Anthracycline Taxane Research Articles

Treatment (Tx) patterns, efficacy and safety of eribulin for advanced and heavily pretreated breast cancer (ABC): Updated results from a single-center, real-world study.

e13118 Background: We evaluated the Tx patterns, efficacy and safety of eribulin for heavily pretreated ABC in real-world practice. Previous results were reported at the 2023 ASCO (e13118), updated results for longer follow-up and additional enrollment are presented here. Methods: Patients (pts) with ABC who had progression on anthracycline taxane Tx and received eribulin (1.4 mg/m2 IV on Days 1 and 8 of a 21-day cycle) between April 2020 and October 2023 were enrolled. Response was evaluated using RECIST v1.1. Pts were considered as taxanes sensitive if taxanes treatment duration of last line use exceeds 6 months, otherwise were considered as taxanes resistant. Results: 89 pts were enrolled. Median (range) age was 54 (30–79) years; 80.9% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1, and 40.4% pts had a median of 3 prior lines of chemotherapy. 67.4% of pts had Ki67 >30% and 46.0% had HR+/HER2− disease. 88.7% of pts had visceral metastasis. Eribulin was monotherapy in 30.3% of pts, and combined with bevacizumab, capecitabine, bevacizumab + capecitabine, and anti-HER2 agents in 28.1%, 9.0%, 3.4%, and 25.8%, respectively. The objective response rate was 22.5%; disease control rate was 84.3%. Median progression-free survival (PFS) overall was 6.0 (95% CI, [3.5–8.5]) months (mo). Univariate analysis indicated pts with HER2+ disease had longer PFS than pts with HR+/HER2− or triple-negative BC (median, 13.5, 4.5, and 3.7 mo, respectively; P = 0.011; Table). Pts with Ki67 expression ≤30% had longer PFS than pts with Ki67 >30% (median, 8.0 vs. 4.0 mo; P = 0.02). Pts with grade I-II had longer PFS than pts with grade III (median, 10.5 vs. 4.0 mo; P = 0.003). Pts sensitive to Taxane had longer PFS than pts resistant to Taxane (median, 8.0 vs. 4.0 mo; P = 0.007). Among the 18 pts with a partial response, median PFS was 11.4 mo. The most common adverse events were leukopenia (44.9%), neutropenia (37.1%) and anemia (36.0%). Neurotoxicity was rare (6.7%). Conclusions: In this single-center study of pts with heavily pre-treated ABC in China, eribulin Tx resulted in favorable PFS irrespective of molecular subtype, with a manageable safety profile. In pts with a large tumor burden and a good PS, eribulin-based combinations may further improve outcomes. [Table: see text]

Abstract PO4-01-12: Efficacy of neoadjuvant dose-dense versus standard chemotherapy regimens in ER+ HER2-negative breast cancer: a single-center matched-cohort study. Exploratory analysis of immune markers

Abstract Introduction: Dose-dense adjuvant CT improves long-term outcomes, which has been proved in clinical trials and meta-analysis. However, the efficiency of thе modern dose dence (dd) anthracycline-taxane (A-T) sequential regimens in the neoadjuvant (NA) setting of ER+HER2- breast cancer (BC) has not been assessed. Tumour-infiltrating lymphocytes (TILs) play a key role in the formation of anti-tumor immunity and can be one of the markers of treatment efficacy and prognosis. Studies evaluating TILs in ER+ BC have mixed results. Materials and methods. The aim of the study was to assess the rate of RCB 0-I of 4xddAC (doxorubicine/cyclophosphamide)–T (4xdocetaxel once every 3 weeks or 12xpaclitaxel weekly) NA chemo compared to standart regimen and to study the subpopulation composition of the lymphoid infiltrate and its effect on achieving RCB 0-I. RCB 0-I as a primary end point was chosen due comparable long-term results in ER+HER2- BC as per meta-analisys. Results: The study included pts with stage II-III ER+(ER≥10%) HER2- BC who received NA A-T chemo in a single center from Jan 2017 to Aug 2022. The majority of patients (85,2%) had stage III disease. Statistical hypothesis: NA ddAC–T chemo would increase the rate of RCB 0-1 to 32% from 22% with ACq3w (once every 3 weeks)-T, with a study power of 80%, ά = 0.05, 138 patients should be included in the study. A total of 315 patients were included, 147 received ddAC-T and 168 - ACq3w-T. After propensity matching analysis 138 patients in each group were included in the final analysis. TILs were studied in core-biopsy samples before NA chemo in 79 patients by flow cytometry. The following 8 subpopulations of lymphocytes were assessed as percentage in the cell pool: CD3+, CD3+CD4+, CD3+CD8+, CD4+CD127+CD25+, CD3-CD19+, CD3-CD16+CD56+, CD3+CD16+CD5+, CD8+CD279+(PD-1). The results are presented in medians (Me) due to abnormal distribution. The RCB 0 rate was 18.8% in the ddAC-T group vs 14.5% in the ACq3w-T group (p=0.379), RCB 0-1 - 33.3% vs 21.7% respectively (p=0.04). According to subgroup analysis, significant benefit of ddAC regimen found in patients ≤ 50 y.o., cN0, with PR ≥20%. For the following populations of TILs significant differences in Me for RCB0-I vs RCB II-III were observed: CD3+CD8+, CD3–CD19+, CD3–CD19+, CD8+CD279+. In multivariative analisys CD8+CD279+(PD-1)≤Me proved to be an independent predictive factor for RCB 0-I (p=0,048). Immunological signature CD8+CD279+ ≤ Me, CD3+CD8+ ≤ Me, CD4+CD25+ > Me, CD3-CD19+ > Me was associated with the rate of 66,7% of RCB 0-I vs 0% with the signature with the opposite values. Conclusion: ddAC-T NA chemo compared to standart regimen in ER+HER2- BC increases RCB0-1 rate. CD8+CD279+(PD-1)≤Me is an independent predictive factor for RCB 0-I. Citation Format: Elena Kovalenko, Elena Artamonova, Yaroslav Zhulikov, Maxim Khoroshilov, Alexander Petrovskiy, Igor Vorotnikov, Tatiana Zabotina, Zaira Kadagidze. Efficacy of neoadjuvant dose-dense versus standard chemotherapy regimens in ER+ HER2-negative breast cancer: a single-center matched-cohort study. Exploratory analysis of immune markers [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 PO4-01-12.

Toxicity and Solution of Trastuzumab Combined Therapy

Trastuzumab is a kind of monoclonal antibody widely used in cancer, especially in breast and stomach cancer. Due to the HER-2 expression in cardiomyocytes, it is most likely to affect normal cardiac function. Although combination therapies can reduce its toxicity to some extent, we still found toxicity in some combination therapies. In this review, we aim to summarize and analyze the toxicity found in combination therapy and give novel solutions to them. We have analyzed the combination toxicity including trastuzumab with ACE inhibitor, premedication, Emtansine, doxorubicin, and anthracycline taxane chemotherapy regimen. And we chose two main solutions as examples, including serum biomarkers and zingerone.

Abstract P3-07-14: A phase II study of CFI-400945 in patients with advanced/metastatic cancer: Canadian Cancer Trials Group (CCTG) IND.237

Abstract Background: CFI-400945 is a selective oral inhibitor of Polo-like Kinase 4 (PLK4), a controller of centriole duplication and mitotic progression identified by functional screening of genomically unstable breast cancer (BC). IND.237 (NCT01954316) is an open label, multicentre, phase 2 study in HER2 negative metastatic breast cancer (MBC) with 3 cohorts, 1 enriched for PTEN loss of function. Enrollment started in 2018 at 64mg based on a previously established recommended phase 2 dose (RP2D). The initial patients had higher than expected grade 3/4 neutropenia which led to a voluntary hold and dose de-escalation; the new RP2D was declared at 32mg as previously reported Here we report the results of the phase 2 study of CFI-400945 in advanced BC patients. Materials and Methods: 49 patients were enrolled across 3 cohorts: 1: triple negative; 2: ER+/HER2- PTEN low (by IHC); 3: ER+/HER2-, PTEN intact. The primary outcome is objective response rate (ORR); secondary outcomes included disease control rate (DCR) >16w, and safety. A Simon 2-stage design was used (9 – 25 pts planned for each cohort). CFI-400945 would be considered active if ≥3 responses were observed in any given cohort. Eligibility included ECOG 0-1, adequate organ function and receipt of at ≥1 prior line of cytotoxic chemotherapy in any setting including anthracycline taxane (unless contraindicated). Treatment was 32mg 7d on 7d off in cycle 1 (cycle length=28d), then continuously starting cycle 2. Safety assessments were performed each cycle and response (RECIST 1.1) every 2 cycles. Results: 60 patients have been screened, 49 enrolled: 10 were in initial dose ranging and were excluded from phase 2 response assessment. 10 patients were enrolled in cohort 1, 4 in cohort 2, and 25 in cohort 3. Table 1 presents patient characteristics and response results. 1 patient in cohort 3 has not had disease re-assessed at time of abstract submission. The most common adverse events have been cytopenias, nausea, fatigue, headache, constipation and vomiting. Less than 5% of patients experienced a non-hematologic AE > grade 3; 33% experienced ≥ grade 3 neutropenia. Conclusions: CFI-400945 32mg is well tolerated in this MBC population with moderate incidence of uncomplicated neutropenia. The TNBC cohort so this arm has been closed to further accrual for lack of responses. The PTEN loss group has been slow to accrue and remains open. Responses in the ER+/HER2- arm are encouraging – results from patients remaining on study are awaited and correlative studies to identify features associated with responses are underway. Acknowledgements: Sponsored by the Canadian Cancer Trials Group. Supported by Stand Up To Cancer Canada (scientific partner AACR) Canadian Cancer Society (CCS) Breast Cancer Dream Team Research Funding, Ontario Institute for Cancer Research (funding provided by the Government of Ontario) and grants from CCS to CCTG. Table 1. Table 1. Patient characteristics and response rates in each cohort treated with CFI-400945. Citation Format: David W. Cescon, John Hilton, Philippe Bedard, Phillip Blanchette, Rossanna C. Pezo, Ayesha Bashir, Vikaash Kumar, Terry L. Ng, Arif Awan, Anthony Lott, Jacques Antoun Raphael, Linda Hagerman, Mark Bray, Lindsay Muyot, Jesus Fuentes Antras, Lesley Seymour, Dongsheng Tu, Pierre-Olivier Gaudreau, Moira Rushton. A phase II study of CFI-400945 in patients with advanced/metastatic cancer: Canadian Cancer Trials Group (CCTG) IND.237 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-14.

196P Molecular profiling to identify recurrent mutations comparing pre and post-neoadjuvant chemotherapy tumour specimens of TNBC patients with residual disease

The change in mutational landscape of TNBC patients with residual disease after neoadjuvant chemotherapy(NAC) might provide valuable insights into its biology and provide targets for therapy. TNBC patients with residual disease after anthracycline taxane NAC +/- platinum were included. Archival paired (pre and post NAC) samples were processed for NGS with a custom-designed 72-gene panel. The sequences were aligned to human reference genome (GRCh37/hg19) using BWA program. Somatic mutations identified using UMI corrected .clc pipeline and LoFreq (v2) variant caller. Mutations annotated using in-house annotation pipeline (VariMAT). Gene annotation of the variants was performed using VeP program against the Ensembl release 90 human gene Model. 25 patients treated from 2018-2019 were included. 72% patients had stage III disease. Among all 50 tumour samples (pre and post NAC), a median of 12 mutations per sample was observed. 73.5% were missense mutations. Post Platinum NAC an average of 12.8±7 gene mutations were seen and 11.3±5 gene mutations without platinum(p 0.94). Following platinum-NAC, the common genes mutated were TP53(81%), AR(62%), PTEN(62%), PMS2(43%) and ERBB2(33%). In post-NAC samples, private mutations were present only in the platinum group. The major differences between no platinum vs. platinum group was seen with AKT1 (50 vs. 14.3%; p 0.17), MSH6(50 vs. 14.3%; p 0.17), ERBB2(75 vs. 33.3%; p 0.16), HRAS(25 vs. 4.8%; p 0.3) and STK11 (0 vs. 33.3%; p 0.24). Five patients had recurrence of breast cancer. Post-NAC they had on average 14±7 mutated genes vs. 12.2±6 in those recurrence-free (p 0.49).Table: 196PProportion of patients with mutationsPre-NACPost-NACTP53(80%)TP53(84%)PMS2(64%)AR(60%)PTEN(64%)PTEN(60%)ERBB2(48%)PMS2(44%)NOTCH1(44%)ERBB2(40%)Recurrence-freeRecurrent diseaseTP53(85%)TP53(80%)PTEN(65%)AR(60%)AR(60%)ERBB2(60%)PMS2(45%)PMS2(45%)SMARCA4(40%)AKT1(40%) Open table in a new tab The somatic mutational profile was distinct comparing pre vs. post-NAC tumour samples, platinum vs. non-platinum NAC and recurrence vs. no recurrence. AR mutations were present in a higher proportion post-NAC. These findings need further elucidation in larger prospective studies.

26P Evaluation of tumor-infiltrating lymphocytes on matched baseline and residual disease samples of triple-negative breast cancer patients treated with anthracycline-taxane based neoadjuvant chemotherapy with or without carboplatin

In patients with triple-negative breast cancer (TNBC) undergoing neoadjuvant chemotherapy (NACT), higher tumor-infiltrating lymphocytes (TILs) strongly correlate with increased rates of pathologic complete response (pCR) and improved survival. The aim of the present work is to investigate the changes of TIL levels from baseline biopsy to residual disease (RD) in TNBC patients failing to achieve pCR after standard NACT with anthracycline-taxane (A-T) +/- carboplatin (Cb).

Evaluating anthracycline\u2009+\u2009taxane versus taxane-based chemotherapy in older women with node-negative triple-negative breast cancer: a SEER-Medicare study

PurposeAdjuvant chemotherapy reduces recurrence in early-stage triple-negative breast cancer (TNBC). However, data are lacking evaluating anthracycline + taxane (ATAX) versus taxane-based (TAX) chemotherapy in older women with node-negative TNBC, as they are often excluded from trials. The purpose of this study was to evaluate the effect of adjuvant ATAX versus TAX on cancer-specific (CSS) and overall survival (OS) in older patients with node-negative TNBC.Patients and methodsUsing the SEER-Medicare database, we selected patients aged ≥ 66 years diagnosed with Stage T1-4N0M0 TNBC between 2010 and 2015 (N = 3348). Kaplan–Meier survival curves and adjusted Cox proportional hazards models were used to estimate 3-year OS and CSS. Multivariant Cox regression analysis was used to identify independent factors associated with use of ATAX compared to TAX.ResultsApproximately half (N = 1679) of patients identified received chemotherapy and of these, 58.6% (N = 984) received TAX, 25.0% (N = 420) received ATAX, and 16.4% (N = 275) received another regimen. Three-year CSS and OS was improved with any adjuvant chemotherapy from 88.9 to 92.2% (p = 0.0018) for CSS and 77.2% to 88.6% for OS (p < 0.0001). In contrast, treatment with ATAX compared to TAX was associated with inferior 3-year CSS and OS. Three-year CSS was 93.7% with TAX compared to 89.8% (p = 0.048) for ATAX and OS was 91.0% for TAX and 86.4% for ATAX (p = 0.032).ConclusionWhile adjuvant chemotherapy was associated with improved clinical outcomes, the administration of ATAX compared to TAX was associated with inferior 3-year OS and CSS in older women with node-negative TNBC. The use of adjuvant ATAX should be considered carefully in this patient population.

Four Cycles of Docetaxel-Cyclophosphamide versus Anthracycline-Taxane as Adjuvant Chemotherapy for HER2-Negative, Axillary Lymph Node Negative Breast Cancer: A Real-World Comparison of Alberta Patients Treated 2008-2012.

Uncertainty exists around the need to include an anthracycline if taxane-based adjuvant chemotherapy is being used for human epidermal growth factor receptor-2 (HER2) negative and axillary lymph node negative (LNN) breast cancer. We identified all patients who were diagnosed with HER2-negative, LNN breast cancer treated with docetaxel-cyclophosphamide for four cycles (DC4) or an anthracycline-taxane (AT) regimen following surgical resection in Alberta from 2008 through 2012. We used propensity score methods to match each patient treated with AT to up to four patients treated with DC4 on potentially confounding clinicopathologic and treatment variables. We compared the 10-year invasive disease free survival (iDFS), breast cancer specific-survival (BCSS) and overall survival (OS) and assessed the effect of the type of adjuvant chemotherapy on these outcomes using Cox regression. Of the 726 eligible patients, 657 (90.5%) were treated with DC4 and 69 (9.5%) were treated with AT. Matching created a group of 202 women treated with DC4 and eliminated differences in clinicopathologic and treatment factors. There was no statistically significant difference for the treatment effects of matched DC4 patients compared to the AT patients on iDFS (75.7% vs. 76.8%, p = 0.75; hazard ratio (HR) = 1.05, 95% CI = 0.65 to 1.8), BCSS (88.1% vs. 87%, p = 0.8; HR = 0.91, 95% CI = 0.42 to 1.9), or OS (87.1% vs. 86.9%, p= 0.96; HR = 0.98, 95% CI = 0.46 to 2.1). Four cycles of DC as compared with an AT regimen yielded similar 10-year iDFS, BCSS and OS amongst patients with HER2-negative, LNN breast cancer.

Abstract PS13-40: Real-world outcomes in patients receiving neo-adjuvant chemotherapy for early-stage breast cancer

Abstract Background: Real-world data on characteristics, outcomes, and toxicity in patients with early breast cancer (EBC) receiving neo-adjuvant chemotherapy (NACT) is lacking. This study characterises experience of NACT in a single UK NHS specialist oncology centre. Methods: Retrospective case note review of sequential patients with EBC treated with NACT between April 2013 and Sept 2019. Treatment regimens, toxicity data, pathological response (PathCR, defined as no residual invasive tumour in the breast and lymph nodes), recurrence-free survival (RFS) and overall survival (OS) were compared between groups according to baseline characteristics and tumour subtype, defined by oestrogen receptor (ER) and HER2 status. Results: 405 patients (median age 52 years (IQR 45–61)) were included with a median follow up of 36.4 months. At diagnosis most (253 (62%)) were symptomatic, 368 (91%) had invasive ductal carcinoma, 19 (5%) invasive lobular carcinoma and 18 (4%) inflammatory, spindle or mixed histology. Most were pre-NACT stage 2 or above (Stage 1 - 12 (3%), Stage 2a - 129 (32%), Stage 2b 148 (37%), Stage 3a - 73 (18%), Stage 3b – 25 (6%), Stage 3c -14 (3%)) with no clear trend in stage by year of diagnosis or disease subtype and overall 244 (60%) were node positive pre-NACT. 99% had grade 2 or grade 3 cancer; 320 patients (79%) had Ki-67 &amp;gt;15% and 72 patients (18%) had Ki-67 &amp;lt;15%. 392 (96.8%) patients received primary prophylaxis with Granulocyte-Colony Stimulating Factor (GCSF) and 327 patients (76.9%) received an anthracycline-taxane (AT) containing schedule. There were few dose delays due to toxicity (no delay 353 (87%) v delay 51 (13%)) however, 187 (46%) had one or more dose reductions which was significantly more common in patients &amp;gt;61 years (Odds Ratio (OR) v patients &amp;lt;45 years 1.32, 95% (CI 1.10-1.58,P=0.003). PathCR rates did not significantly vary by year of treatment, tumour size or nodal stage but did vary by subtype: ER+/HER2- 8/128 (6.25%), ER+/HER2+ 34/111 (30.6%), ER-/HER2+ 42/69 (60.9%), ER-/HER2- 32/97 (33%). PathCR was predictive of RFS: recurrence occurred in ER+/HER2- pathCR 0/8 (0%) v non-pathCR 24/120 (20%), ER+/HER2+ 0/34 (0%) v 7/77 (9.1%), ER-/HER2+ 4/42 (9.5%) v 6/27 (22%) and ER-/HER2- 4/32 (12.5%) v 21/65 (32%). There was a non-significant trend towards improved pathCR with the addition of platinum (P) to AT in ER-/HER2- disease (19/43 (44.2%) v 11/41 (26.8%) respectively, OR 2.16 (95% CI 0.86-5.40, p=0.09). In HER2+ disease, the addition of pertuzumab (P) to trastuzumab (H) with AT chemotherapy did not increase pathCR rates. At time of analysis 10% of patients had died precluding meaningful analysis of OS by response. Ki-67, Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) had no significant associations with pathCR. Conclusions: Real-world outcomes from NACT at a single UK centre are consistent with published randomised data for pathCR rates by tumour subtype. Despite 96.8% of patients receiving GCSF almost half had at least one dose reduction, potentially compromising dose intensity. Whilst this retrospective analysis must be interpreted with caution, as expected there was a trend toward improved response with the addition of platinum in ER-/HER2- disease but an interesting lack of further pathCR when adding pertuzumab in HER2 positive disease. Further analyses will be presented including site of recurrence, type of surgery by response, radiotherapy treatment given and multi-variate analysis. Citation Format: Catherine McDonald, Rebecca Squires, Mark Gormley, Ryan Langdon, Ann Archer, Jessica Ball, Georgina Gullick, Chloe Caws, John Boardman, Vivek Mohan, Amit Bahl, Jessica Jenkins, Charles Comins, Lara Gibbs, Jeremy Braybrooke, Timothy Robinson. Real-world outcomes in patients receiving neo-adjuvant chemotherapy for early-stage breast cancer [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 PS13-40.

Impact of the addition of carboplatin to anthracycline-taxane-based neoadjuvant chemotherapy on survival in BRCA1/2-mutated triple-negative breast cancer.

Whether adding carboplatin to standard neoadjuvant chemotherapy improves survival in BRCA1/2-mutated triple-negative breast cancer (TNBC) is unknown. In this retrospective study, we aimed to explore the efficacy of anthracycline-taxane (A-T)-based or anthracycline-taxane/carboplatin (A-TP)-based neoadjuvant chemotherapy in BRCA1/2-mutated TNBC. A total of 1585 operable primary breast cancer patients were treated with either neoadjuvant A-T (n = 886) or A-TP regimen (n = 699). BRCA1 and BRCA2 germline mutations were determined in all subjects. Pathological complete response (pCR), recurrence-free survival (RFS), distant recurrence-free survival (DRFS) and overall survival (OS) were estimated. Of the entire cohort, 102 patients (6.4%) carried a pathogenic BRCA1/2 germline mutation. After a median follow-up of 81 months, no significant differences in survival between the A-T and A-TP arms were found in the entire cohort. However, among 288 TNBC patients, BRCA1/2 mutation carriers had significantly better survival when treated with the A-TP regimen than with the A-T regimen (5-year RFS: 82.6% vs 47.9%; P = .024; 5-year DRFS: 88.5% vs 46.9%; P = .010; 5-year OS: 88.2% vs 49.9%; P = .036). Multivariate analyses revealed that the A-TP regimen was a significantly favourable factor for RFS and DRFS and showed a trend towards better OS when compared with the A-T regimen in BRCA1/2-mutated TNBC (RFS: adjusted hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.06-0.91, P = .035; DRFS: HR, 0.17; 95% CI, 0.03-0.80; P = .025; OS: HR, 0.29; 95% CI, 0.06-1.49; P = .14). Our study suggested that BRCA1/2-mutated TNBC patients gain a survival benefit when carboplatin is added to standard A-T-based neoadjuvant chemotherapy.

Inhibiting fatty acid synthase in operable triple negative breast cancer.

584 Background: Fatty acid synthase (FASN) is overexpressed in 70% of newly diagnosed triple negative breast cancer (TNBC) and is associated with poor prognosis. In vitro, FASN overexpression induces drug resistance to DNA damaging agents. Proton pump inhibitors (PPI) selectively inhibit FASN activity and induce apoptosis in breast cancer cell lines with minimal effect on non-malignant cells. We report the results of a single arm phase II study of high dose omeprazole (OMP) in combination with anthracycline- taxane (AC-T) based neoadjuvant chemotherapy. Methods: Patients (pts) with operable TNBC independent of baseline FASN expression; and no prior PPI use within 12 months were enrolled. Pts began OMP 80 mg PO BID for 4-7 days prior to AC-T; carboplatin was allowed per physician discretion. OMP was continued until surgery. Paired biopsy samples were obtained before and after OMP monotherapy. The primary endpoint was pathologic complete response (pCR), defined as no residual invasive disease in breast or axilla, in pts with baseline FASN expression (FASN+) assessed using immunohistochemistry. Relevant secondary endpoints included pCR in the intent to treat population, change in FASN expression, enzyme activity and downstream target gene expression after OMP monotherapy; safety and limited OMP pharmacokinetics. We targeted a pCR rate of 60% in FASN+ pts (null pCR ~ 40%) with 80% power and alpha of 0.10. Results: A total of 42 pts were recruited from 5 US sites. Median age was 51y (28-72). Most pts had &gt;cT2 (33, 79%) and ≥N1 (22, 52%) disease. 14 (33%) were African American. FASN expression prior to AC-T was identified in 28 (85%) samples available for analysis. The pCR rate was 71.4% (95% CI 51.3 to 86.8) in FASN+ pts and 71.8 %( 95% CI 55.1 to 85.0) in all enrolled pts. Fifteen pts (36%) received carboplatin with AC-T; pCR in this subset was 73%. Peak OMP concentration was significantly higher than IC50 observed during preclinical testing; FASN positivity significantly decreased with OMP monotherapy from 0.53(SD 0.25) at baseline to 0.38(SD 0.30; p = 0.02). OMP was well tolerated with no known grade (G) 3 or 4 toxicities. Chemotherapy toxicity was similar to prior studies using AC-T with G3 or 4 neutropenia (19%), febrile neutropenia (7%) and peripheral neuropathy (7%) being the most common. Conclusions: Consistent with previous studies, FASN is frequently expressed in early stage TNBC. OMP can be safely administered in doses that inhibit FASN. The addition of high dose OMP to neoadjuvant AC-T yields a promising pCR rate without adding toxicity. Funded by the Breast Cancer Research Foundation. Clinical trial information: NCT02595372 .

Abstract P1-10-11: Pathological complete response after carboplatin-based neoadjuvant chemotherapy in triple negative breast cancer: The importance of stromal tumor infiltrating lymphocytes as a predictive biomarker

Abstract Background: Lymphocyte predominant breast cancers (LPBC) account for 5-30% of TNBCs; 65-80% of TNBCs have low/moderate levels of sTILs and 15-20% have no lymphocyte infiltration. TNBCs with high stromal tumor infiltrating lymphocytes (sTILs) have higher rates of pathological complete response (pCR) with anthracycline-taxane (AT) neoadjuvant chemotherapy (NACT), but the effect of carboplatin (Cb) is unclear. In GeparSixto, Cb increased pCR rates in LPBC but there was no interaction between LPBC and Cb in TNBCs. This study examines the predictive role of sTILs in TNBCs, focusing on the association between sTILs and pCR with and without Cb based NACT. Methods: Patients diagnosed with TNBC and treated with NACT in University Hospital Galway, Ireland from 2004-2016 were identified. Patients were treated with a carboplatin-anthracycline-taxane regimen (Cb-AT) (n=30) or an AT regimen (n=54). As per the International TILs Working Group, sTILs were scored on digitized slides of full-face tumor sections from diagnostic needle core biopsies. sTILs were categorized as 0-10%; 11-25%; 26-49%; ≥50% (LPBC). Odds ratio (OR) was calculated using non-pCR as the baseline. pCR was defined as ypT0/isN0. Results: Eighty-eight (n=88) cases with sufficient sTILs for analysis were identified. The median sTIL count was 12.5% (range 0-75%): 50% of cases (n=44) had sTILs 0-10%; 25% (n=22) had sTILs 11-25%; 14% (n=12) had sTILs 26-49% and 11% (n=10) had sTILs ≥50%. Cases with sTILs &amp;gt;10% had higher rates of pCR compared to those with sTILs ≤10% (52% vs 29%; p=0.021). In cases treated with an AT regimen, tumors with sTILs &amp;gt;10% had higher pCR rates than those with sTILs ≤10% (46% vs 12%; p=0.005). In cases treated with a Cb-AT regimen, there was no difference in pCR rates between sTILs &amp;gt;10% tumors and sTILs ≤10% tumors (60% vs 53%; p=0.500). In this cohort, pCR rates were higher in LPBC compared to non-LPBCs (80% vs 36%; p=0.010). In cases treated with AT, pCR rates were higher in LPBC than non-LPBC (83% vs 23%; p=0.007). However, in cases treated with Cb-AT, there were no differences in pCR rates between LPBC and non-LPBC (67% vs 56%; p=0.603). In LPBC, the choice of chemotherapy did not affect pCR rates: 67% vs 83% for Cb-AT and AT regimens respectively (p=0.583). In non-LPBC, pCR rates increased with Cb: 56% vs 23% for Cb-AT and AT regimens respectively (p=0.005). By univariate analysis, there was a significant association between sTILs and pCR. The association was greatest in LPBC (OR 0.14; p=0.016) and remained significant in those treated with AT (OR 0.06; p=0.014) but not in cases treated with Cb-AT (OR 0.63; p=0.714). In a multivariable model, with tumor grade and Cb use as co-variables, LPBC was independently associated with pCR (OR0.14; p=0.030). In cases treated with AT, sTILs were associated with pCR (OR 0.18, p=0.019 for sTILs &amp;gt;10%; OR 0.08, p=0.029 for LPBC). In cases treated with Cb-AT, sTILs were not associated with pCR (p=0.372 and p=0.622 for sTILs &amp;gt;10% and LPBC respectively). Conclusions: In TNBC, sTILs are predictive of response to NACT: as sTILs increase, pCR rates increase. The likelihood of a pCR increased by 86% for LPBC vs non-LPBC. The effect of sTILs on pCR was most notable in LPBC treated with AT based NACT where the odds of a pCR increased by 94%. In cases treated with Cb-AT, there was no association between sTILs and pCR. This study suggests that tumors with high sTILs are more chemosensitive than tumors with low sTILs. High sTIL tumors had high pCR rates with AT based NACT but the addition of Cb did not increase pCR rates. Cb-AT NACT could be reserved for patients with low sTIL tumors, in order to increase the rates of pCR in that subgroup, who had low rates of pCR in this study. In the future, sTILs could be used as a predictive biomarker to guide chemotherapy selection. Citation Format: Elaine M Walsh, Mark O'Loughlin, Aliaa Shalaby, Mark Webber, Michael J Kerin, Sharon A Glynn, Grace Callagy, Maccon M Keane. Pathological complete response after carboplatin-based neoadjuvant chemotherapy in triple negative breast cancer: The importance of stromal tumor infiltrating lymphocytes as a predictive biomarker [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-11.

Abstract P3-05-06: Impact on outcome and response to neoadiuvant chemotherapy in triple negative breast cancer patients and BRCA mutations

Abstract Background: The effect of germline BRCA mutations on the outcomes of patients with triple-negative breast cancer (TNBC) is not well understood and the expanding access to genetic testing could provide further information about drug sensitivity and patients’ prognosis. In this retrospective study, data collected from TNBC patients with locally advanced disease and susceptible to neoadjuvant chemotherapy (NAC) were used in order to define whether the presence of germline BRCA pathogenic variants could help defining clinical features, prognosis and outcome of this population. Materials and Methods: Seventy-four women with newly diagnosed locally advanced TNBC from July 1, 2014 to July 30, 2017, were enrolled. DNA derived from whole-blood specimens was available for all the TNBC-NAC cohort. We investigated the presence of gBRCA mutations by employing next generation sequencing (NGS) techniques. Tumor and patients’ characteristics, genetic testing results, and outcomes were collected by patients’ medical records. Statistical calculations were performed using the SPSS 24.0 software. Pearson χ2- test for frequencies was used to compare the demographics, tumor characteristics and response to treatment between pathogenic and not pathogenic BRCA variants. Two-sided p-values were considered to be statistically significant if &amp;lt 0.05. Results: Of our 74 TNBC-NAC cohort, 23 patients (31.1%) tested positive for a pathogenic BRCA variant, 4 (5.4%) tested VUS (variant of uncertain significance) and 47 (63.5%) tested negative. Patients were divided in two group according to the presence of pathogenic or not pathogenic BRCA variants. There were no significant differences between the two group respect to the age at cancer diagnosis (median age in BRCA positive women: 50.6, in VUS: 42.2, in BRCA negative: 47.6), the rate of pathologic response after neoadjuvant anthracycline taxane based chemotherapy and the disease recurrence. Conclusion: In our preliminary study, for the first time all the 74 TNBC-NAC patients have been genetically screened for the presence of BRCA variants. Although larger cohort and longer follow-up are needed in order to fully understand if BRCA variants can assess TNBC patients prognosis, our results showed that the BRCA status does not correlate with response to chemotherapy and disease-free survival of TNBC patients. Citation Format: Ida Paris, Roberta Rizza, Carmela Paolillo, Luisa Carbognin, Alessandra Calegari, Giovanni Scambia, Emilio Bria, Ettore Capoluongo, Riccardo Masetti, Andrea Urbani, Mariangela Pasqualoni, Concetta Santonocito. Impact on outcome and response to neoadiuvant chemotherapy in triple negative breast cancer patients and BRCA mutations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-05-06.

Nab-paclitaxel in Treatment of Metastatic Breast Cancer

Despite the development of new systems for the treatment of metastatic breast cancer (mBC), chemotherapy remains an integral and significant stage of treatment for any molecular tumor subtype. In accordance with modern concepts, the optimal strategy of therapy in the vast majority of cases of mBC is the sequential administration of cytostatics in mono modes. This approach allows long-term control of tumor growth, translating pathology into a chronic discharge and maintaining a high quality of life. The emergence of new drugs or innovative dosage forms of existing cytostatics expands the possibilities of treatment of this chronic disease and allows long-term control over the disease. One of such new options was nab-paclitaxel, nano-dispersed paclitaxel stabilized with albumin. This dosage form provides active transport of the drug through the vascular endothelium with the creation of its high concentration in the tumor tissue. Clinical studies comparing nab-paclitaxel with traditional taxanes (paclitaxel and docetaxel) demonstrated high efficacy and safety of the drug both in a wide population of patients and in individual subgroups, including patients previously treated with anthracycline taxane, cases with aggressive disease, lesions of visceral organs, elderly patients and others. In addition, due to its unique formula, the drug does not cause hypersensitivity reactions, differing from traditional These taxanes are easy to use and safe. The lack of need for premedication with dexamethasone allows it to be prescribed for such comorbidities as severe hypertension, diabetes mellitus, stomach ulcer and duodenal ulcer, etc., and also successfully combine it with inhibitors of control points of the immune response, which confidently removes the drug on arena of immuno-oncology.

The role of stromal tumor infiltrating lymphocytes (sTILs) as a predictive biomarker for carboplatin-based neoadjuvant chemotherapy (NACT) in triple-negative breast cancer (TNBC).

e12085 Background: High numbers of sTILs are predictive of pCR in TNBCs. This study examines the role of sTILs as a predictive biomarker for carboplatin (Cb) based NACT. Methods: sTILs were scored on 88 pre NACT TNBC biopsies as per the International TILs Working Group and were scored as continuous and categorical variables: 0-10%; 11-25%; 26-49%; ≥50%. OR was calculated using non-pCR as baseline parameter. Results: Patients with sTILs &gt; 10% had increased pCR rates compared to those with sTILs ≤10%: pCR breast (B) (61% vs 31% p = 0.004); pCR breast/axilla (BA) (52% vs 29% p = 0.021). In those treated with Cb, there were no differences in pCR B between sTILs &gt; 10% or ≤10% (67% vs 53%; p = 0.355) or pCR BA (60% vs 53%; p = 0.500). In those who did not receive Cb, sTILs &gt; 10% had increased pCR B (57% vs 15%; p = 0.002) and pCR BA (46% vs 12%; p = 0.005) compared to sTILs ≤10%. Similar trends were seen with sTILs &gt; 25% and ≥50%: differences were seen in patients who did not receive Cb, but not in those treated with Cb. In LPBCs, the addition of Cb did not significantly increase pCR rates: 67% vs 83% for Cb and non-Cb regimens (p = 0.583). In non-LPBC, pCR rates were increased with Cb: pCR B 59% vs 31% (p = 0.017), and pCR BA 56% vs 23% (p = 0.005) for Cb and non-Cb regimens. The association between sTILs and pCR was significant in multivariable models adjusting for grade and Cb. In patients who did not receive Cb (n = 54), increasing sTILs were associated with increased pCR B (OR 0.15 p = 0.004; OR 0.27 p = 0.039; OR 0.10 p = 0.05 for &gt; 10%, &gt; 25%, ≥50%) and pCR BA (OR 0.18 p = 0.019; OR 0.08 p = 0.029 for &gt; 10%, ≥50%). In patients treated with Cb (n = 30), increasing sTILs were not associated with pCR B (OR 1.97 p = 0.581; OR 0.27 p = 0.334; OR 0.50 p = 0.719) or pCR BA (OR 2.93 p = 0.372; OR 0.79 p = 0.831; OR 0.40 p = 0.622 for &gt; 10%, &gt; 25%, ≥50%). Conclusions: sTILs are predictive of pCR: as sTILs increase, pCR rates increase. Tumors with high sTILs had high pCR rates to anthracycline-taxane (AT) NACT. The effect of increasing sTILs on pCR was most notable in patients who did not receive Cb based NACT, suggesting that tumors with high sTILs are inherently sensitive to AT based chemotherapy. Intensifying NACT with Cb could be used to increase pCR rates in patients with low sTILs. sTILs should be explored as a biomarker to intensify chemotherapy in those with low sTILs, and to de-escalate chemotherapy in tumors with high sTILs.

Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study

BackgroundChemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy. Patients and methodsHER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline–taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety. ResultsA total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89–1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74–1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22–0.50, P < 0.0001). ConclusionsThis study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse. Trial RegistrationEUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

Pooled analysis of two randomized phase III trials (PlanB/SuccessC) comparing six cycles of docetaxel and cyclophosphamide to sequential anthracycline taxane chemotherapy in patients with intermediate and high risk HER2-negative early breast cancer (n=5,923).

522 Background: Recent studies draw different conclusions concerning whether omission of anthracyclines (A) in adjuvant chemotherapy for HER2-negative early breast cancer (EBC) may reduce toxicity without compromising efficacy. Methods: The prospectively randomized PlanB and Success C trials compared 6 cycles of docetaxel (D) and cyclophosphamide (C) with either 4 cycles of epirubicin (E) and C, followed by 4 cycles of D (EC-D, PlanB) or 3 cycles of 5-FU, E and C, followed by 3 cycles of D (FEC-D, SuccessC). Disease-free survival (DFS) was analyzed using univariable and multivariable Cox models adjusted for hormone receptor status (HRS) and histologic grade (G), age, menopausal status, type of surgery, pT, pN, and histologic type. Results: Overall, 5923 patients with follow-up data were available for this pooled analysis, with 2979 and 2944 patients randomized to A-free and A-containing chemotherapy, respectively. After 62 months median follow-up, DFS of patients receiving A-free vs A-containing chemotherapy was quite similar in univariable analysis (hazard ratio, HR = 1.04; 95% confidence interval, CI: 0.88 – 1.22, p = 0.64) and in multivariable analysis (HR = 1.00, 95% CI: 0.85 – 1.19, p = 0.96). Defining biological subtypes “luminal A-like” as HRS positive, G1/2, “luminal B-like” as HRS positive, G3, and TN (triple negative), no significant differences were seen in DFS between A-free and A-containing chemotherapy in luminal A-like (HR = 1.06, 95% CI 0.81 – 1.39, p = 0.66), luminal B-like (HR = 1.07, 95% CI 0.78 – 1.48, p = 0.68), or TN tumors (HR = 0.99, 95% CI 0.76 – 1.30, p = 0.95). However, in high-risk patients with four or more affected lymph nodes (pN2-3), A-containing chemotherapy was associated with significantly better DFS (HR = 0.69, 95%-CI 0.48- 0.98, p = 0.04). Conclusions: Our results suggest that 6 cycles of DC provide sufficient efficacy compared to an anthracycline-containing regimen in most patients with HER2-negative EBC. However, subgroup analyses indicate that high-risk patients might benefit from anthracycline-containing chemotherapy.

EarlyR genomic signature to predict pathological complete response following neoadjuvant anthracycline-taxane chemotherapy in estrogen-receptor positive (ER+) breast cancer.

579 Background: EarlyR is a prognostic signature computed from expression values of ESPL1, SPAG5, MKI67, PLK1 and PGR that stratifies ER+ breast cancer (BC) into EarlyRLow, EarlyRInt, and EarlyRHigh risk strata. Here, we show that EarlyR is also predictive of pathological complete response (pCR) following neoadjuvant anthracycline-taxane (AT) based chemotherapy. Methods: The ability of EarlyR gene signature to predict pCR was assessed in Affymetrix microarrays datasets (GSE25065, GSE25066, GSE20194, GSE20271; n = 541, pCR = 42 (7.8%) collectively labeled as Cohort A) derived from patients with ER+ breast cancer treated with neoadjuvant TFAC or FEC. For 2 of these datasets (GSE25065, GSE25066 (n = 291)) distant metastasis-free survival (DMFS) results were also available. The DMFS data in cohort A were compared to that of BC patients not treated with chemotherapy (denoted Cohort B, n = 1269) derived from ER+ samples from 7 GEO datasets (GSE3494, GSE7390, GSE12093, GSE6532, GSE2034, GSE11121, GSE17705). Results: In cohort A, EarlyR is a significant predictor of pCR (p = 1.0 x 10-6) (EarlyRLow, n = 273, pCR = 5, 1.8%; EarlyRInt, n = 11, pCR = 1, 9.1% and EarlyRHigh, n = 256, pCR = 36, 14.1%). Notably, 86% of the 42 cases with pCR have EarlyRHigh. Of the 291 patients with 8-year DMFS data from Cohort A, who had received chemotherapy, the survival of EarlyRHigh [0.79 (95%CI 0.70-0.89)] was nearly the same as that of EarlyRLow [0.82 (95%CI 0.74-0.90)]. In contrast, in cohort B, who were not treated with chemotherapy, 8-year DMFS is significantly (p = 5 x 10-15) lower in EarlyRHigh [0.57 (95%CI 0.51-0.64)] than in EarlyRLow[0.81 (95%CI 0.78-0.84)]. Conclusions: EarlyR is a strong predictor of pathological complete response in patients treated with TFAC or FEC. In addition, EarlyR also predicts poor DMFS outcomes for patients in EarlyRHigh not receiving chemotherapy. More importantly, neoadjuvant chemotherapy dramatically improved survival of patients in EarlyRHigh. These results document that EarlyR identifies a set of patients, EarlyRHigh, with a high risk of distant metastasis, who are also likely to respond favorably to chemotherapy.

Reduced Rates of Severe Complications Following a Change in Anthracycline–Taxane Regimen for Early Breast Cancer: a Single Centre Experience

Reduced Rates of Severe Complications Following a Change in Anthracycline–Taxane Regimen for Early Breast Cancer: a Single Centre Experience

Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis.

BackgroundTriple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease, and although no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR) from standard-of-care anthracycline/taxane (ACT) chemotherapy. The heterogeneity of these tumors, however, has hindered the discovery of effective biomarkers to identify such patients.Methods and FindingsWe performed whole exome sequencing on 29 TNBC cases from the MD Anderson Cancer Center (MDACC) selected because they had either pCR (n = 18) or extensive residual disease (n = 11) after neoadjuvant chemotherapy, with cases from The Cancer Genome Atlas (TCGA; n = 144) and METABRIC (n = 278) cohorts serving as validation cohorts. Our analysis revealed that mutations in the AR- and FOXA1-regulated networks, in which BRCA1 plays a key role, are associated with significantly higher sensitivity to ACT chemotherapy in the MDACC cohort (pCR rate of 94.1% compared to 16.6% in tumors without mutations in AR/FOXA1 pathway, adjusted p = 0.02) and significantly better survival outcome in the TCGA TNBC cohort (log-rank test, p = 0.05). Combined analysis of DNA sequencing, DNA methylation, and RNA sequencing identified tumors of a distinct BRCA-deficient (BRCA-D) TNBC subtype characterized by low levels of wild-type BRCA1/2 expression. Patients with functionally BRCA-D tumors had significantly better survival with standard-of-care chemotherapy than patients whose tumors were not BRCA-D (log-rank test, p = 0.021), and they had significantly higher mutation burden (p < 0.001) and presented clonal neoantigens that were associated with increased immune cell activity. A transcriptional signature of BRCA-D TNBC tumors was independently validated to be significantly associated with improved survival in the METABRIC dataset (log-rank test, p = 0.009). As a retrospective study, limitations include the small size and potential selection bias in the discovery cohort.ConclusionsThe comprehensive molecular analysis presented in this study directly links BRCA deficiency with increased clonal mutation burden and significantly enhanced chemosensitivity in TNBC and suggests that functional RNA-based BRCA deficiency needs to be further examined in TNBC.