Abstract Background: Stromal tumor-infiltrating lymphocytes (sTILs) quantification is associated with pathological response to neoadjuvant chemotherapy (NAC) and long term outcomes in setting of adjuvant anthracycline based chemotherapy. A previous study in TNBC patients treated with adjuvant anthracycline chemotherapy shows that at a cut point of 30%, sTILs can up and downstage traditional AJCC stage groups. Additive impact of sTILs on refining outcomes beyond pathological response and TNM stage for patients treated with anthracycline-free chemotherapy is not known. This study aimed to investigate impact of sTILs on outcomes in a large cohort of TNBC patients treated with Docetaxel plus carboplatin NAC. Methods: Patients with stage I (T size > 1cm) to III TNBC scheduled to receive 6 cycles of NAC docetaxel (75 mg/m2) plus carboplatin (AUC 6) (TCb) every 3 weeks from two studies (NCT01560663 and NCT02302742) were combined for this analysis. sTILs were evaluated on pre-treatment H&E slide using standard criteria centrally by one of the investigators (RS). Pathological complete response (pCR) was defined as ypT0/is ypN0. Logistic regression analysis was used to examine the effect of multiple variables on Event free survival (EFS) and overall survival (OS). Results: For 474 patients included in this analysis, median age was 52 years, 8% were Black, 13% had germline BRCA1/2 mutation, 44% had clinical Lymph node (LN) positive disease and 13%, 62% and 25% respectively had TNM stage I, II and III disease. Median sTILs were 5% (range 1-95%) and 25% had >30% sTILs. pCR and RCB 0+1 rates were 50.2% and 60.4% respectively. On multivariable analysis, T stage (OR=0.51, p=0.030), nodal status (OR=0.56, p=0.028), Ki67 (OR=2.74, p< 0.001) and sTILs (OR=2.01, p=0.014) were associated with pCR. pCR rate in those with sTILs < 30 vs sTILs >30 was 45.9% and 63.9% respectively (p=0.0014). At median follow-up of 58 months, 5 years EFS was 81.05% in all patients, 93.94% in those with pCR and 68.67% in those without pCR, 5 year OS was 84.83% in all patients, 96.53% in those with pCR and 74.13% in those with residual disease. On multivariate analysis lower T stage, negative LN status and increasing sTILS were associated with better EFS (T stage: HR =1.98, p=0.018; LN status: HR=2.92, p< 0.001; sTILs: HR:0.46, p=0.04) and OS (T stage: HR=1.89, p=0.040; LN status: HR=3.13, p=0.001; sTILs: HR=0.30, p=0.008). At a cut-point of 30%, sTILs up and downstaged anatomic AJCC TNM stage groups (table 1). Conclusions and Relevance: In patients treated with anthracycline-free TCb chemotherapy, sTILs were independent predictors of EFS and OS beyond clinicopathological features. Notably, 30% sTILs cut-point stratified outcomes beyond anatomical TNM staging. These, findings can aid in patient stratification for chemotherapy backbone de-escalation in future trials and have the potential to inform patient selection for adjuvant treatment escalation and de-escalation trials. Tumor infiltrating lymphocyte stratification refines AJCC TNM staging based outcomes of early-stage triple negative breast cancer treated with neoadjuvant anthracycline-free, docetaxel and carboplatin chemotherapy. Table. Citation Format: Miguel Martín, Rachel Yoder, Roberto Salgado, María del Monte-Millán, Enrique Álvarez, Isabel Echavarria, Joshua Staley, Coralia Bueno-Muiño, Yolanda Jerez Gilarranz, Andrew Godwin, María Cebollero, Oscar Bueno, José Ángel García-Sáenz, Fernando Moreno Antón, Uriel Bohn, Henry L Gómez, Tatiana Massarrah, Sara López-Tarruella, Priyanka Sharma. Tumor infiltrating lymphocyte stratification refines AJCC TNM staging based outcomes of early-stage triple negative breast cancer treated with neoadjuvant anthracycline-free, docetaxel and carboplatin chemotherapy [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 PS16-07.
<div>AbstractPurpose:<p>Addition of carboplatin (Cb) to anthracycline chemotherapy improves pathologic complete response (pCR), and carboplatin plus taxane regimens also yield encouraging pCR rates in triple-negative breast cancer (TNBC). Aim of the NeoSTOP multisite randomized phase II trial was to assess efficacy of anthracycline-free and anthracycline-containing neoadjuvant carboplatin regimens.</p>Patients and Methods:<p>Patients aged ≥18 years with stage I–III TNBC were randomized (1:1) to receive either paclitaxel (P) weekly × 12 plus carboplatin AUC6 every 21 days × 4 followed by doxorubicin/cyclophosphamide (AC) every 14 days × 4 (CbP → AC, arm A), or carboplatin AUC6 + docetaxel (D) every 21 days × 6 (CbD, arm B). Stromal tumor-infiltrating lymphocytes (sTIL) were assessed. Primary endpoint was pCR in breast and axilla. Other endpoints included residual cancer burden (RCB), toxicity, cost, and event-free (EFS) and overall survival (OS).</p>Results:<p>One hundred patients were randomized; arm A (<i>n</i> = 48) or arm B (<i>n</i> = 52). pCR was 54% [95% confidence interval (CI), 40%–69%] in arm A and 54% (95% CI, 40%–68%) in arm B. RCB 0+I rate was 67% in both arms. Median sTIL density was numerically higher in those with pCR compared with those with residual disease (20% vs. 5%; <i>P</i> = 0.25). At median follow-up of 38 months, EFS and OS were similar in the two arms. Grade 3/4 adverse events were more common in arm A compared with arm B, with the most notable differences in neutropenia (60% vs. 8%; <i>P</i> < 0.001) and febrile neutropenia (19% vs. 0%; <i>P</i> < 0.001). There was one treatment-related death (arm A) due to acute leukemia. Mean treatment cost was lower for arm B compared with arm A (<i>P</i> = 0.02).</p>Conclusions:<p>The two-drug CbD regimen yielded pCR, RCB 0+I, and survival rates similar to the four-drug regimen of CbP → AC, but with a more favorable toxicity profile and lower treatment-associated cost.</p></div>
Abstract Background: Triple negative breast cancer is defined by lack of expression of ER/PR (immunohistochemistry expression <1%) and absence of HER2 gene amplification. However, data regarding endocrine therapy benefit in patients with low levels (1-10%) of ER/PR expression are lacking. Furthermore, gene expression studies show tremendous similarities between HER2 negative tumors with low and negative ER/PR status. Accordingly, the 2020 ASCO/CAP guideline designates that ER expression of 1-10% be reported as a distinct “ER low positive” category. Utilizing data from a prospective registry, the aim of this study was to determine the impact of low versus negative ER/PR status on clinico-pathologic characteristics and survival outcomes in patients with HER2 negative breast cancers. Methods: 516 subjects with stage I-III HER2 negative breast cancer and ER/PR IHC ≤10% were enrolled in an IRB-approved multisite prospective registry between 2011 and 2019. Demographic, clinical, pathologic, and treatment information was collected, and patients were followed for recurrence and survival. Patients were categorized according to ER/PR expression into two groups: TNBC (ER and PR <1%) and Low-ER (ER and/or PR 1-10%). Recurrence free survival (RFS) and overall survival (OS) were estimated according to the Kaplan-Meier method and compared among groups by log-rank test, followed by Cox regression analysis. Results: TNBC and Low-ER groups comprised 451/516 (87.4%) and 65/516 (12.6%) patients, respectively. Demographic, clinical, pathologic, and treatment characteristics of the two groups are described in Table 1. Median follow-up was 39 months. Three-year RFS was 82% for both TNBC and Low-ER groups (p=0.70). Three-year OS was 88% and 83% for TNBC and Low-ER groups, respectively (p=0.63). Twenty percent of patients in the Low-ER group received adjuvant endocrine therapy, and endocrine therapy use did not impact outcomes in the Low-ER group (RFS: p=0.32; OS: p=0.88). On multivariate analysis, T stage, nodal status, and age significantly impacted RFS (T stage 3/4 vs 1/2, HR=2.7, p<0.001; nodal status positive vs negative, HR=2.4, p<0.001; age above vs below median, HR=1.8, p=0.006) and OS (T stage 3/4 vs 1/2, HR=3.6, p<0.001; nodal status positive vs negative, HR=2.8, p<0.001; age above vs below median, HR=1.026, p=0.01). For patients who received neoadjuvant chemotherapy, achievement of pathological complete response (pCR) was associated with superior RFS (3-year RFS of 95% and 67% in those with and without pCR, respectively, HR=0.18, p<0.001). Conclusions: Patients with TNBC and Low-ER HER2 negative breast cancer present with similar clinico-pathologic characteristics, including prevalence of germline BRCA1/2 mutation. Prognosis and rate of pCR (with neo-adjuvant chemotherapy) in patients with Low-ER HER2 negative breast cancer is similar to those with TNBC. The role and efficacy of adjuvant endocrine therapy in patients with Low-ER breast cancer is unclear. These findings support consideration for inclusion of patients with Low-ER disease along with TNBC for future clinical trial eligibility and planning. Table 1. Demographic, clinical, pathologic, and treatment characteristicsCharacteristics - N (%)All N=516TNBC (ER & PR <1%) n=451Low-ER (ER or PR 1-10%) n=65pAge at diagnosis, years - median (range)53 (23-97)54 (23-97)51 (28-76)0.61RaceWhite386 (75%)335 (74%)51 (79%)0.69Black101 (20%)89 (20%)12 (19%)Asian8 (2%)8 (2%)0 (0%)Menopausal statusPre214 (42%)181 (41%)33 (51%)0.25Post295 (58%)263 (59%)32 (49%)Histological gradeI2 (0.4%)2 (0.4%)0 (0%)0.82II86 (17%)76 (17%)10 (15%)III428 (83%)373 (83%)55 (85%)T stageT1-2446 (87%)388 (87%)58 (89%)0.56T3-467 (13%)60 (13%)7 (11%)N statusPositive177 (34%)158 (35%)19 (29%)0.36Negative339 (66%)293 (65%)46 (71%)TNM stageI179 (35%)150 (33%)29 (44%)0.10II263 (51%)232 (52%)31 (48%)III74 (14%)69 (15%)5 (8%)Germline BRCA1/2 mutationYes70 (14%)64 (14%)6 (9%)0.53No357 (69%)309 (69%)48 (74%)Unknown89 (17%)78 (17%)11 (17%)ChemotherapyNeoadjuvant357 (69%)318 (71%)39 (60%)0.23Adjuvant147 (29%)123 (27%)24 (37%)None12 (2%)10 (2%)2 (3%)Surgery typeMastectomy308 (60%)275 (61%)33 (51%)0.10Lumpectomy205 (40%)173 (39%)32 (49%)Adjuvant endocrine therapyYes20 (4%)7 (2%)13 (20%)<0.001No496 (96%)444 (98%)52 (80%)pCR (in patients with neoadjuvant chemotherapy, n=357)176 (49%)157 (49%)19 (49%)0.94 Citation Format: Rachel Yoder, Bruce F Kimler, Joshua M Staley, Kelsey Schwensen, Yen Y Wang, Karissa Finke, Anne O'Dea, Lauren Nye, Manana Elia, Gregory Crane, Richard McKittrick, Robert Pluenneke, Sheshadri Madhusudhana, Larry Beck, Roberto Rodriguez, Anuj Shrestha, Larry Corum, Mark Marsico, Andrew K Godwin, Qamar Khan, Priyanka Sharma. Impact of low versus negative estrogen/progesterone receptor status on clinico-pathologic characteristics and survival outcomes in HER2 negative 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 PS6-04.
Abstract Introduction: The TNBC-DX risk score includes the 14-gene immunoglobulin (IGG) immune signature, tumor size, and nodal status and has shown prognostic value for survival in early-stage TNBC (B. Conte et al., ESMO Breast 2021). However, currently unknown are the value of the TNBC-DX risk score and IGG immune signature in 1) predicting pathologic complete response (pCR) following neoadjuvant therapy, and 2) predicting outcomes the context of neoadjuvant anti-PD1 treatment. Here, we assessed the IGG signature and the TNBC-DX risk score in patients with TNBC treated with neoadjuvant chemoimmunotherapy (NeoPACT; NCT03639948) and neoadjuvant chemotherapy without immunotherapy (NeoSTOP; NCT02413320). Methods: NeoPACT trial enrolled 120 patients with stage I-III TNBC who received carboplatin (AUC 6) + docetaxel (75 mg/m2) + pembrolizumab (200 mg) every 21 days x 6 cycles. NeoSTOP randomized 100 patients with stage I-III TNBC to two chemotherapy regimens; Arm B of NeoSTOP was included in this correlative study as the chemotherapy regimen was identical to NeoPACT. RNA isolated from pretreatment tumor tissue was subjected to next-generation sequencing. The 14-gene IGG immune signature and TNBC-DX risk score were calculated in silico as previously described. Evaluation of stromal tumor-infiltrating lymphocytes (sTILs) was performed as previously described. Markers were tested for prediction of pCR. Logistic regression analysis was used to examine the effect of multiple variables. Event-free survival (EFS) curves were assessed by the Kaplan-Meier method and groups compared by the log-rank test, followed by Cox regression analysis. Results: In this analysis, 112 patients were treated with chemoimmunotherapy on NeoPACT (node-positive = 38%, pCR rate = 58%). In the NeoPACT trial, the 14-gene IGG signature (as a continuous variable) was significantly associated with improved pCR (odds ratio [OR]=1.105, 95% CI 1.019-1.197, P=0.015 for every 0.2 increment). The pCR rates in IGG-high (≥ median) and IGG-low (< median) groups were 71% and 44%, respectively (OR=3.152, 95% CI 1.420-6.996, P=0.005). In terms of EFS, the 14-gene IGG signature was not prognostic (hazard ratio [HR]=0.507, 95% CI 0.148-1.735, p=0.269). In contrast, TNBC-DX risk score was strongly associated with EFS (HR=5.684, 95% CI 1.226-26.356, P=0.012), even when adjusted for sTILs and pCR status (HR=8.415, 95% CI 1.054-67.169, P=0.044). Estimated 3-year EFS rates in TNBC-DX high and low risk groups (above and below median) were 77% and 89%, respectively (P=0.012). In 43 NeoSTOP patients treated with neoadjuvant chemotherapy only (node-positive = 33%, pCR rate = 53%), no association of IGG signature with pCR or TNBC-DX score with EFS was observed. Finally, we observed a moderate correlation between IGG signature and sTILs in both trial datasets combined (r=0.642, P< 0.001). Conclusions: High expression of the 14-gene IGG immune signature in baseline pretreatment tumor samples in early-stage TNBC is significantly associated with pCR following pembrolizumab-based neoadjuvant chemotherapy. The combination of this signature with tumor burden as assessed by TNBC-DX is prognostic for long-term outcomes. Availability of biomarkers that can predict both pathological response and survival with chemoimmunotherapy can optimize this therapy, and evaluation of this biomarker in larger studies is warranted. Citation Format: Priyanka Sharma, Shane R. Stecklein, Rachel Yoder, Joshua M. Staley, Roberto Salgado, Laia Paré, Benedetta Conte, Fara Brasó-Maristany, Anne O’Dea, Lauren Nye, Manana Elia, Deepti Satelli, Gregory Crane, Richard McKittrick, Qamar Khan, Andrew K. Godwin, Aleix Prat. PD11-07 Association of TNBC-DX scores with outcomes in triple-negative breast cancer (TNBC) treated with neoadjuvant pembrolizumab and chemotherapy: a correlative analysis from NeoPACT and NeoSTOP trials [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 PD11-07.
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