination Index) values, the DNA damage response (product of the percentage of cells positive for 53BP1 and mean 53BP1 foci per cell), and the apoptotic index (percentage of cells positive for cleaved-PARP). We also used an orthotopic xenograft model of MDAMB231 in NSG (NOD scid gamma) mice, with 8-14 mice in each treatment group. We treated mice with carboplatin (C) (35 mg/kg intraperitoneally) in combination with talazoparib (T) (0.03 mg/kg oral gavage) using 2 dosing strategies: a) concomitant administration of C + T; and b) T first, followed by C three days later, each compared to vehicle control. Results: We found a synergistic effect of the combination of talazoparib and carboplatin (CI < 1) in all 7 cell lines, with the greatest synergy (CI< 0.65) identified in three cell lines that were PARPi (PARP inhibitor)-resistant, namely HCC1143, MDAMB231, and Hs578T. For these three cell lines, we found that the mean 53BP1 product score increased by 7-16 fold in combination versus talazoparib alone at 0.2 µM, and the apoptotic index also increased by 4-26 fold at the same conditions. Concomitant administration of talazoparib and carboplatin in the MDAMB231 xenograft resulted in a 53.1% inhibition in primary tumor volume in comparison to control (P=0.0004), whereas sequential administration resulted in a 69.2% primary tumor volume inhibition (P<0.0001). The talazoparib first combination approach also resulted in a 53.9% decrease in lung micrometastasis (P=0.0003). Conclusion: The combination of talazoparib and carboplatin demonstrated a synergistic effect in 7 TNBC cell lines. We found greater DNA damage and cell death amongst PARPi-resistant cell lines and at lower concentrations of talazoparib when combined with carboplatin. In-vivo, sequential administration of talazoparib and carboplatin was the most effective approach to inhibit primary tumor growth. Citation Format: Alexia Cotte, Michèle Beniey, Takrima Haque, Nelly Béchir, Audrey Hubert, Korotoum W. Diallo, Danh Tran-Thanh, Saima N. Hassan. Pre-clinical combination of a PARP inhibitor, talazoparib, and carboplatin in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1066.

Abstract PD14-09: Nci 10013 - A randomized phase 2 study of neoadjuvant carboplatin and paclitaxel, with or without atezolizumab in triple negative breast cancer (TNBC)

Abstract Background Inhibition of PD-L1 with atezolizumab combined with chemotherapy has shown acceptable safety and improved survival in patients with metastatic PD-L1 positive triple negative breast cancer (TNBC). Patients with TNBC who do not achieve a pathological complete response (pCR) to neoadjuvant chemotherapy have a high risk of disease recurrence and death. This randomized, open-label, phase 2 trial evaluates neoadjuvant carboplatin and paclitaxel with or without atezolizumab in patients with previously untreated clinical stages II and III TNBC. Methods Women aged ≥18 years with clinical stage T2-T4c, any N, M0 primary tumor by AJCC 7th edition staging TNBC; ECOG PS 0-2; and no prior systemic therapy for the indexed breast cancer were eligible. Patients were randomized in a 1:2 ratio to carboplatin AUC5 q 3 weeks x 4 + paclitaxel 80 mg/m2 q week x 12 (Arm A), or carboplatin AUC5 q 3 weeks x 4 + paclitaxel 80 mg/m2 q week x 12 + atezolizumab 1200 mg q3 weeks x 4 (Arm B). Surgery was 3-6 weeks following neoadjuvant chemotherapy. Adjuvant dose-dense doxorubicin and cyclophosphamide was administered q2 weeks with growth factor support to all patients as per routine care. pCR and tumor infiltrating lymphocyte (TIL) percentages are the co-primary endpoints. pCR-evaluable population includes all eligible women who have been randomized and received at least one dose of combination therapy, while the TIL-evaluable population includes all eligible women who have evaluable TIL percentage after one cycle of therapy. A sample size of 67 (22 in Arm A, and 45 in Arm B) provided 80% power at 1-sided alpha = 0.10 to detect a minimum of 15% difference in TIL and 29% improvement (40% vs. 69%) in pCR, respectively. Herein, we report pCR results in the per protocol modified intent-to-treat population (mITT), which includes all eligible patients who were randomized and received at least one dose of combination therapy. Results Sixty-seven patients were randomized between 8/2017 and 9/2019. Six patients randomized to Arm A withdrew consent; 2 of these received protocol therapy but are excluded from the mITT analyses as they are not evaluable because definitive pathology reports are not available. Median follow up is 6 months (range 0.3 - 12.6 months). Median age is 52 years (range 25 - 78). Forty-three (64.2%) were Caucasian and thirteen (19.4%) were African American. Twenty-five (37.3%) were pre-menopausal. 67.2% and 32.8% had stages II and III disease respectively. Nine (13.4%) had a germline mutation in either BRCA1 or BRCA2. In the mITT population, 3 of 16 patients achieved pCR in Arm A - 18.8% (95% CI 4.0%- 45.6%), versus 25 of 45 patients in Arm B - 55.6% (95% CI 40.0%-70.4%); p value 0.018. pCR in those with BRCA mutations was 50% and 80% in Arm A and Arm B, respectively. Treatment delays were observed in 9 patients (40.9%) in Arm A, and 20 (44.4%) in Arm B; dose reductions occurred in 4 patients (18.1%) in Arm A, and in 6 (13.3%) in Arm B. There were 4 SAEs in Arm A and 10 in Arm B. One patient in Arm B had grade 3 adrenal insufficiency. One patient in Arm B died from recurrent disease during the follow-up period. Conclusions: The addition of atezolizumab to neoadjuvant carboplatin and paclitaxel resulted in an increased pCR rate in patients with clinical stages II and III TNBC. However, the pCR in the control Arm A was lower than expected, possibly due to the absence of neoadjuvant anthracyclines. The high pCR rate observed in the experimental arm of this study is similar to that observed in other neoadjuvant trials utilizing anthracyclines, taxanes, and carboplatin in TNBC. Clinical trial information: NCT02883062. Citation Format: Foluso O Ademuyiwa, Feng Gao, Ina Chen, Donald W Northfelt, Robert Wesolowski, Mili Arora, Adam Brufsky, Claire Dees, Cesar A Santa-Maria, Roisin M Connolly, Jeremy Force, Alvaro Moreno-Aspitia, Sarah Larson, Elad Sharon, William Gillanders. Nci 10013 - A randomized phase 2 study of neoadjuvant carboplatin and paclitaxel, with or without atezolizumab in triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD14-09.

160O Survival analysis of the randomized phase III GeparOcto trial comparing neoadjuvant chemotherapy (NACT) of iddEPC versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer, TNBC) (PM(Cb)) for patients (pts) with high-risk early breast cancer (BC)

160O Survival analysis of the randomized phase III GeparOcto trial comparing neoadjuvant chemotherapy (NACT) of iddEPC versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer, TNBC) (PM(Cb)) for patients (pts) with high-risk early breast cancer (BC)

Dasatinib attenuates overexpression of Src signaling induced by the combination treatment of veliparib plus carboplatin in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) has a poor prognosis because of limited treatment options. The combination of a poly ADP ribose polymerase (PARP) inhibitor with a DNA-damaging agent has shown promise in treating TNBC; however, not all patients respond to this combination. The Src protein kinase modulates multiple cancer cell properties and plays a key role in tumorigenic processes. However, Src inhibitors as single agents have shown limited effects in solid tumors. Here, we examined the antitumor effects of the Src inhibitor dasatinib, the PARP inhibitor veliparib, and the DNA-damaging agent carboplatin in TNBC models to try and identify the combination with the most clinical potential. Dasatinib, veliparib and carboplatin were tested in TNBC cells in vitro and in xenograft tumors in vivo. Surprisingly, treatment with the combination of veliparib plus carboplatin led to an increase in Src phosphorylation. Importantly, dasatinib attenuated Src overexpression induced by veliparib plus carboplatin and further inhibited the downstream signaling of Src. In xenograft models, the triple combination of dasatinib with veliparib plus carboplatin showed greater tumor growth inhibitory effects compared with single agents or double combinations. No systemic toxicity was observed in mice treated with the triple combination. This study emphasizes the merit of evaluating the triple combination therapy, dasatinib with veliparib plus carboplatin, in TNBC clinical trials.

Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response—final results from GeparSixto

BackgroundIn the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD). Patients and methodsPatients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA). ResultsA significantly better DFS (hazard ratio 0.56, 95% CI 0.34–0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) [odds ratio (OR) 2.60, 95% CI 1.26–5.37, P = 0.008]. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46–9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17–1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23–1.04, P = 0.059). ConclusionsThe addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.

PEARLY: A randomized, multicenter, open-label, phase III trial comparing anthracyclines followed by taxane versus anthracyclines followed by taxane plus carboplatin as (neo)adjuvant therapy in patients with early triple-negative breast cancer.

TPS587 Background: Triple-negative breast cancer (TNBC) is an aggressive tumor with poor prognosis. There are no molecular targets for TNBC, and there is an unmet need to provide new drugs to patients with TNBC. Platinum agents are known to have an anti-tumor activity in TNBC, especially in BRCA-mutated tumor. Addition of carboplatin significantly increased pathologic complete response rates with neoadjuvant chemotherapy in recent randomized studies. There are no data about adjuvant role of carboplatin for TNBC in a randomized trial. Methods: PEARLY is a randomized, multicenter, open-label, phase III trial comparing anthracyclines followed by taxane versus anthracyclines followed by taxane plus carboplatin as (neo)adjuvant therapy in patients with triple-negative breast cancer (TNBC). Patients with stage II or III TNBC who need adjuvant or neoadjuvant chemotherapy were included. Any prior systemic therapy for breast cancer was not allowed. Bilateral, metastatic, and inflammatory breast cancer are excluded. A total of 840 patients will be enrolled for 3 years. Patients were randomized 1:1, stratified based on the node positivity (N0 vs N+), institution, treatment setting (neoadjuvant vs. adjuvant), and BRCA mutation status (positive vs. negative). Standard arm treatment consists of doxorubicin 60 mg/m2 IV + cyclophosphamide 600 mg/m2 IV every 3 weeks for 4 cycles followed by taxane treatment (paclitaxel 80 mg/m2 IV weekly for 12 doses or docetaxel 75mg/m2 IV every 3 weeks for 4 cycles). Experimental arm added carboplatin AUC5 IV every 3 weeks for 4 cycles during taxane treatment. The primary objective was to evaluate 5-year event free survival (EFS) rate. Secondary objectives included overall survival, distant recurrence free survival, pathologic complete response, and tolerability. The analysis is planned at 248 EFS events, which provides approximately 80% power to detect superiority of standard treatment plus carboplatin versus standard treatment using a log-rank test, assuming a hazard ratio of 0.7 at a two sided alpha of 0.05. Data is expected in 2023. Clinical trial information: NCT02441933.

Abstract P3-06-16: Thrombocytopenia is associated with pathological complete response to neoadjuvant carboplatin/docetaxel chemotherapy in BRCA wild type triple negative breast cancer

Abstract Introduction: Growing evidence demonstrates activity of neoadjuvant carboplatin in triple negative breast cancer (TNBC). Underlying germline and somatic Homologous Recombination (HR) repair deficiency may predict response to DNA damaging agents like platinum compounds in TNBC. Certain DNA repair machinery genes (Fanconi Anemia gene) are also involved in the maintenance of hematopoetic stem cell (HSC) function and impaired repair of DNA double strand breaks can lead to HSC and progenitor cell dysfunction. Thus, in presence of HR defects DNA damaging chemotherapy may lead to unique hematological toxicity. It is also possible that in presence of HR defects breast cancer response and hematological toxicity with DNA damaging agents will parallel each other. Aim: To evaluate the impact of hematological toxicity on response to neoadjuvant Carboplatin/Docetaxel chemotherapy in patients with sporadic and BRCA associated TNBC utilizing clinical and BRCA mutation data from a prospective TNBC registry. Methods: 288 patients with Stage I (T>1cm) II and III TNBC were enrolled on a multisite prospective registry between 3/2011 to 4/2014, out of which 49 patients received neoadjuvant Carboplatin AUC 6 + Docetaxel 75mg/m2 every 21 days (4-6 cycles) and have undergone breast surgery. Carboplatin was dosed using the modified Cockcroft-Gault formula. Hematologic toxicity was graded using the CTCAE version 4.03. All patients received prophylactic pegfilgrastim on day 2. Pathological complete response (pCR) was defined as absence of invasive disease in the breast and axilla. All patients underwent comprehensive BRACAnalysis®(Myriad). Results: For the 49 eligible patients median age was 50 years, median weight was 172 lbs, 18% were African American, and 37% had LN+ disease. 26% (13 /49) of patients carried deleterious BRCA mutation (9 BRCA1, 4 BRCA2). pCR of the cohort was 65%. Overall 61%, 96%, and 12 % patients demonstrated > Grade1 thrombocytopenia (Tp), anemia, or neutropenia, respectively; 4%, 6%, and 6% patients demonstrated grade 3/4 thrombocytopenia, anemia, or neutropenia, respectively. There was no association between pCR and anemia or neutropenia. Carboplatin dose reductions/delays/omission was more common in patients with Tp compared to patients without Tp (33% vs. 5%; p=0.02). Patients with Tp were more likely to achieve a pCR compared to patients without Tp (85% vs. 47%; p=0.013). 77% of BRCA carriers and 64% of BRCA wild type TNBC demonstrated Tp (NS). pCR rates in BRCA wild type patients with and without Tp were 82% and 47%, respectively (p=0.041). pCR rates in BRCA mutation carriers with and without Tp were 89% and 50%, respectively (p=0.20). On multivariable platelet count was independently associated with pCR (p=0.001)Conclusions: Tp was associated with decreased dose delivery of carboplatin but an improved pCR in BRCA wild type TNBC. Comprehensive assessment of HR defects beyond germline BRCA mutation status may be required to elucidate the biological process that explains this observation. Tp may be a harbinger of underlying HR deficiency and further correlative studies exploring this association of Tp with pathological response to carboplatin in TNBC are warranted. Citation Format: Priyanka Sharma, Benjamin C Powers, Bruce F Kimler, Claire Ward, Jennifer R Klemp, Carol S Connor, Marilee K McGinness, Joshua MV Mammen, Jamie L Wagner, Qamar J Khan, Roy A Jensen, Andrew K Godwin, Carol J Fabian. Thrombocytopenia is associated with pathological complete response to neoadjuvant carboplatin/docetaxel chemotherapy in BRCA wild type triple negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-16.

36th annual San Antonio Breast Cancer Symposium. Resumen de lo más destacado

Among the many papers were presented at the 36th San Antonio Breast Cancer Symposium in 2013; the most important −mainly oral presentations−are summarized below. Notable for their clinical applicability were two studies on the management of the primary tumor in metastatic breast cancer and the PRIME II trial evaluating the impact of omitting adjuvant radiotherapy in elderly patients. The expected data from the BETH trial, evaluating the benefit of adding bevacizumab in the adjuvant treatment of HER2-positive tumors, were also reported, and interesting information was presented on the efficacy of carboplatin in triple-negative breast cancer. From the point of view of tumor biology, the organizers wanted to provide a platform for the potential role of immunity in the prognosis of breast cancer, and mutations in the estrogen receptor gene, which are emerging as a new mechanism of acquisition of hormone resistance.

Multicentre phase II trial of bevacizumab combined with docetaxel–carboplatin for the neoadjuvant treatment of triple-negative breast cancer (KCSG BR-0905)

BackgroundThis phase II neoadjuvant trial evaluated bevacizumab–docetaxel and carboplatin in triple-negative breast cancer. Patients and methodsWomen with hormone receptor- and human epidermal growth factor receptor 2 (HER2)-negative, stage II/III breast cancer received six cycles of 75 mg/m2 docetaxel, carboplatin (AUC = 5) and 15 mg/kg bevacizumab every 21 days. The primary end point was pathological complete response (pCR) in breasts and axillary lymph nodes (ALN). ResultsForty-five patients were recruited from the Korean Cancer Study Group. The median age was 45 (range 30–72) years. ALNs were positive in 80% of patients (n = 36) at diagnosis. Overall, 98% of patients (n = 44) completed therapy and underwent surgery. The pCR rate was 42% (n = 19); clinical response rate 96% (n = 43); complete 13% (n = 6); partial 82% (n = 37); stable disease 2% (n = 1). Breast-conserving surgery was undertaken in 78% of patients (n = 35). Most frequent grade 3/4 adverse events were neutropenia (84%, n = 38) and febrile neutropenia (9%, n = 4). One patient experienced delayed wound healing after surgery. ConclusionsNeoadjuvant bevacizumab, docetaxel and carboplatin resulted in an encouraging pCR rate and negligible wound healing problems after surgery.

A multicenter phase II neoadjuvant trial of bevacizumab combined with docetaxel plus carboplatin in the treatment of triple-negative breast cancer: Korean Cancer Study Group (KCSG-BR 0905, NCT 01208480).

2542 Background: Triple negative breast cancer (TNBC) is dismal disease that is ineligible for endocrine or anti-HER2 therapy. We have conducted a phase II neoadjuvant trial to evaluate efficacy and tolerability of bevacizumab combined with docetaxel plus carboplatin in TNBC. Methods: Women with a histologically confirmed stage II or III TNBC were eligible. Hormone receptors and HER2 negativity were confirmed by immunohistochemistry and/or fluorescence in situ hybridization. Patients received 6 cycles of docetaxel 75 mg/m2, carboplatin AUC 5, and bevacizumab 15 mg/kg on day1 every 21 days. Bevacizumab was omitted in the last cycle to avoid wound complication. The primary endpoint was pathologic complete response (pCR) rate in both breast and axillary lymph node and secondary endpoints were clinical response rate, toxicity profiles, and breast conserving surgery (BCS) rate. Results: Forty-five TNBC patients were recruited from 7 institutes in the Korean Cancer Study Group (KCSG) between October 2010 and August 2011. The median age of the patients was 45 years (30-72 years). The T1, T2, and T3 were 4.4 %, 68.9 %, and 26.7 %, respectively and axillary lymph node was positive in 80% by breast MRI. Among 45 patients, 44 patients completed 6 cycles of therapy followed by surgery and one patient was withdrawn due to patient’s refusal of further therapy after 3rd cycle. The pCR rate was 42.2 % (19/45) and clinical response rate was 95.5 % (43/45) (CR, n= 6; PR, n=37; SD, n=1; not evaluable, n=1) based on RECIST criteria 1.1. BCS was undertaken in 77.7 % (35/45). The grade 3 or 4 adverse events were neutropenia (38), febrile neutropenia (4), vomiting (3), nausea (2), anemia (1), thrombocytopenia (1), stomatitis (1), gastrointestinal bleeding (1), and increased ALT (1). Only one patient experienced delayed wound healing after breast surgery. Conclusions: Bevacizumab in combination with docetaxel and carboplatin as neoadjuvant treatment provided an encouraging pCR rate (42.2 %) and a negligible wound healing problem after surgery. The adverse events were manageable.