Neoadjuvant Treatment Of Triple-negative Breast Cancer Research Articles

Early-stage triple negative breast cancer: the therapeutic role of immunotherapy and the prognostic value of pathological complete response.

Triple negative breast cancer (TNBC) represents an aggressive disease associated with a high risk of recurrence after curative treatment and a poor prognosis in the metastatic setting. Chemotherapy was for years the only treatment available in the early and metastatic setting, due to the lack of actionable targets. Clinical practice has changed following the results obtained with the addition of immunotherapy to standard chemotherapy, the development of novel drugs [i.e. antibody-drug conjugates (ADCs)], and the use of targeted treatments for patients carrying germline pathogenic breast cancer susceptibility genes (BRCA) 1 or BRCA 2 variants. The treatment of early-stage disease has had a shift in clinical practice since July 2021, after the Food and Drug Administration (FDA) approval of pembrolizumab in association with chemotherapy as neoadjuvant treatment for TNBC and as a single agent in the subsequent adjuvant setting. This intensive treatment based on the combination of a poly-chemotherapy and an immune checkpoint inhibitor (ICI) led to the improvement of short- and long-term outcomes, but it has highlighted some new unmet clinical needs in the treatment of early-stage TNBC: the selection of the most effective adjuvant therapy and the integration of pembrolizumab with other therapeutic strategies [capecitabine, poly(ADP-ribose) polymerase (PARP) inhibitors] based on the achievement of pathologic complete response (pCR); the identification of predictive biomarkers to select patients who could most benefit from the addition of ICI, to minimize toxicities and to maximize outcomes; the possibility of de-escalating chemotherapy in favor of immune-combo or novel agents, such as ADCs; the role of immunotherapy in estrogen receptor (ER)-low patients. The advent of immunotherapy not only addresses current challenges in TNBC treatment but also holds the promise of a radical transformation in its therapeutic paradigm, enhancing significantly clinical outcomes and offering new perspectives for patients grappling with this aggressive form of breast cancer.

Taxane combined with lobaplatin or anthracycline for neoadjuvant treatment of triple-negative breast cancer: A single-center, randomized, controlled, phase-II clinical study.

593 Background: Previously, we showed that addition of lobaplatin (L) to taxane combined with anthracycline could improve the pathologic complete response (pCR) rate and lengthen survival significantly if employed as neoadjuvant therapy in patients with triple-negative breast cancer (TNBC). We evaluated the efficacy and safety of neoadjuvant chemotherapy of taxane (T) combined with lobaplatin (L) or anthracycline (E) for patients with TNBC. Methods: Ninety-five patients with TNBC (stage I–III) who had not undergone any type of treatment were divided randomly into two groups: TL (docetaxel at 75 mg/m2 and lobaplatin at 30 mg/m2, D1, one cycle = 21 days, a total of six cycles) or TE (docetaxel at 75 mg/m2 and epirubicin at 80 mg/m2, D1, one cycle = 21 days, a total of 6 weeks or epirubicin at 80 mg/m2 and cyclophosphamide at 600 mg/m2, sequential docetaxel at 75 mg/m2, D1, one cycle = 21 days, a total of eight cycles). Efficacy was evaluated every two cycles. The final surgical procedure was completed after fulfillment of neoadjuvant chemotherapy. The primary endpoint was the total pathologic complete response (tpCR) rate. The secondary endpoints were the objective response rate (ORR), safety, event-free survival (EFS), and overall survival (OS). The exploratory endpoint was biomarker analysis. Results: From June 2019 to November 2022, 97 patients were screened. Finally, 95 patients were enrolled. The median age of the study cohort was 49 years. Nine patients (9.5%) had stage-I disease, 61 patients (64.2%) had stage II, and 25 patients (26.3%) had stage III. Sixty-five patients (68.4%) had Ki67 ≥40% and 30 patients (31.6%) had Ki67 < 40%. Seventy patients (73.7%) were cytokeratin (CK)5/6+ and 25 patients (26.3%) were CK5/6−. Of 95 patients, 47 were in the TL group and 48 in the TE group. The tpCR rate in the TL group was 46.8% (22/47), which was significantly higher than that in the TE group (22.9% (11/48); odds ratio (OR) = 2.960, 95% confidence interval (CI) = 1.223–7.164, P = 0.016). The ORR in the TL group was 95.7% (45/47), which was significantly higher than that in the TE group (75.0% (36/48); OR = 27.500, 95% CI = 1.576–35.683, P = 0.011). The prevalence of grade III/IV neutropenia in the TE group was 41.0% (9/22), which was significantly higher than that in the TL group (7.7% (2/26); OR = 8.308, 95% CI = 1.557–44.320, P = 0.013). There was no significant difference in the prevalence of other adverse reactions between the two groups. Conclusions: In the neoadjuvant treatment of TNBC, the TL regimen had a higher tpCR rate and ORR than those of the TE regimen, and was safer. Clinical trial information: ChiCTR1900023776 .

Homologous Repair Deficiency Status and Response to Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer: The Best Current Biomarker to Select the Most Appropriate Treatment?

Despite recent discoveries regarding the genomic characterization of triple-negative breast cancer (TNBC), the neoadjuvant treatment of TNBC is focused on the anthracycline- and taxane- (AT) based chemotherapy regimens. Clinical studies have highlighted the role of platinum in the neoadjuvant setting, because its addition to AT-based neoadjuvant chemotherapy (NACT) increases the rate of pathological complete response (pCR). Retrospective analysis showed that the pCR rate is not influenced by the BRCA mutational status in relation to platinum use, while promising data found homologous repair deficiency (HRD) status as a potential predictive factor of response to platinum based neoadjuvant treatment. We will look specifically at the role of HRD status in platinum response prediction for two reasons: first, to understand whether the anthracycline use can be avoided in some TNBC subpopulations, sparing toxicity; second, to understand if it is possible, through the modulation of known oncogenic pathways, to make a TNBC from HRD-low to HRD-high phenotype and to exploit its sensitivity to DNA-damaging agents.

Abstract P3-10-09: Relationship between tumor infiltrating lymphocytes (TILs) and response to pembrolizumab (Pembro)+chemotherapy (Chemo) as neoadjuvant treatment (NAT) for triple-negative breast cancer (TNBC): phase Ib KEYNOTE-173 trial

Abstract Background:Increasing quantities of stromal TILs (sTILs) are associated with higher pathologic complete response (pCR) rates with conventional chemo in early-stage TNBC. We evaluated the association between sTILs and PD-L1 expression with response to pembro+chemo as NAT for TNBC in the KEYNOTE-173 trial (NCT02622074). Methods: sTILs were quantified using light microscopy of H&E-stained slides from pretreatment and on-treatment (during first 3 weeks of pembro monotherapy) tumor biopsies by a pathologist blind to response data. Pretreatment PD-L1 expression was assessed using the PD-L1 IHC 22C3 pharmDx assay and reported as combined positive score (CPS). Endpoints were pCR rate by ypT0 ypN0 and ypT0/Tis ypN0 and objective response rate (ORR; RECIST v1.1) after the first 4 cycles of NAT (taxane±carboplatin+pembro) by MRI. sTILs and PD-L1 CPS were evaluated as continuous variables. Association between sTILs and PD-L1 CPS with response was assessed using logistic regression and area under the reciever operating curve (AUROC) analyses, with a 1-sided alpha level of 0.10. Correlation between PD-L1 and sTILs was assessed by Spearman's rank correlation coefficient. Multivariate analysis included sTILs (pretreatment and on-treatment) and PD-L1 CPS. Likelihood ratio tests were used to evaluate the added value of factors in predicting pCR rate. Results: Of 60 total pts, 34 had tumors evaluated for pretreatment sTILs, 52 for PD-L1 CPS, and 33 for both sTILs and CPS. On-treatment sTILs were evaluated in 31 pts. Overall pCR rates were 56.7% and 60% by ypT0 ypN0 and ypT0/Tis ypN0, respectively; ORR was 78.3%. In pts evaluated for sTILs and CPS (individually), pCR rates and ORR were comparable with overall pCR rates and ORR. There was a significant correlation between pretreatment sTILs and PD-L1 CPS (ρ=0.65, P<0.001).Higher pretreatment sTILs were significantly associated with response: ypT0 ypN0 P= 0.011; ypT0/Tis ypN0 P=0.006; ORR P=0.061. On-treatment sTILs were also significantly associated with response: ypT0 ypN0 P=0.061; ypT0/Tis ypN0 P=0.041; ORR P=0.031. Pretreatment PD-L1 CPS was significantly associated with response: ypT0 ypN0 P=0.073; ypT0/is ypN0 P=0.030; and ORR P=0.021. AUROC of pretreatment sTIL association with pCR was numerically higher than with on-treatment sTILs and PD-L1 CPS (0.69 vs 0.61 vs 0.56 for ypT0ypN0 and 0.72 vs 0.67 vs 0.62 for ypT0/Tis ypN0). Responders had higher median pretreatment sTIL levels vs nonresponders: 45% [10, 75] vs 10% [5, 20] for pCR rate by ypT0 ypN0 and 52.5% [10, 73.8] vs 10% [5, 20] for pCR rate by ypT0/Tis ypN0; 25% [5, 70] vs 10% [6.3, 27.5] for ORR. In multivariate analysis, only pretreatment sTILs were significant for both pCR endpoints (ypT0 ypN0 P=0.031; ypT0/Tis ypN0 P=0.034). Likelihood ratio tests demonstrated that for both pCR endpoints, PD-L1 CPS (P=0.683/P=0.422) and on-treatment sTILs (P=0.984/P=0.568) did not add significantly more value to pretreatment sTILs when predicting pCR. Conclusions:Higher quantities of pretreatment sTILs and PD-L1 CPS and on-treatment sTILs were significantly associated with higher pCR rates and ORR in primary TNBC treated with pembro and NAT. Citation Format: Loi S, Schmid P, Cortés J, Park YH, Muñoz-Couselo E, Kim S-B, Sohn J, Im S-A, Holgado E, Foukakis T, Kuemmel S, Dent R, Wang A, Aktan G, Karantza V, Salgado R. Relationship between tumor infiltrating lymphocytes (TILs) and response to pembrolizumab (Pembro)+chemotherapy (Chemo) as neoadjuvant treatment (NAT) for triple-negative breast cancer (TNBC): phase Ib KEYNOTE-173 trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-09.

Abstract P5-05-01: A molecularly annotated collection of breast cancer patient-derived xenograft models aligned with ongoing clinical trials built from fine needle aspiration samples throughout neoadjuvant treatment

Abstract BACKGROUND: Patient-derived xenograft (PDX) models of breast cancer replicate the diverse histologic and molecular features of patient tumors and provide a renewable source of human tumor tissue. However, collection of tissue by core needle biopsy is problematic due to patient discomfort, bleeding risk and the limited number of passes a patient can tolerate. Several studies have catalogued the maintenance of molecular features of patient tumors in PDX models of breast cancer. METHODS: To support the neoadjuvant molecular diagnostic and drug development program in triple negative breast cancer (TNBC), a pilot study was conducted to determine if fine needle aspiration (FNA) could be used for building PDX models. Subsequently, PDX models are being established in alignment with ongoing clinical trials at MDACC. The molecular evolution of patient's tumors, matched with PDXs engrafted from their tumors, is under study throughout the neoadjuvant treatment of TNBC using RNA sequencing, whole-exome sequencing, deep sequencing of cancer genes, and histologic analyses. RESULTS: To date, 20 established PDX models have been developed and stable PDX models continue to be generated at a rate of 2-3 per month. Several of these models are derived from serial FNAs derived from patients throughout neoadjuvant treatment. These models retain histologic and molecular features of the original patient tumors. Serial patient biopsies, matched with PDX models, have enabled measurement of the mutational and transcriptomic evolution in vivo of TNBC undergoing neoadjuvant treatment. We have standardized the use of FNAs to generate PDX models both pre- and post-neoadjuvant therapy in the following ongoing neoadjuvant clinical trials: 1. MDACC 2014-0185 (PI Stacy Moulder, 360 patients), 'ARTEMIS: A Randomized TNBC-Enrolling trial to confirm Molecular profiling Improves Survival' 2. MDACC 2014-0045 (PI Jennifer Litton, 20+ patients), 'A pilot study of BMN673 as a neoadjuvant study in patients with a diagnosis of invasive breast cancer and a deleterious BRCA mutation' CONCLUSION: We demonstrated that PDX models from tissue collected by FNA recapitulate the biology and clinical course of the patient's tumor. Sequencing analyses revealed that neoadjuvant chemotherapy and PDX engraftment enrich for cancer gene mutations. We observe association of the rate of successful PDX engraftment with clinical parameters such as the patient's residual cancer burden (RCB) status at the time of surgery (upon completion of neoadjuvant treatment). In addition, we observe that PDX models derived from serial patient biopsies throughout treatment are more resistant to chemotherapy treatment. These models recapitulate the variety of chemotherapy responses observed in patients with TNBC and serve as powerful tools for preclinical biomarker and discovery studies. Citation Format: Echeverria GV, Cai S, Tu Y, McCoy A, Lau R, Redwood A, Rauch G, Adrada B, Candelaria R, Santiago L, Thompson A, Litton J, Moulder S, Symmans F, Chang JT, Piwnica-Worms H. A molecularly annotated collection of breast cancer patient-derived xenograft models aligned with ongoing clinical trials built from fine needle aspiration samples throughout neoadjuvant treatment [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-05-01.