Early Triple-negative Breast Cancer Research Articles

3MO IMpassion031: Results from a phase III study of neoadjuvant (neoadj) atezolizumab + chemo in early triple-negative breast cancer (TNBC)

3MO IMpassion031: Results from a phase III study of neoadjuvant (neoadj) atezolizumab + chemo in early triple-negative breast cancer (TNBC)

10P Neoadjuvant immunotherapy plus chemotherapy in early triple-negative breast cancer: A meta-analysis of randomized controlled trials

10P Neoadjuvant immunotherapy plus chemotherapy in early triple-negative breast cancer: A meta-analysis of randomized controlled trials

Preoperative Pembrolizumab Treatment Changes Tils in Naïve Stage I/IIA TNBC Patients Within a Window of Opportunity Trial

High levels of stromal tumor–infiltrating lymphocytes (sTILs) are significantly associated with chemosensitivity and improved overall survival for patients with triple negative breast cancer (TNBC). Our aim is to determine if we can significantly increase sTILs from biopsy to lumpectomy in a presurgical window of opportunity trial with pembrolizumab (pembro) and intraoperative radiation (IORT) in treatment-naïve early stage TNBC compared to matched IORT only controls. The hypothesis is that preoperative pembro treatment in TNBC patients will increase the density and change the spatial distribution of TILs from biopsy to lumpectomy. Seven women with node negative TNBC <2.5 cm were enrolled in either our presurgical trial with pembro and IORT as an upfront boost (NCT02977468) or a parallel study with IORT alone (NCT03165487). The treatment consisted of two doses of pre-operative pembro (200mg IV) given alone with the second dose -10 to -18 days from surgery; 20Gy IORT was delivered during surgery to the lumpectomy bed. All patients completed standard of care adjuvant chemotherapy and whole breast irradiation. Assessments of sTILs and intraepithelial TILs (iTILs) was performed by H&E and qmIF from the initial biopsy and lumpectomy. Deep learning algorithms for tumor annotation and lymphocyte detection were used also to measure of iTILs. Spatial clustering analysis to measure the mean dispersion with iTILs was evaluated by calculating Ball-Hall index. Transcriptomic analysis of tumor-associated and immune genes was performed using the slide-mounted tissue. Seven patients were enrolled between Nov 2017-Apr 2019; 3 patients received pembro+IORT; and 4 patients received IORT alone. Initial H&E pathology assessment of sTILs demonstrated no significant changes between biopsy and lumpectomy in control patients. No consistent patterns of iTILs dispersion were observed in the control patients. Out of the 3 pembro-treated patients, one patient demonstrated a marked increase in sTILs with a shift from a neutrophil-rich to lymphoplasmacytic stromal infiltrate, where the mean dispersion of iTILs doubled. The 2 other pembro patients, one remained stable and one showed a slight increase in sTILs. The iTILs dispersion increased significantly in these patients. QmIF analysis showed overall increase in stromal immune cell infiltrate in all cases after Pembro treatment, with an increase in stromal CD68+ macrophage noted in all cases. Transcriptomic analysis showed increased expression of CD68 and CD163 after pembro treatment. In this preliminary analysis, we observe preoperative pembro-induced increases in sTILs with increased mean dispersion of iTILs in treatment-naïve TNBC. Further investigation is warranted to elucidate the impact of preoperative pembro in early stage TNBC and other potential therapeutic implications.

The influence of age, comorbidity and frailty on treatment with surgery and systemic therapy in older women with operable triple negative breast cancer (TNBC) in England: A population-based cohort study

BackgroundSurgery and chemotherapy use were studied among older women with early stage triple negative breast cancer (TNBC) in a population-based cohort. MethodsWomen aged ≥50 years with unilateral early (stage 1-3a) TNBC diagnosed in 2014–2017 were identified from English cancer registration data. Information on surgery and chemotherapy was from linked Hospital Episode Statistics and Systemic Anti-Cancer Therapy datasets, respectively. Logistic regression was used to investigate the influences of patient age, comorbidity and frailty on uptake of surgery and chemotherapy. ResultsThere were 7094 women with early stage TNBC. Overall rate of surgery was 94%, which only decreased among women aged ≥85 years (74%) and among the most frail. Among the 6681 women receiving surgery, 16% had neoadjuvant and 42% had adjuvant chemotherapy; the use of both decreased with age. More comorbidities and greater frailty were associated with lower rates of chemotherapy. There were differences in the uptake of chemotherapy across geographical regions and in the neoadjuvant and adjuvant chemotherapy regimens between age groups. ConclusionMajority of older women with early TNBC had surgery, although some physically fit older women did not. Chemotherapy use varied by age and fitness.

National Trends in Treatment Patterns and Clinical Outcomes of Patients with Early Triple Negative Breast Cancer

Goldbach, Macy BS; Burkbauer, Laura BA; Tchou, Julia C. MD, PhD, FACS Author Information

243 Poster - A high rate of pathological complete response is possible by incorporating cisplatin in neoadjuvant therapy of locally advanced triple-negative breast cancer: A single-institution experience

Background: Breast cancer is the commonest cancer among women in India with 162468 new cases diagnosed in 2018. Triple-negative breast cancer accounts for 20–30% of these cases. It is a heterogeneous and poorly understood disease that has worse outcomes as compared to the other subtypes of breast cancer. Carboplatin has been shown to improve outcomes in the neoadjuvant setting in early triple-negative breast cancer. Studies on cisplatin in the neoadjuvant setting, especially in combination with anthracyclines and taxanes are very few. This study analysed the safety and efficacy of neoadjuvant cisplatin-based combination chemotherapy.

Tissue Immune Profile: A Tool to Predict Response to Neoadjuvant Therapy in Triple Negative Breast Cancer.

Simple SummaryPathological complete response (pCR) after neoadjuvant chemotherapy can predict survival outcomes in patients with early triple negative breast cancer (TNBC). The immune microenvironment can affect response to chemotherapy. We combined several immune-related biomarkers (TILs, PD-L1 and CD73) in a tissue immune profile (TIP) and investigated if can predict pCR better than single biomarkers in TNBC. The association between TIP and pCR could be proposed as a novel link between immune background and response to chemotherapy. As a future perspective, our results could help to select patients eligible for combinations with immunotherapy or for escalating and de-escalating strategies.Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) can predict better survival outcomes in patients with early triple negative breast cancer (TNBC). Tumor infiltrating lymphocytes (TILs), Programmed Death-Ligand 1 (PD-L1), and Cluster of Differentiation 73 (CD73) are immune-related biomarkers that can be evaluated in the tumor microenvironment. We investigated if the contemporary expression of these biomarkers combined in a tissue immune profile (TIP) can predict pCR better than single biomarkers in TNBC. Tumor infiltrating lymphocytes (TILs), CD73 expression by cancer cells (CC), and PD-L1 expression by immune cells (IC) were evaluated on pre-NACT biopsies. We defined TIP positive (TIP+) as the simultaneous presence of TILS ≥ 50%, PD-L1 ≥ 1%, and CD73 ≤ 40%. To consider the effects of all significant variables on the pCR, multivariate analysis was performed. Akaike information criterion (AIC) and Bayesian information criterion (BIC) were used for model selection. We retrospectively analyzed 60 biopsies from patients with TNBC who received standard NACT. Pathological complete response was achieved in 23 patients (38.0%). Twelve (20.0%) cases resulted to be TIP+. The pCR rate was significantly different between TIP+ (91.7%) and TIP− (25.0%) (p < 0.0001). Using a multivariate analysis, TIP was confirmed as an independent predictive factor of pCR (OR 49.7 (6.30–392.4), p < 0.0001). Finally, we compared the efficacy of TIP versus each single biomarker in predicting pCR by AIC and BIC. The combined immune profile is more accurate in predicting pCR (AIC 68.3; BIC 74.5) as compared to single biomarkers. The association between TIP+ and pCR can be proposed as a novel link between immune background and response to chemotherapy in TNBC, highlighting the need to consider an immunological patients’ profile rather than single biomarkers.

Prognostic and predictive value of circulating tumor DNA during neoadjuvant chemotherapy for triple negative breast cancer

Response to neoadjuvant chemotherapy (NAC) in triple negative breast cancer (TNBC) is highly prognostic and determines whether adjuvant chemotherapy is needed if residual tumor is found at surgery. To evaluate the predictive and prognostic values of circulating tumor DNA (ctDNA) in this setting, we analyzed tumor and serial bloods from 26 TNBC patients collected prior, during, and after NAC. Individual digital droplet PCR assays were developed for 121 variants (average 5/patient) identified from tumor sequencing, enabling ctDNA detection in 96% of patients at baseline. Mutant allele frequency at baseline was associated with clinical characteristics. Levels drastically fell after one cycle of NAC, especially in patients whose tumors would go on to have a pathological complete response (pCR), but then rose significantly before surgery in patients with significant residual tumor at surgery (p = 0.0001). The detection of ctDNA early during treatment and also late at the end of NAC before surgery was strongly predictive of residual tumor at surgery, but its absence was less predictive of pCR, especially when only TP53 variants are considered. ctDNA detection at the end of neoadjuvant chemotherapy indicated significantly worse relapse-free survival (HR = 0.29 (95% CI 0.08–0.98), p = 0.046), and overall survival (HR = 0.27 95% CI 0.075–0.96), p = 0.043). Hence, individualized multi-variant ctDNA testing during and after NAC prior to surgery has prognostic and predictive value in early TNBC patients.

219P Relationship among PDL1, androgen receptor (AR) and tumour infiltrating lymphocytes (TILs) in early triple negative breast cancer

219P Relationship among PDL1, androgen receptor (AR) and tumour infiltrating lymphocytes (TILs) in early triple negative breast cancer

194P Neoadjuvant immunotherapy plus chemotherapy in early triple-negative breast cancer: A meta-analysis of randomized controlled trials

194P Neoadjuvant immunotherapy plus chemotherapy in early triple-negative breast cancer: A meta-analysis of randomized controlled trials

LBA11 IMpassion031: Results from a phase III study of neoadjuvant (neoadj) atezolizumab + chemotherapy in early triple-negative breast cancer (TNBC)

LBA11 IMpassion031: Results from a phase III study of neoadjuvant (neoadj) atezolizumab + chemotherapy in early triple-negative breast cancer (TNBC)

196P Neoadjuvant and adjuvant chemotherapy (NACT/ACT) treatment (tx) patterns in a real-world cohort of US pts with early triple-negative breast cancer (eTNBC)

196P Neoadjuvant and adjuvant chemotherapy (NACT/ACT) treatment (tx) patterns in a real-world cohort of US pts with early triple-negative breast cancer (eTNBC)

A population-based comparison of treatment patterns, resource utilization, and costs by cancer stage for Ontario patients with triple-negative breast cancer.

BackgroundThere have been few publications exploring the characteristics, treatment pathways, and health‐care costs by stage in patients with a triple‐negative breast cancer (TNBC) phenotype.MethodsData from a publicly funded health‐care system in Ontario were assessed. Baseline characteristics, treatment patterns, and health‐care costs were descriptively compared by cancer stage (I‐III vs IV) for adult women diagnosed with invasive TNBC between 2012 and 2016. Resource use was multiplied by unit costs for publicly funded health‐care services to calculate health system‐related costs.ResultsA total of 3271 cases were identified, 3081 with stage I‐III and 190 with stage IV TNBC. Baseline characteristics were aligned with previous reports. Surgery was the most common treatment among patients with stage I‐III disease (n = 2979, 96.7%); 557 (18.7%) received neoadjuvant therapy (NAT) and 1974 (66.3%) received adjuvant therapy (AT), the latter at a median of 44 days postsurgery, and 2446 (79.4%) in the stage I‐III cohort received radiation. Treatment for metastatic TNBC included surgery in 48 (25.3%), systemic therapy in 138 (72.6%), and radiotherapy in 112 (58.9%) patients. Top drug regimens included anthracyclines/taxanes. Annual per‐patient health care costs were four times higher for stage IV vs. stage I‐III TNBC.ConclusionPer‐patient costs were higher in metastatic TNBC, despite a less frequent use of all treatment modalities compared to early TNBC. Treatment patterns were aligned with the options available at the time; however, neoadjuvant treatment rates were low.

Canonical ErbB-2 isoform and ErbB-2 variant c located in the nucleus drive triple negative breast cancer growth.

Triple negative breast cancer (TNBC) refers to tumors that do not express clinically significant levels of estrogen and progesterone receptors, and lack membrane overexpression or gene amplification of ErbB-2/HER2, a receptor tyrosine kinase. Transcriptome and proteome heterogeneity of TNBC poses a major challenge to precision medicine. Clinical biomarkers and targeted therapies for this disease remain elusive, so chemotherapy has been the standard of care for early and metastatic TNBC. Our present findings placed ErbB-2 in an unanticipated scenario: the nucleus of TNBC (NErbB-2). Our study on ErbB-2 alternative splicing events, using a PCR-sequencing approach combined with an RNA interference strategy, revealed that TNBC cells express either the canonical (wild-type) ErbB-2, encoded by transcript variant 1, or the non-canonical ErbB-2 isoform c, encoded by alternative variant 3 (RefSeq), or both. These ErbB-2 isoforms function in the nucleus as transcription factors. Evicting both from the nucleus or silencing isoform c only, blocks TN cell and tumor growth. This reveals not only NErbB-2 canonical and alternative isoforms role as targets of therapy in TNBC, but also isoform c dominant oncogenic potential. Furthermore, we validated our findings in the clinic and observed that NErbB-2 correlates with poor prognosis in primary TN tumors, disclosing NErbB-2 as a novel biomarker for TNBC. Our discoveries challenge the present scenario of drug development for personalized BC medicine that focuses on wild-type RefSeq proteins, which conserve the canonical domains and are located in their classical cellular compartments.

Prognostication of a 13-immune-related-gene signature in patients with early triple-negative breast cancer.

We investigated the expression profiles of immune genes in patients with triple-negative breast cancer (TNBC) to identify the prognostic value of immune genes and their clinical implications. NanoString nCounter Analysis of 770 immune-related genes was used to measure immune gene expression in patients with TNBC who underwent curative surgery followed by adjuvant chemotherapy at Samsung Medical Center between 2000 and 2004. Statistical analyses were conducted to identify the associations between gene expression and distant recurrence-free survival (DRFS). Of 1189 patients who underwent curative BC surgery, 200 TNBC patients were included and stage was the only clinical factor predictive of DRFS. In terms of immune genes, 155 of 770 genes were associated with DRFS (p < 0.01). Further multivariate analysis revealed that 13 genes, CD1B, CD53, CT45A1, GTF3C1, IL11RA, IL1RN, LRRN3, MAPK1, NEFL, PRKCE, PTPRC, SPACA3 and TNFSF11, were associated with patient prognosis (p < 0.05). The prognostic value of stage and expression levels of 13 immune genes was analyzed and the area under the receiver operating characteristic curve (AUC) was 0.923. Based on the AUC, we divided patients into three genetic risk groups and DRFS rate was significantly different according to genetic risk groups, even in the same stage (p < 0.001). In this study, a 13-gene expression profile in combination with stage precisely predicted distant recurrence of early TNBC. Therefore, this 13-immune-gene signature could help predict TNBC prognosis and provide guidance for treatment as well as the opportunity to develop new targets for immunotherapy in TNBC patients.

Abstract 5669: Differential prognosis of immune biomarkers in metastatic vs. early triple negative breast cancer (TNBC) settings

Abstract Background: A pre-existing intratumoral immune response, as characterized by presence of tumor infiltrating lymphocytes or cytotoxic effector T cells, is linked to improved prognosis in early TNBC (eTNBC). Recent data in metastatic TNBC (mTNBC) suggest that immune rich tumors are not prognostic (Emens et al., SABCS 2018). Since different immune biomarkers were used across studies to make these observations, it is uncertain whether the T-cell immune biology has differential prognosis between eTNBC and mTNBC. The aim of this study was to evaluate the prognostic value of the T effector RNA gene signature (Teff), across two eTNBC and two mTNBC clinical studies using the same biomarker methodology. Methods: FFPE breast tumor samples from two adjuvant (BO20289 [n = 955] and NO17629 [n = 260]) and two front line metastatic (GO25632 [n = 62] and OAM4861G [n = 150]) TNBC clinical studies were evaluated for RNA gene expression by using customized Nanostring panels. Normalization was carried out across all 4 datasets combined, and Teff signature (CD8A, IFNG, PRF1, CXCL9 and CXCL10) values were generated using mean z-scores. Overall survival (OS) was evaluated in all the studies. Results: While levels of Teff were similar within the eTNBC studies (p = 0.43) and the mTNBC studies (p = 0.44), Teff score was significantly higher in eTNBC compared to the mTNBC studies (p &amp;lt;0.0001). Lymph node involvement in the eTNBC studies was the only baseline prognostic characteristic associated with Teff (p = 0.014 and 0.023) out of those assessed. Using the Teff global mean across the studies and adjusting for baseline characteristics, multivariate analysis showed that elevated Teff was associated with improved OS in the BO20289 and NO17629 eTNBC studies (HR 0.36 [95% CI 0.24-0.53] and 0.40 [95% CI 0.20-0.75], respectively), while no prognostic value was linked to the GO25632 or OAM4861G mTNBC trials (HR 1.28 [95% CI 0.35-3.91] and 1.01 [95% CI 0.57-1.73], respectively). Similar results were observed at different Teff cutoffs. Finally, Teff was lower in recurrent tumors compared to matched primary samples from the BO20289 study (n = 25, p = 0.002). Conclusions: Our data suggest that tumor immune biology, as assessed by Teff RNA gene expression 1) is lower in patients with mTNBC than eTNBC and 2) improves OS prognosis in patients with eTNBC but not in those with mTNBC. Using four clinical studies independently executed but simultaneously assessed increases the robustness of this analysis. Notably, eTNBC patients whose disease recurs are those with lower Teff levels, consistent with the finding that Teff is lower in mTNBC than the curative eTNBC setting. Taken together, our results highlight that the prognosis of immune biology in TNBC is not interchangeable between the metastatic and early disease settings. Finally, these results have implications for assessing clinical activity of immune checkpoint inhibitors in single arm studies. Citation Format: Kelly J. Dupree, Ching-Wei Chang, Meghna Das Thakur, Timothy R. Wilson, David Shames, David Cameron, Luciana Molinero. Differential prognosis of immune biomarkers in metastatic vs. early triple negative breast cancer (TNBC) settings [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5669.

Abstract 1709: New targeted therapy on SOCS1-related immune-response in triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) includes heterogenous molecular subtypes, e.g., basal-like, immunomodulatory, mesenchymal, mesenchymal stem cell and luminal androgen receptor subtypes. Chemotherapy is the standard care for patients with early TNBC, but advanced or metastatic disease has unfavorable prognosis. PARP inhibitors and immune checkpoint inhibitors are effective for patients with BRCA gene mutation and PD-L1-positive TNBC, respectively. However, their clinical benefits seem to be limited. Thus, we are investigating new therapy targeted on immune modulation in TNBC. Materials and methods: First, we performed microarray expression analysis (Agilent Technologies, Inc.) of small RNA extracted from 11 breast cancer specimens. Second, miRNA subset was compared in TNBC and non-TNBC, and several genes were identified as predicted targets for interaction of miRNA in TNBC. Third, we examined a targeted gene and protein expressions in cancer tissues by real-time qPCR and immunohistochemical staining. Tissues samples were obtained from breast cancer patients with TNBC and non-TNBC, who were scheduled to receive neoadjuvant chemotherapy (NAC). Statistical significance is evaluated by chi-squared test. This study is approved at IRB in Kyorin University School of Medicine and also supported by Grant-in-Aid for Scientific Research C of Japan Society for the Promotion of Science. Results: From comprehensive analysis, SOCS1 (suppressor of cytokine signaling 1), IL-13 and several genes were predicted as interactive targets of miRNA in TNBC. We focused on SOCS1 gene amplification and its protein overexpression in breast cancer. Most patients were treated with NAC of anthracycline- and/or taxane-based regimens. Their pathological response was graded in surgical specimens according to classification of the Japanese Breast Cancer Society. From 55 tissue specimens stained by anti-SOCS1 antibody, there was no difference among staining intensity graded at score 0-3 and pathological response of chemotherapy. However, gene amplification of SOCS1 was not statistically different but relatively lower in 6 cases with pathologically partial or complete response (grade 2 or 3) than in 11 cases with no pathological response (grade 1a or 1b). Discussions: SOCS1 is well known as a negative regulator of JAK-STAT pathway. SOCS1 is also related to suppression of T cell activation and modulation of M1 macrophage. Our data suggest that down regulation of SOCS1 gene influences clinical benefit of chemotherapy as well as host immune response like tumor-infiltrating lymphocytes (TIL). We will examine relationship between SOCS1 protein expression and TIL in breast cancer and also examine cell proliferation and T cell activation in TNBC and non-TNBC cell lines under presence and absence of SOCS1 gene expression. Conclusion: SOCS1 is a promising molecular target to modulate immune editing in TNBC. Citation Format: Shigeru Imoto, Tomohiro Chiba, Sota Asaga, Hirotsugu Isaka, Shigehiro Yokoi, Yoshiharu Ishizaka, Ai Tsuchiya, Hiroshi Kamma. New targeted therapy on SOCS1-related immune-response in triple-negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1709.

Circulating immune cell dynamics in patients with triple negative breast cancer treated with neoadjuvant chemotherapy.

BackgroundLymphopenia has been associated with inferior cancer outcomes, but there is limited data in breast cancer. We describe the effects of neoadjuvant chemotherapy on circulating immune cells and its association with pathological complete response (pCR) rates in triple negative breast cancer (TNBC).MethodsWe constructed a database of patients with early stage TNBC treated with neoadjuvant chemotherapy. Circulating lymphocytes and monocytes were assessed before and after neoadjuvant chemotherapy. These were correlated with pCR rates and disease‐free survival (DFS) using Fisher's exact test, logistic regression, and the log‐rank test.ResultsFrom 2000 to 2015, we identified 95 eligible patients. Median age was 50; 29 (31%) were treated with platinum‐containing chemotherapy; and 66 (69%) with nonplatinum‐containing chemotherapy (anthracycline‐taxane, or either alone). About 32 (34%) patients achieved a pCR; and 33 (35%) had recurrence events. Median follow‐up time was 47 months. No significant associations were found between changes in lymphocytes and pCR or DFS. There was a correlation between lower monocyte levels after neoadjuvant chemotherapy and pCR (mean monocyte 0.56 in those with no‐pCR vs 0.46 in those with pCR, P = .049, multivariate P = .078) and DFS (median DFS in highest monocyte quartile was 30 vs 107 months in lowest quartile, P = .022, multivariate P = .023). In patients who received nonplatinum regimens, DFS was better among those who had larger decreases in monocytes.ConclusionsDevelopment of lymphopenia from neoadjuvant chemotherapy was not associated with pCR in patients with TNBC. However, lower absolute circulating monocytes after neoadjuvant chemotherapy was associated with improved outcomes.

Integration of tumour infiltrating lymphocytes, programmed cell-death ligand-1, CD8 and FOXP3 in prognostic models for triple-negative breast cancer: Analysis of 244 stage I–III patients treated with standard therapy

BackgroundTumour infiltrating lymphocytes (TILs) are an established prognostic biomarker for triple-negative breast cancer (TNBC). We evaluated the role of programmed cell-death ligand-1 (PD-L1), CD8 and FOXP3 expression in refining a prognostic model for non-metastatic TNBC beyond classic factors and TILs. MethodsPrimary tumour samples from 244 early patients with TNBC, all treated with surgery and chemotherapy, were collected. Stromal TILs were evaluated on haematoxylin–eosin slides according to guidelines. PD-L1, CD8 and FOXP3 were assessed by immunohistochemistry and evaluated by digital pathology. ResultsTILs, PD-L1, CD8 and FOXP3 were positively correlated with each other (P < 0.001). TILs were confirmed as an independent prognostic factor. When PD-L1, CD8 and FOXP3 were added to multivariable models including classic factors (age, stage, histologic grade) and TILs, PD-L1 provided the largest amount of additional prognostic information: likelihood ratio χ2 4.60, P = 0.032 (in a model including classic factors and TILs 10% increments) and likelihood ratio χ2 6.50, P = 0.011 (in a model including classic factors and TILs >30% versus <30%). In the subset of patients treated with neoadjuvant chemotherapy, FOXP3 provided further prognostic information beyond classic factors, TILs and pathological complete response (pCR) (likelihood ratio χ2 5.01, P = 0.025). For patients who did not achieve a pCR, the expression of CD8 and PD-L1 was significantly increased from baseline to residual disease. ConclusionsBeyond clinicopathological factors and TILs, other immune biomarkers may add prognostic information for early TNBC. The increased PD-L1 expression on residual disease after neoadjuvant chemotherapy strengthens the rationale of testing immune checkpoint inhibitors in the post-neoadjuvant setting.

Association of Tumor-Infiltrating Lymphocytes with Homologous Recombination Deficiency and BRCA1/2 Status in Patients with Early Triple-Negative Breast Cancer: A Pooled Analysis.

Patients with triple-negative breast cancer (TNBC) with homologous recombination deficient tumors achieve significantly higher pathologic complete response (pCR) rates when treated with neoadjuvant platinum-based therapy. Tumor-infiltrating lymphocytes (TIL) are prognostic and predictive of chemotherapy benefit in early stage TNBC. The relationship between TILs, BRCA1/2 mutation status, and homologous recombination deficiency (HRD) status in TNBC remains unclear. We performed a pooled analysis of five phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to evaluate the association of TILs with HRD status (Myriad Genetics) and tumor BRCA1/2 mutation status. Furthermore, the relationship between pathologic response assessed using the residual cancer burden (RCB) index and HRD status with adjustment for TILs was evaluated. Among 161 patients, stromal TIL (sTIL) density was not significantly associated with HRD status (P = 0.107) or tumor BRCA1/2 mutation status (P = 0.391). In multivariate analyses, sTIL density [OR, 1.23; 95% confidence interval (CI), 0.94-1.61; P = 0.139] was not associated with pCR, but was associated with RCB 0/I status (OR 1.62; 95% CI, 1.20-2.28; P = 0.001). HRD was significantly associated with both pCR (OR 12.09; 95% CI, 4.11-44.29; P = 7.82 × 10-7) and RCB 0/I (OR 10.22; 95% CI, 4.11-28.75; P = 1.09 × 10-7) in these models. In patients with TNBC treated with neoadjuvant platinum-based therapy, TIL density was not significantly associated with either tumor BRCA1/2 mutation status or HRD status. In this pooled analysis, HRD and sTIL density were independently associated with treatment response, with HRD status being the strongest predictor.