Overall Survival In Triple-negative Breast Cancer Research Articles

Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy

Tumour-infiltrating lymphocytes (TILs) are predictive for response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) and HER2-positive breast cancer, but their role in luminal breast cancer and the effect of TILs on prognosis in all subtypes is less clear. Here, we assessed the relevance of TILs for chemotherapy response and prognosis in patients with TNBC, HER2-positive breast cancer, and luminal-HER2-negative breast cancer. Patients with primary breast cancer who were treated with neoadjuvant combination chemotherapy were included from six randomised trials done by the German Breast Cancer Group. Pretherapeutic core biopsies from 3771 patients included in these studies were assessed for the number of stromal TILs by standardised methods according to the guidelines of the International TIL working group. TILs were analysed both as a continuous parameter and in three predefined groups of low (0-10% immune cells in stromal tissue within the tumour), intermediate (11-59%), and high TILs (≥60%). We used these data in univariable and multivariable statistical models to assess the association between TIL concentration and pathological complete response in all patients, and between the amount of TILs and disease-free survival and overall survival in 2560 patients from five of the six clinical trial cohorts. In the luminal-HER2-negative breast cancer subtype, a pathological complete response (pCR) was achieved in 45 (6%) of 759 patients with low TILs, 48 (11%) of 435 with intermediate TILs, and 49 (28%) of 172 with high TILs. In the HER2-positive subtype, pCR was observed in 194 (32%) of 605 patients with low TILs, 198 (39%) of 512 with intermediate TILs, and 127 (48%) of 262 with high TILs. Finally, in the TNBC subtype, pCR was achieved in 80 (31%) of 260 patients with low TILs, 117 (31%) of 373 with intermediate TILs, and 136 (50%) of 273 with high TILs (p<0·0001 for each subtype, χ2 test for trend). In the univariable analysis, a 10% increase in TILs was associated with longer disease-free survival in TNBC (hazard ratio [HR] 0·93 [95% CI 0·87-0·98], p=0·011) and HER2-positive breast cancer (0·94 [0·89-0·99], p=0·017), but not in luminal-HER2-negative tumours (1·02 [0·96-1·09], p=0·46). The increase in TILs was also associated with longer overall survival in TNBC (0·92 [0·86-0·99], p=0·032), but had no association in HER2-positive breast cancer (0·94 [0·86-1·02], p=0·11), and was associated with shorter overall survival in luminal-HER2-negative tumours (1·10 [1·02-1·19], p=0·011). Increased TIL concentration predicted response to neoadjuvant chemotherapy in all molecular subtypes assessed, and was also associated with a survival benefit in HER2-positive breast cancer and TNBC. By contrast, increased TILs were an adverse prognostic factor for survival in luminal-HER2-negative breast cancer, suggesting a different biology of the immunological infiltrate in this subtype. Our data support the hypothesis that breast cancer is immunogenic and might be targetable by immune-modulating therapies. In light of the results in luminal breast cancer, further research investigating the interaction of the immune system with different types of endocrine therapy is warranted. Deutsche Krebshilfe and European Commission.

Apoptosis regulator Bcl-2 is an independent prognostic marker for worse overall survival in triple-negative breast cancer patients.

The objective of this study was to examine the prognostic significance of carbonic anhydrase IX (CAIX), an endogenous marker for tumor hypoxia; the cellular tumor antigen p53; and the apoptosis regulator Bcl-2, in triple-negative breast cancer (TNBC) patients. Immunohistochemically determined expression of CAIX, p53, Bcl-2 and proliferation factor Ki-67, analyzed in 64 paraffin-embedded TNBC tissue samples, was used to assess their relation to clinicopathological variables and prognostic implications for overall survival (OS). Bcl-2 expression was negatively correlated with histological grade of tumor, while expression of p53 was positively correlated with the same clinical variable (p = 0.036 and p = 0.033, respectively). The p53 expression was also positively correlated with tumor size (p = 0.010). Survival analysis showed that patients with high Bcl-2 expression (above cutoff value determined by receiver operator characteristic [ROC] curve analysis) had shorter OS (p = 0.020). The same was observed for patients with tumors larger than 5 cm (p = 0.034) or positive lymph nodes (p = 0.004). Among all 3 examined markers, multivariate analysis showed that only Bcl-2 expression was a strong independent prognostic indicator for decreased OS (hazard ratio [HR] = 15.16, 95% confidence interval [95% CI], 2.881-79.727, p = 0.001). Elevated expression of Bcl-2 was an independent prognostic factor for poorer OS in TNBC and as such a significant marker for tumor aggressiveness.

Prognostic value of IMP3 expression as a determinant of chemosensitivity in triple-negative breast cancer

Triple negative breast cancer (TNBC) has an aggressive phenotype and poor prognosis. Neoadjuvant chemotherapy (NAC) is often used to treat TNBC, but some patients are resistant to NAC. We postulated that a subpopulation of TNBC cells expressing IMP3, an oncofetal protein, could be resistant to NAC, contributing to the poor prognosis. We investigated immunohistochemical expression of IMP3 in 42 TNBC patients who underwent NAC in association with clinical outcomes. The patients were divided into IMP3 positive (+) (n=19) and negative (−) (n=23) groups. High Ki67 positivity was detected in 13 patients of the IMP3+group and 8 cases in the IMP3 – group (p=0.03). While 9 patients in the IMP3 – group (39%) were responders, the majority of the IMP3+patients (84.2%) were non-responders (p=0.01). In a Cox proportional hazard model, IMP3 expression was independently associated with poor NAC response and clinical outcomes (p=0.03 and 0.046, respectively). The IMP3+group showed a tendency toward shorter overall survival compared to the IMP3 – group with marginal significance (p=0.07). These findings suggest that IMP3+tumor cells contributed to the poor clinical outcomes by exerting a chemoresistance to NAC, and that IMP3 expression has prognostic value as a biomarker for chemosensitivity and overall survival in TNBC.

MicroRNA-211-5p suppresses tumour cell proliferation, invasion, migration and metastasis in triple-negative breast cancer by directly targeting SETBP1

Background:Triple-negative breast cancer (TNBC) accounts for 15–20% of all breast cancer in women globally. This subtype often has early and high recurrence rates, resulting in poor survival, partially due to lack of targeted therapies. To date, the detailed molecular mechanisms underlying TNBC progression are unclear. Given the crucial role of microRNAs (miRNAs) in cancer metastasis, we aimed to analyse the expression and function of a metastasis-associated miRNA named miR-211-5p in TNBC.Methods:MiRNA array analysis was performed to search for metastasis-associated miRNAs in TNBC. The miR-211-5p expression in tumour tissues, adjacent non-tumourous breast tissues of TNBC patients and cell lines were evaluated by real-time PCR. The protein expression levels were analysed by western blot, immunohistochemistry and in situ hybridisation. Luciferase reporter assays were employed to validate the target of miR-211-5p. The effect of miR-211-5p on TNBC progression was investigated in vitro and in vivo.Results:MiR-211-5p was significantly downregulated in TNBC, and its expression level was associated with overall survival in TNBC. The expression of miR-211-5p suppressed TNBC cell proliferation, invasion, migration and metastasis in vitro and in vivo. Furthermore, SETBP1 was identified as a target of miR-211-5p. Through gain-of-function and loss-of-function studies, SETBP1 was shown to significantly affect colony and cell number in vitro. Enforced expression of miR-211-5p inhibited the expression of SETBP1 significantly and the restoration of SETBP1 expression reversed the inhibitory effects of miR-211-5p on TNBC cell proliferation and metastasis.Conclusions:These findings collectively demonstrate a tumour suppressor role of miR-211-5p in TNBC progression by targeting SETBP1, suggesting that miR-211-5p could serve as a potential prognostic biomarker and therapeutic target for TNBC.

The role of BRCA1-IRIS in the development and progression of triple negative breast cancers in Egypt: possible link to disease early lesion

BackgroundBreast cancer is the most globally diagnosed female cancer, with the triple negative breast cancer (TNBC) being the most aggressive subtype of the disease. In this study we aimed at comparing the effect of BRCA1-IRIS overexpression on the clinico-pathological characteristics in breast cancer patients with TNBC or non-TNBC in the largest comprehensive cancer center in Egypt.MethodsTo reach this goal, we conducted an observational study at the National Cancer Institute (NCI), Cairo University (Cairo, Egypt). The data on all diagnosed breast cancer patients, between 2009 and 2012, were reviewed. BRCA1-IRIS expression measured using real time RT/PCR in these patients’ tumor samples was correlated to tumor characteristics, such as to clinico-pathological features, therapeutic responses, and survival outcomes.Results96 patients were enrolled and of these 45% were TNBC, and 55% were of other subtypes (hereafter, non-TNBC). All patients presented with invasive ductal carcinomas. No significant difference was observed for risk factors, such as age and menopausal status between the TNBC and the non-TNBC groups except after BRCA1-IRIS expression was factored in. The majority of the tumors in both groups were ≤5 cm at surgery (p = 0.013). However, in the TNBC group, ≤5 cm tumors were BRCA1-IRIS-overexpressing, whereas in the non-TNBC group they were BRCA1-IRIS-negative (p = 0.00007). Most of the TNBC patients diagnosed with grade 1 or 2 were BRCA1-IRIS-overexpressing, whereas non-TNBCs were IRIS-negative (p = 0.00035). No statistical significance was measured in patients diagnosed with grade 3 tumors. Statistically significant difference between TNBCs and non-TNBCs and tumor stage with regard to BRCA1-IRIS-overexpression was observed. Presence of axillary lymph node metastases was positively associated with BRCA1-IRIS overexpression in TNBC group, and with BRCA1-IRIS-negative status in the non-TNBC group (p = 0.00009). Relapse after chemotherapy (p < 0.00001), and local recurrence/distant metastasis after surgery (p = 0.0028) were more pronounced in TNBC patients with BRCA1-IRIS-overexpressing tumors compared to non-TNBC patients. Finally, decreased disease-free survival in TNBC/BRCA1-IRIS-overexpressing patients compared to TNBC/BRCA1-IRIS-negative patients, and decreased overall survival in TNBC as well as non-TNBC patients was driven by BRCA1-IRIS overexpression.ConclusionsTNBC/BRCA1-IRIS-overexpressing tumors are more aggressive than TNBC/BRCA1-IRIS-negative or non-TNBC/BRCA1-IRIS-overexpressing or both negative tumors. Further studies are warranted to define whether BRCA1-IRIS drives the early TNBC lesions growth and dissemination and whether it could be used as a diagnostic biomarker and/or therapeutic target for these lesions at an early stage setting.

Capecitabine in early breast cancer: A meta-analysis of randomised controlled trials

PurposeCapecitabine is an effective therapy for metastatic breast cancer. Its role in early breast cancer is uncertain due to conflicting data from randomised controlled trials (RCTs). MethodsPubMed and major conference proceedings were searched to identify RCTs comparing standard chemotherapy with or without capecitabine in the neoadjuvant or adjuvant setting. Hazard ratios (HRs) for disease-free survival (DFS) and overall survival (OS), as well as odds ratios (ORs) for toxicities were extracted or calculated and pooled in a meta-analysis. Subgroup analysis compared triple-negative breast cancer (TNBC) to non-TNBC and whether capecitabine was given in addition to or in place of standard chemotherapy. Meta-regression was used to explore the influence of TNBC on OS. ResultsEight studies comprising 9302 patients were included. In unselected patients, capecitabine did not influence DFS (hazard ratio [HR] 0.99, p = 0.93) or OS (HR 0.90, p = 0.36). There was a significant difference in DFS when capecitabine was given in addition to standard treatment compared with in place of standard treatment (HR 0.92 versus 1.62, interaction p = 0.002). Addition of capecitabine to standard chemotherapy was associated with significantly improved DFS in TNBC versus non-TNBC (HR 0.72 versus 1.01, interaction p = 0.02). Meta-regression showed that adding capecitabine to standard chemotherapy was associated with improved OS in studies with higher proportions of patients with TNBC (R = −0.967, p = 0.007). Capecitabine increased grade 3/4 diarrhoea (odds ratio [OR] 2.33, p < 0.001) and hand-foot syndrome (OR 8.08, p < 0.001), and resulted in more frequent treatment discontinuation (OR 3.80, p < 0.001). ConclusionAdding capecitabine to standard chemotherapy appears to improve DFS and OS in TNBC, but increases adverse events in keeping with its known toxicity profile.

Abstract P5-14-05: Capecitabine in early breast cancer: A meta-analysis of randomized controlled trials

Abstract Background Capecitabine is an effective therapy for metastatic breast cancer. Its role in early breast cancer is uncertain due to conflicting data from randomized controlled trials (RCTs). Methods PubMed and major conference proceedings were searched to identify RCTs comparing standard chemotherapy (defined as cyclophosphamide/methotrexate/5-fluorouracil, anthracycline-based regimens or anthracycline/taxane combinations) with or without capecitabine in the neo-adjuvant or adjuvant setting. Hazard ratios (HR) for disease-free (DFS) and overall survival (OS), as well as odds ratios (ORs) for safety and tolerability were extracted or calculated and pooled in a meta-analysis. Subgroup analysis compared triple negative breast cancer (TNBC) to non-TNBC and whether capecitabine was given in addition to or in place of standard chemotherapy. Meta-regression was used to explore the influence of TNBC on OS. Results Eight studies comprising 9302 patients were included. In unselected patients, capecitabine did not influence DFS (HR 0.99, p=0.93) or OS (HR 0.90, p=0.36). There was a significant difference in DFS when capecitabine was given in addition to, compared to in place of standard treatment (HR 0.92 vs. 1.62, interaction p=0.002). Addition of capecitabine to standard chemotherapy was associated with significantly improved DFS in TNBC vs non-TNBC (HR 0.72 vs. 1.01, interaction p=0.02). Meta-regression confirmed this association with OS (R=-0.967, p=0.007). Capecitabine increased Grade 3/4 diarrhea (OR 2.33, p&amp;lt;0.001) and hand foot syndrome (OR 8.08, p&amp;lt;0.001), and resulted in more frequent treatment discontinuation (OR 3.80, p&amp;lt;0.001). Conclusion Adding capecitabine to standard chemotherapy appears to improve DFS and OS in TNBC, but increases adverse events in keeping with its known toxicity profile. Consideration of this treatment is warranted, especially in high-risk patients. Citation Format: Natori A, Ethier J-L, Amir E, Cescon DW. Capecitabine in early breast cancer: A meta-analysis of randomized controlled trials [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-14-05.

An immune stratification reveals a subset of PD-1/LAG-3 double-positive triple-negative breast cancers.

BackgroundStromal tumor-infiltrating lymphocytes (TILs) are a robust prognostic factor in triple-negative breast cancer (TNBC). However, the clinical significance of TILs may be influenced by the complex landscape of the tumor immune microenvironment. In this study, we aimed to evaluate the composition and the functionality of lymphocytic infiltration and checkpoint receptors in TNBC.MethodsFormalin-fixed, paraffin-embedded tissues were retrospectively collected from a cohort of patients with early-stage TNBC treated with adjuvant anthracycline-based chemotherapy (n = 259). Results were validated in an independent cohort of patients with TNBC (n = 104). Stromal TILs were evaluated on hematoxylin-and-eosin-stained sections. The density of CD4+, CD8+, and FOXP3+ lymphocytes, and the expression of the immune checkpoints PD-1 and LAG-3, were assessed by immunohistochemical analysis.ResultsThe presence of elevated TILs positively correlated with the density of all T cell subtypes, especially cytotoxic CD8+ lymphocytes. We showed that increasing stromal TILs assessed as a continuous variable is an independent prognostic marker of prolonged relapse-free survival and overall survival in TNBC. Among immune subpopulations, CD8+ lymphocytes are the main effectors of anti-tumor immune responses. In two independent cohorts, we found that PD-1 and LAG-3 were concurrently expressed in approximately 15% of patients with TNBC. The expression of both checkpoint receptors positively correlated with the presence of TILs, but was not significantly associated with patient outcome.ConclusionsOverall, our data indicate that the evaluation of stromal TILs remains the most reliable immune prognostic marker in TNBC, and support the clinical evaluation of anti-PD-1/PD-L1 and anti-LAG-3 in a subset of patients with TNBC who have concurrent expression of both checkpoint receptors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0783-4) contains supplementary material, which is available to authorized users.

MiR-26a suppresses tumour proliferation and metastasis by targeting metadherin in triple negative breast cancer

It has been reported that miR-26a plays an important role in various cancers. In this study, we found that miR-26a was downregulated in triple-negative breast cancer (TNBC), and its expression levels were associated with lymph node metastasis and overall survival in TNBC. We also found that the ectopic expression of miR-26a inhibited TNBC cell proliferation and metastasis in vitro and in vivo by downregulating MTDH (a miR-26a' target gene) mRNA and protein and that the overexpression of MTDH could partially abrogate miR-26a-mediated suppression. Our data suggest that miR-26a functions as a tumour suppressor in TNBC development and serves as a prognostic marker for breast cancer.

Activated PI3K/AKT and MAPK pathways are potential good prognostic markers in node-positive, triple-negative breast cancer

Triple-negative breast cancer (TNBC) patients are a poor prognostic subgroup, and currently, there is no biomarker for targeted therapy. Tissue samples were obtained from 75 TNBC patients with lymph-node metastases who had received adjuvant chemotherapy. We examined 11 biomarkers, including PIK3CA and AKT1mutation, with regard to event-free survival (EFS) and overall survival (OS) of patients. In the tumor tissues, phospho-AKT (pAKT) expression was significantly related to HER4 expression. Expression of each of these biomarkers was significantly related to longer EFS (P = 0.024 and 0.03, respectively). pERK expression was also a good prognostic factor regarding EFS and OS in TNBC (P = 0.002 and 0.006, respectively). We also identified a correlation between epidermal growth factor receptor positivity and insulin-like growth factor receptor type 1 positivity (P = 0.001). pERK and T-stage (1-3 versus >3) were independent good prognostic factors by multivariate analysis. We determined that tumors expressing pAKT or pERK are a good prognostic subtype in node-positive TNBC. Different targeted therapies may be necessary for TNBC that involves activation of PI3K/AKT or MAPK pathways.

Triple-negative breast cancer: the impact of guideline-adherent adjuvant treatment on survival—a retrospective multi-centre cohort study

Triple-negative breast cancer (TNBC) (ER-/PGR-/erb-2-) constitutes an aggressive subtype in breast cancer because it is accompanied by a significant decrease in overall survival (OAS) and recurrence-free survival (RFS) compared with hormone receptor positive breast cancers. This retrospective cohort study investigates the following issues: (1) Is there an impact of guideline-adherent treatment on RFS and OAS in TNBC? (2) Which adjuvant treatment has the most important impact on RFS and OAS in TNBC? This German retrospective multi-centre cohort study included 3,658 patients with primary breast cancer recruited from 2000 to 2005. The definition of guideline adherence was based on the German national S3 guideline for diagnosis and treatment of breast cancer (2004). A total of 371 patients (10.1%) had TNBC. Compared with HR+/erb-2- breast cancer (P = 0.001; HR = 1.75; 95% CI: 1.27-2.40), the recurrence rate of TNBC was significantly higher (P < 0.001; HR = 2.86; 95% CI: 2.17-3.76). Furthermore, the 5-year RFS and OAS was significantly lower in TNBC (RFS: 74.8% [95% CI: 68.8-80.8%] vs. 86.5% [95% CI: 84.6-88.4%] [log-rank P = 0.0001]) (OAS: 75.8% [95% CI: 69.9-81.8%] vs. 86.0% [95% CI: 84.1-87.9%] [log-rank P = 0.0001]). The most important parameters predicting RFS and OAS in TNBC after receiving guideline-conform chemotherapy are guideline-adherent surgery, radiotherapy, nodal status and grading. Overall, 66.8% TNBC were found with one or more (18%) guideline violations, which subsequently impaired OAS and RFS. The most important impact on OAS and RFS in TNBC patients was because of guideline violations (GV) concerning adjuvant radiotherapy and GV concerning adjuvant chemotherapy. Patients with TNBC primarily have a worse prognosis in terms of RFS and OAS than patients of a primarily non-TNBC phenotype. There is a strong association between guideline-adherent adjuvant treatment and improved survival outcome in TNBC. The outcome significantly decreases with the number of guideline violations.

Triple-negative breast cancer: The effect of guideline-adherent adjuvant treatment on the cumulative survival—A retrospective multicenter cohort study of 3,658 patients.

1063 Background: Triple negative breast cancer (TNBC) constitutes an aggressive subtype in breast cancer accompanied with a significant decrease in overall survival (OAS) and disease free survival (RFS). This retrospective cohort study investigates the following queries: (1) Is there an impact of guideline adherent treatment on RFS and OAS in TNBC? (2) Which adjuvant treatment has the most important impact on RFS and OAS in TNBC? Methods: This German multi-center [16 participating hospitals all are certified as breast centers] retrospective cohort study included 3658 patients from 2000 until 2005. The definition of guideline adherence was based on the German national S3 guideline (2004). Results: 371(10.1%) were TNBC [median age(years): 60(range 28-97)]. 13.8% premenopausal/ 9.3% postmenopausal of the patients were TNBC. 90.3% of TNBC-patients were intermediate-/high-risk (Nottingham-prognostic index) and 76.5% were GIII. Compared to HR-pos./HER2-neg.-BC as reference, RFS of TNBC was significantly worse (HR=2.86; 95%CI: 2.17-3.76; p<0.001). Furthermore 5 years RFS (OAS) is significantly lower in TNBC vs. non-TNBC [RFS: 74,8% (95%CI:68.8%-80.8%) vs. 86.5%(95%CI:84.6%-88,4%); logrank p<0.001)] (OAS:75.8%(95%CI:69.9%-81.8%) vs. 86.0%(95%CI:84.1%-87.9%); logrank p<0.001)]. The most important parameters predicting RFS or OAS in TNBC are nodal status, grading, guideline adherent surgery, radiotherapy and chemotherapy. Overall 66.9% TNBC had one or more guideline violations, which subsequently impaired RFS and OAS (Ranking of guideline violations with respect to RFS: Radiotherapy (HR=2.92;95%CI(2.24-3.81); p<0.001), chemotherapy(HR=2.16;95%CI(1.70-2.74); p<0.001), initial surgical intervention(HR=2.03;95%CI(1.36-3.04); p=0.001) and lymph node dissection(HR=1.54;95%CI(1.05-2.25); p=0.027). Conclusions: Patients with TNBC have primarily a worse prognosis in terms of RFS and OAS than patients with primarily non-TNBC phenotype. There is a strong association between guideline adherence and RFS/OAS of patients with TNBC. The outcome decreases significantly with the number of guideline violations.

Response to Paclitaxel in Node-positive Triple Negative Breast Cancer

Purpose: Triple negative breast cancer (TNBC) has had poor prognosis compared with the luminal subtype. And there has been no benefit from doxorubicin. However, the addition of paclitaxel is known to improve both disease-free survival (DFS) and overall survival (OS). The aim of our study was to assess the effect of the addition of paclitaxel after adjuvant chemotherapy with doxorubicin plus cyclophosphamide in TNBC. Methods: We randomly selected 87 women from 104 women with TNBC who had been randomly assigned to receive doxorubicin (60 ㎎ per square meter of body-surface area) plus cyclophosphamide (600 ㎎ per square meter) for four cycles, followed by four cycles of paclitaxel (175 ㎎ per square meter) or two more cycles of doxorubicin plus cyclophosphamide. Due to predictions of clinical outcomes in women who receive adjuvant paclitaxel based chemotherapy, immunohistochemical analyses of these tissue specimens for CK5/6 were used. Results: Among patients with TNBC, 24 patients (27.6%) were classified as CK5/6-positive triple negative type. Twelve patients were classified as paclitaxel chemotherapy group and 75 patients were classified as no paclitaxel group. No interaction was observed between DFS or OS and paclitaxel regimens. CK5/6 was, however, not associated with a significant benefit from paclitaxel in our study. Conclusion: In our study, the addition of paclitaxel after adjuvant treatment with doxorubicin (＜60 ㎎ per square meter) is not associated with DFS or OS in TNBC.