<b><i>Introduction:</i></b> Triple-negative breast cancer (TNBC) is considered the most aggressive type of breast cancer (BC) with limited options for therapy. TNBC is a heterogeneous disease and tumors have been classified into TNBC subtypes using gene expression profiling to distinguish basal-like 1, basal-like 2, immunomodulatory, mesenchymal, mesenchymal stem-like, luminal androgen receptor (LAR), and one nonclassifiable group (called unstable). <b><i>Objectives:</i></b> The aim of this study was to verify the clinical relevance of molecular subtyping of TNBCs to improve the individual indication of systemic therapy. <b><i>Patients and Methods:</i></b> Molecular subtyping was performed in 124 (82%) of 152 TNBC tumors that were obtained from a prospective, multicenter cohort including 1,270 histopathologically confirmed invasive, nonmetastatic BCs (NCT 01592825). Treatment was guideline-based. TNBC subtypes were correlated with recurrence-free interval (RFI) and overall survival (OS) after 5 years of observation. <b><i>Results:</i></b> Using PAM50 analysis, 87% of the tumors were typed as basal with an inferior clinical outcome compared to patients with nonbasal tumors. Using the TNBCtype-6 classifier, we identified 23 (15%) of TNBCs as LAR subtype. After standard adjuvant or neoadjuvant chemotherapy, patients with LAR subtype showed the most events for 5-year RFI (66.7 vs. 80.6%) and the poorest probability of 5-year OS (60.0 vs. 84.4%) compared to patients with non-LAR disease (RFI: adjusted hazard ratio [aHR] = 1.87, 95% confidence interval [CI] 0.69–5.05, <i>p</i> = 0.211; OS: aHR = 2.74, 95% CI 1.06–7.10, <i>p</i> = 0.037). <b><i>Conclusion:</i></b> Molecular analysis and subtyping of TNBC may be relevant to identify patients with LAR subtype. These cancers seem to be less sensitive to conventional chemotherapy, and new treatment options, including androgen receptor-blocking agents and immune checkpoint inhibitors, have to be explored.
Tumour-infiltrating lymphocytes (TILs) are considered to have prognostic and predictive value for patients with early breast cancer. We examined 1166 breast cancer patients from a prospective, multicentre cohort (Prognostic Assessment in Routine Application (PiA), n = 1270, NCT 01592825) following recommendations from the International TILs Working Group. TIL quantification was performed using predefined groups and as a continuous variable in 10% increments. The primary objective was the distribution of TILs in different breast cancer types. The second objective was the association with the recurrence-free interval (RFI) and overall survival (OS). Stromal infiltration with more than 60% TILs appeared in 2% of hormone receptor (HR)-positive and HER2-negative tumours, in 9.8% of HER2-positive tumours (any HR) and 19.4% of triple-negative breast cancers (TNBCs). Each 10% increment was associated with an improvement in the prognosis in HER2-positive samples (RFI, hazard ratio 0.773, 95% CI 0.587–1.017; OS, hazard ratio 0.700, 95% CI 0.523–0.937). When defining exploratory cut-offs for TILs, the use of a 30% threshold for the HR-positive and HER2-negative group, a 20% threshold for the HER2 group and a 60% threshold for the TNBC group appeared to be the most suitable. TILs bore prognostic value, especially in HER2-positive breast cancer. For clinical use, additional research on the components of immune infiltration might be reasonable.
Introduction: HER2-positive breast cancer is considered aggressive, but due to the development of targeted drugs in the past 20 years, a substantial improvement of therapy results can be postulated. Proven evidence is provided by data of randomized clinical trials. The present study aimed at demonstrating the improvement of therapy results over time using single-center real world data. Material and Methods: In our center, we prospectively built a consecutive tumor and data base from 2000 to 2020 and identified patients with early HER2-positive breast cancer (n=396). The cohort was divided in four groups by year of diagnosis according to the changing therapy concepts: A) 2000-2004 (no HER2-directed therapy, n=83), B) 2005-2011 (trastuzumab, n=96), C) 2012-2017 (trastuzumab/pertuzumab, n=135), D) 2018-2020 (T-DM1 in patients with non-pCR), n=55). HER2 was measured by IHC and ISH corresponding to the ASCO-CAP guidelines. HER2-directed therapy was indicated according to the respective national guidelines (AGO). The median follow-up was 58 months in the entire cohort (1-266), group A 84 months (10-266), group B 94 months (2-201), group C 56 months (1-118), group D 32 months (8-53). The primary endpoint was overall survival (OS), and secondary endpoint was iDFS. Kaplan-Meier estimates were calculated and multivariate analyses were performed using SPSS 28 (IBM, Armonk, NY, USA). Results: Overall, 57% of the 396 patients had an age of 50 years or more, 85% had a NST histology, 54% of the tumors were larger than 2cm, 45% were node-positive; 34% were steroid hormone receptor negative. HER2-directed therapy was delivered to 7 of 83 pts in group A (8.4%), to 62 of 96 pts in group B (64.6%), to 119 of 135 in group C (88.15%), and to 50 of 55 pts in group D (90.91%), resp.. Overall, in the first 3 years we observed 19 deaths and the probability for OS was 89.7 % for group A, 92.2 % for group B, 96.4 % for group C and 100% for group D, resp.; iDFS was 77.4% in A, 86.8% in B, 94.9% in C and 95.2% in D, resp.. After adjustment for nodal status, grading and steroid hormone receptor status, we calculated the effect size of the incremental improvement of treatment for OS and iDFS as HRs referred to group A (Table 1). Conclusion: With this prospectively established single center cohort, we are able to confirm a significant improvement of the treatment results in patients with HER2-positive early breast cancer over the last 20 years applying individualized HER2-directed therapies. Table 1. Multivariate analyses of OS and iDFS adjusted for nodal status, grading and hormone receptor status. Citation Format: Christoph Thomssen, Julia Engel, Kristin Reinhardt, Hans-Georg Strauß, Regina Große, Susanne Barrot, Marcus Bauer, Lisa van Uden, Sandy Kaufhold, Kathleen Schüler, Vanessa Wieder, Eva J. Kantelhardt, Martina Vetter. HER2-directed therapy in early breast cancer – improvement over 20 years [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 P1-11-11.
Background. Guidelines recommend broad use of carboplatin (CBDCA) for neoadjuvant therapy (NACT) of patients with triple negative breast cancer (TNBC). However, current evidence is contradictory. The aim of this prospective observational study was to assess efficacy and feasibility of CBDCA-containing neoadjuvant therapy in clinical routine. Patients and Methods. Patients who received NACT for early TNBC (n=150) were consecutively enrolled between 2000 and 2021. The following regimens were used: dose-dense epirubicin-cyclophosphamide (ddEC) followed by taxanes (n=62); CBDCA-taxane combination followed by ddEC (n=49), CBDCA-taxane combination, no anthracyclines (n=25), other chemotherapy regimen (n=14). Some CBDCA therapies were given every 3 weeks (n=18), the majority was given in a weekly fashion (n=56). The efficacy and feasibility including toxicities of these carboplatin regimen were analyzed. Median follow-up iDFS: 36.2 months (6-154), median Follow-up OS 39.3 months (6-214).Primary objective was the pCR rate (ypT0 N0) in patients who were treated with CBDCA in comparison to those who received standard non-platinum containing NACT. Secondary objectives were toxicity, therapy adherence, cancer associated recurrences and association of pCR rate with invasive disease-free survival (iDFS) and overall survival (OS). Results. Half of the patients (n=74) were treated with CBDCA, two third (69%) of them received the complete intended cycles if necessary with primary GCSF-support. Overall, the addition of CBDCA slightly increased the pCR rate from 43.4% to 48.6% with a 1.8 times reduced risk for iDFS events. The highest pCR rate was observed in those patients (n=50) who had received all CBDCA-courses as planned (50% vs 45%). By 48 months, pCR with CBDCA treatment was associated with an improved course of the disease (86.3 % iDFS probability), followed by non-pCR and CBDCA-therapy (81.1% iDFS probability), pCR and no platinum (79.8%) and non-pCR and no platinum (70.7%). Considering OS, patients without CBDCA and no pCR had the highest mortality (19.5%), all other groups had over 90% OS-probability. Dose-modification of CBDCA was associated to pCR (4 of 5 patients), whilst with discontinuation of CBDCA, 12 of 20 patients had residual disease. Although neutropenia, thrombocytopenia or anemia occurred in 36 patients, CBDCA discontinuation due to hematological effects was only necessary in 10 cases. Conclusion. In our prospective cohort, the addition of CBDCA to neoadjuvant chemotherapy for patients with TNBC was highly effective. Even after dose-modification of CBDCA (e.g. for toxicity) it seems to be effective compared to discontinuation or no inclusion of CBDCA. Our data support the current recommendations to include CBDCA in neoadjuvant therapy for TNBC. Citation Format: Christoph Thomssen, Kathleen Schüler, Marcus Bauer, Kristin Reinhardt, Hans-Gerorg Strauß, Martina Vetter. Efficacy of neoadjuvant systemic carboplatin therapy in triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-05.
Introduction. Tumor cells are influenced by their microenvironment, including immune infiltration. These tumor infiltrating lymphocytes (TILs) are considered to have prognostic and predictive value for patients with early breast cancer. The aim of this study was to evaluate the distribution of TILs and the association with survival in unselected sample of breast cancers. Patients and Methods. From a prospective, multicenter cohort of 1,270 breast cancer patients (PiA, Prognostic Assessment in routine application, NCT 01592825), 1,136 samples were evaluated for TIL infiltration inside the borders of the invasive tumor, following the recommendations of the international TILs working group. TILs were assigned to one of these three TILs groups: low TILs (<10%) intermediate (10-60%) and high TILs (>60%) and additionally scored as a continuous parameter per 10% increment. Primary objective was the distribution of TILs in different groups dependent on hormone receptor and HER2 status of the tumor (IHC group). Second objective was the association of TILs with recurrence free interval (RFI) and overall survival (OS) in univariate and multivariate analyses. The median observation time was 62 months (1-123). Results. Dependent on the IHC types a specific distribution of TILs was found: more than 60% TILs were detected in 1.5% (12 of 828) of hormone receptor (HR) positive and HER2 negative tumors, 9.7% (17 of 175) of HER2 positive tumors with any HR status and 18.8% (25 of 133) of triple negative breast cancer (TNBC). Patients with HR positive and HER2 negative tumors showed no impact of TILs with regard to RFI and OS. In the HER2 positive group with more than 60% TILs, no RFI event was detected, and with less than 60% TILs, 15% of the patients had an RFI event. The probability of OS was 94% (TILs >60%) and 81% (TILS ≤60%). For TNBC and the same TIL cut off, 88% had no RFI and OS event, compared to 70% with no event for RFI and 74% for OS. Applying 10% increments of TILs to the entire cohort, the multivariate analysis revealed a hazard ratio of 0.895 (95% CI 0.796-1.007) for RFI and a significant hazard ratio of 0.890 (95% CI 0.794-0.997) for OS. Considering the IHC groups, a 10% increment of TILs in HER2 positive tumors led to an increase of RFI (0.792, 95% CI 0.601-1.043) and OS (0.713, 95% CI 0.533-0.955, p<0.05) and in TNBC an increase of RFI (0.906, 95% CI 0.773-1.063) and OS (0.941, 95% CI. 0.795-1.115). There was no effect of TILs for patients with HR positive tumors. For the HER2 positive group the highest likelihood of a significant effect was determined for a cut-off of 20% (RFI: 2.467, 95% CI 0.903-6.735, p=0.078; OS: 4.565, 95% CI 1.583-13.159, p=0.005), for TNBC the highest likelihood was found at a cut-off of 5% (RFI: 1.440, 95% CI 0.627-3.308, p=0.390; OS: 2.035, 95% CI 0.906-4.571, p=0.085). Conclusion. Using data from our multicenter, consecutive enrolled cohort, TILs were ascertained as an independent even not significant prognostic factor for patients with HER2 positive and TN tumours. A 10% increment of TILs led to a 21% better disease specific survival (RFI) for patients with HER2-positive tumors and a 10% better RFI for patients with TNBC. Hence, for clinical implementation of prognostic assessment, we would suggest to use 20% as the cut-off for HER2 positive tumors and 5% for TN tumors. Citation Format: Kathleen Schüler, Daniel Bethmann, Tilmann Lantzsch, Christoph Uleer, Volker Hanf, Susanne Peschel, Jutta John, Marleen Pöhler, Joerg Buchmann, Karl-Friedrich Buerrig, Edith Weigert, Eva Johanna Kantelhardt, Christoph Thomssen, Martina Vetter. Tumor infiltrating lymphocytes as a prognostic factor [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-15.
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