Subject(s)
Antibodies, Monoclonal , CD4-Positive T-Lymphocytes , Triple Negative Breast Neoplasms , Humans , Female , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/pharmacology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Agents, Immunological/pharmacology , Middle Aged , Intraepithelial Lymphocytes/drug effects , Intraepithelial Lymphocytes/immunology , Intraepithelial Lymphocytes/metabolismABSTRACT
PURPOSE: The GeparX study investigated whether denosumab as add-on treatment to nab-paclitaxel-based neoadjuvant chemotherapy (NACT) with two different schedules (125 mg/m² weekly vs. day 1, 8 every 22 days) may increase pathologic complete response (pCR) rate. The addition of denosumab to NACT did not improve pCR rates as recently published. In this study, we investigated whether receptor activator of nuclear factor-kappa B (RANK) expression, as part of the denosumab target pathway: (i) may retrospectively identify a subgroup of patients with additional clinical benefit of denosumab or (ii) may predict response to nab-paclitaxel NACT. EXPERIMENTAL DESIGN: RANK protein was IHC-stained on pre-therapeutic core biopsies from patients of the GeparX study (n = 667) with the antibody RANK/Envision System HRP (DAB) and was analyzed for the percentage of membranous RANK tumor cell staining (>5% RANKhigh vs. ≤5% RANKlow). RESULTS: We could not identify any patient subgroup with differential response under denosumab add-on treatment in patients with RANKhigh expression [139/667, 20.8%; OR, 0.86; 95% confidence interval (CI), 0.44-1.68; P = 0.667] or RANKlow expression (528/667 (79.2%) OR, 1.10; 95% CI, 0.78-1.56; P = 0.589; Pinteraction = 0.528). However, the pCR rate was higher in the RANKhigh subgroup compared with RANKlow (50% vs. 39%; OR, 1.52; 95% CI, 1.04-2.21; P = 0.037). RANK expression constituted an independent predictor of response to NACT frequently in patients with luminal-like subtype (HR+/HER2-; OR, 2.98; 95% CI, 1.30-6.79; P = 0.010). No predictive value of RANK expression among the different nab-paclitaxel regimens was observed. CONCLUSION: We report RANK expression to be an independent predictive biomarker for response to NACT in patients with luminal-like breast cancer.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Receptor Activator of Nuclear Factor-kappa B/genetics , Neoadjuvant Therapy , Retrospective Studies , Denosumab/therapeutic use , Receptor, ErbB-2/metabolism , Paclitaxel , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Treatment OutcomeABSTRACT
This retrospective pooled analysis aims to identify factors predicting relapse despite a pathologic complete response (pCR) in patients with breast cancer (BC). 2066 patients with a pCR from five neoadjuvant GBG/AGO-B trials fulfill the inclusion criteria of this analysis. Primary endpoint is disease-free survival (DFS); secondary endpoints is distant DFS (DDFS) and overall survival (OS). After a median follow-up of 57.6 months, DFS is significantly worse for patients with positive lymph nodes (cN+ vs cN0 hazard ratio [HR] 1.94, 95%CI 1.48-2.54; p < 0.001). In patients with triple-negative tumors, lobular histology (lobular vs other HR 3.55, 95%CI 1.53-8.23; p = 0.003), and clinical nodal involvement (cN+ vs cN0 HR 2.45, 95%CI 1.59-3.79; p < 0.001) predict a higher risk of DFS events. Patients with HER2-positive cT3/4 tumors have a significantly higher risk of relapse (cT3/4 vs cT1 HR 2.07, 95%CI 1.06-4.03; p = 0.033). Initial tumor load and histological type predict relapse in patients with a pCR.
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Introduction: The aim of the present study was to analyze the performance of Oncotype DX® multigene assay (ODX®) in patients with 0-3 lymph nodes in a high-volume community hospital. Methods: Patients with non-metastatic HR*/HER2- EBC and 0-3 positive lymph nodes, who underwent primary surgery at the Red Cross Hospital Munich, Germany and consecutively had ODX® testing were included in this retrospective study. The distribution of clinicopathologic characteristics, recurrence score (RS) risk, and use of systemic therapy were compared among patients without positive lymph nodes (N0) and patients with micrometastases or 1 to 3 positive lymph nodes (N1). Disease-free survival (DFS) and overall survival (OS) were estimated. Results: From 2012 to 2017 ODX® was consecutively performed in 575 (16.4%) of 3,492 women with HR*/HER- EBC, of which 553 were eligible for this analysis (N0: 60.8%; N1: 39.2%). Among the patients included, 441 (79.7%) had an RS of 0 to 25 and 112 (20.3%) had an RS of 26 or higher. In patients with RS 0 to 25 the rate of chemotherapy use was low, independent from nodal status (N0: 17.1% and N1: 19.1%) and 5-year DFS was 90.5% and 91.7% for N0 and N1 patients, respectively. There was no significant difference in DFS (90.5% vs. 93.3%; p = 0.101) or OS (97.2% vs. 96.0%; p = 0.737) for patients with an RS of 0 to 25 when treated with chemo-endocrine therapy or endocrine therapy alone, independent from nodal status. Conclusions: The results of the study confirm the observations from randomized studies on the use of the ODX® in a real-world population in terms of risk distribution and patient outcome. Adjuvant chemotherapy could be safely omitted in patients with HR*/HER2- breast cancer with 0-3 positive lymph nodes and RS <25.
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Introduction: In a prospective non-interventional study involving 2,173 patients, we showed that use of the oral fixed combination of netupitant 300 mg and palonosetron 0.5 mg (NEPA) for prevention of chemotherapy (Ctx)-induced nausea and vomiting has beneficial effects on the quality of life (QoL) of patients with various types of cancers receiving highly or moderately emetogenic Ctx. Here, we report on the effects on QoL, effectiveness, and tolerability of NEPA in patients with breast cancer exposed to anthracycline-cyclophosphamide (AC)-based Ctx. Methods: This is a post hoc subanalysis of a prospective non-interventional study in 1,197 patients with breast cancer receiving up to 3 cycles of doxorubicin or epirubicin plus cyclophosphamide and NEPA. NEPA administration was per the summary of product characteristics. Results: In cycle 1 of Ctx, a large proportion of patients (84%) reported "no impact on daily life" (NIDL) due to vomiting; 53% of patients reported NIDL due to nausea. The complete response rate was 86/88/81% in the acute/delayed/overall phase in cycle 1, and NEPA was well tolerated throughout the study. Conclusion: The real-world beneficial effects of NEPA prophylaxis on QoL were confirmed for patients with breast cancer receiving AC. NEPA was effective with a good safety profile in this patient population in clinical practice.
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Importance: Adjuvant denosumab might improve disease-free survival in hormone receptor (HR)-positive primary breast cancer (BC). The optimal neoadjuvant nab-paclitaxel schedule in terms of efficacy and safety is unclear. Objective: To determine whether adding denosumab to anthracycline/taxane-containing neoadjuvant chemotherapy (NACT) increases the pathological complete response (pCR) rate and which nab-paclitaxel schedule is more effective in the NACT setting. Design, Setting, and Participants: The GeparX was a multicenter, prospective, open-label, phase 2b, 2 × 2 randomized clinical trial conducted by GBG and AGO-B at 38 German sites between February 2017 and March 2019. The analysis data set was locked September 4, 2020; analysis was completed November 13, 2020. Patients had unilateral or bilateral primary BC, stage cT2-cT4a-d or cT1c, with either clinically node-positive or pathologically node-positive or HR-negative disease, or Ki-67 proliferation index greater than 20%, or ERBB2 (formerly HER2)-positive BC. Interventions: Patients were randomized to receive or not receive denosumab, 120 mg subcutaneously every 4 weeks for 6 cycles, and either nab-paclitaxel, 125 mg/m2 weekly for 12 weeks or days 1 and 8 every 3 weeks for 4 cycles (8 doses), followed by 4 cycles of epirubicin/cyclophosphamide, 90/600 mg/m2 (every 2 weeks or every 3 weeks). Carboplatin was given in triple-negative BC (TNBC), and trastuzumab biosimilar ABP980 plus pertuzumab was given in ERBB2-positive BC (ERBB2-positive substudy). Main Outcomes and Measures: The primary outcome was pCR rates between arms for each randomization. Results: A total of 780 female (n = 779) and male (n = 1) patients (median [range] age, 49.0 [22-80] years) were randomized to the 4 treatment groups. The pCR (ypT0 ypN0) rate was 41.0% (90% CI, 37%-45%) with denosumab vs 42.8% (90% CI, 39%-47%) (P = .58) without denosumab, irrespective of BC subtype. Nab-paclitaxel weekly resulted in a significantly (significance level of α = .10) higher pCR rate of 44.9% (90% CI, 41%-49%) vs 39.0% (90% CI, 35%-43%) (P = .06) with nab-paclitaxel days 1 and 8 every 3 weeks. The pCR rates for nab-paclitaxel schedules in subgroups were only significantly different for TNBC (60.4% vs 50.0%; P = .06). Grade 3 to 4 toxic effects did not differ with or without denosumab. Nonhematologic toxic effects of grade 3 to 4 were higher with nab-paclitaxel weekly (33.7% vs 24.1%; P = .004). Conclusions and Relevance: In this randomized clinical trial, denosumab added to anthracycline/taxane-based NACT did not improve pCR rates. Nab-paclitaxel at a dosage of 125 mg/m2 weekly significantly increased the pCR rate compared with the days 1 and 8, every-3-weeks schedule overall and in TNBC, but generated higher toxicity. Trial Registration: ClinicalTrials.gov Identifier: NCT02682693.
Subject(s)
Breast Neoplasms , Triple Negative Breast Neoplasms , Adult , Aged , Aged, 80 and over , Albumins , Anthracyclines , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/pathology , Denosumab/adverse effects , Female , Humans , Male , Middle Aged , Neoadjuvant Therapy/methods , Paclitaxel , Prospective Studies , Receptor, ErbB-2/analysis , Treatment Outcome , Triple Negative Breast Neoplasms/drug therapy , Young AdultABSTRACT
BACKGROUND: The conversion of initially histologically confirmed axillary lymph node-positive (pN+) to ypN0 after neoadjuvant systemic treatment (NAST) is an important prognostic factor in breast cancer (BC) patients and may influence surgical de-escalation strategies. We aimed to determine pCR rates in lymph nodes (pCR-LN), the breast (pCR-B), and both (tpCR) in women who present with pN+ BC, to assess predictors for response and the impact of pCR-LN, pCR-B, and tpCR on invasive disease-free survival (iDFS). METHODS: Retrospective, exploratory analysis of 242 patients with pN+ at diagnosis from the multicentric, randomized GeparOcto trial. RESULTS: Of 242 patients with initially pN+ disease, 134 (55.4%) had a pCR-LN, and 109 (45.0%) a pCR-B. Of the 109 pCR-B patients, 9 (8.3%) patients had involved LN, and 100 (41.3%) patients had tpCR. Those with involved LN still had a bad prognosis. As expected, pCR-B and intrinsic subtypes (TNBC and HER2+) were identified as independent predictors of pCR-LN. pCR-LN (ypN0; hazard ratio 0.42; 95%, CI 0.23-0.75; p = 0.0028 for iDFS) was the strongest independent prognostic factor. CONCLUSIONS: In initially pN+ patients undergoing NAST, the conversion to ypN0 is of high prognostic value. Surgical axillary staging after NAST is still essential in these patients to offer tailored treatment.
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BACKGROUND: GeparOcto demonstrated that pathological complete response (pCR) of intense dose-dense epirubicin, paclitaxel and cyclophosphamide (iddEPC) was comparable to weekly paclitaxel/non-pegylated liposomal doxorubicin (plus carboplatin (PM(Cb) in triple-negative breast cancer [TNBC]) in high-risk early breast cancer (BC). Here, we report time-to-event secondary end-points. PATIENTS AND METHODS: Patients were randomised to receive 18 weeks of E (150 mg/m2) followed by P (225 mg/m2) followed by C (2000 mg/m2), each q2w or weekly P (80 mg/m2) plus M (20 mg/m2) plus, in TNBC, Cb (AUC 1.5). Patients with human epidermal growth factor receptor 2-positive (HER2+)BC received trastuzumab (6[loading dose 8]mg/kg q3w) and pertuzumab (420[840]mg q3w) with P and C cycles. RESULTS: 945 patients started treatment (iddEPC n = 470; PM(Cb) n = 475). After a median follow-up of 47.0 (range 1.6-61.5) months, 162 (75 in iddEPC; 87 in PM(Cb)) invasive disease-free survival (iDFS) events and 79 (41 in iddEPC; 38 in PM(Cb)) deaths were reported. No significant difference was observed in 4-year iDFS (81.9% iddEPC versus 79.7% PM(Cb), HR = 1.16 [95%CI 0.85-1.59], log-rank p = 0.334) or 4-year overall survival (OS) (90.3% iddEPC versus 90.6% PM(Cb), HR = 0.90 [95%CI 0.58-1.40], log-rank p = 0.637) overall and in HER2+ and TNBC subgroups. HR+/HER2- BC patients, however, had significantly better 4-year iDFS (77.9% iddEPC versus 62.5% PM, HR = 2.11 [95%CI 1.08-4.10], log-rank p = 0.025) and 4-year OS with iddEPC (94.7% iddEPC versus 80.1% PM, HR = 3.26 [95%CI 1.06-10.00], log-rank p = 0.029). CONCLUSION: While there was no difference in survival for the entire cohort, the HR+/HER2-subgroup significantly benefits from iddEPC. This supports the concept of an additional effect of NACT beyond pCR in patients with HR+/HER2- BC. CLINICALTRIALS. GOV IDENTIFIER: NCT02125344.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclophosphamide/therapeutic use , Doxorubicin/analogs & derivatives , Epirubicin/therapeutic use , Paclitaxel/therapeutic use , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/mortality , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cyclophosphamide/pharmacology , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Epirubicin/pharmacology , Female , Humans , Paclitaxel/pharmacology , Polyethylene Glycols/pharmacology , Polyethylene Glycols/therapeutic use , Risk Factors , Survival AnalysisABSTRACT
BACKGROUND: The development of anti-HER2 antibody-drug conjugates opens new therapeutic options for patients with breast cancer, including patients with low expression of HER2. To characterise this new breast cancer subtype, we have compared the clinical and molecular characteristics of HER2-low-positive and HER2-zero breast cancer, including response to neoadjuvant chemotherapy and prognosis. METHODS: In this pooled analysis of individual patient data, we evaluated a cohort of 2310 patients with HER2-non-amplified primary breast cancer that were treated with neoadjuvant combination chemotherapy in four prospective neoadjuvant clinical trials (GeparSepto, NCT01583426; GeparOcto, NCT02125344; GeparX, NCT02682693; Gain-2 neoadjuvant, NCT01690702) between July 30, 2012, and March 20, 2019. Central HER2 testing was done prospectively before random assignment of participants in all trials. HER2-low-positive status was defined as immunohistochemistry (IHC) 1+ or IHC2+/in-situ hybridisation negative and HER2-zero was defined as IHC0, based on the American Society of Clinical Oncology/College of American Pathologists guidelines. Disease-free survival and overall survival data were available for 1694 patients (from all trials except GeparX) with a median follow-up of 46·6 months (IQR 35·0-52·3). Bivariable and multivariable logistic regression models and Cox-proportional hazards models were performed based on a predefined statistical analysis plan for analysis of the endpoints pathological complete response, disease-free survival, and overall survival. FINDINGS: A total of 1098 (47·5%) of 2310 tumours were HER2-low-positive and 1212 (52·5%) were HER2-zero. 703 (64·0%) of 1098 patients with HER2-low-positive tumours were hormone receptor positive, compared with 445 (36·7%) of 1212 patients with HER2-zero tumours (p<0.0001). HER2-low-positive tumours had a significantly lower pathological complete response rate than HER2-zero tumours (321 [29·2%] of 1098 vs 473 [39·0%] of 1212, p=0·0002). Pathological complete response was also significantly lower in HER2-low-positive tumours versus HER2-zero tumours in the hormone receptor-positive subgroup (123 [17·5%] of 703 vs 105 [23·6%] of 445, p=0·024), but not in the hormone receptor-negative subgroup (198 [50·1%] of 395 vs 368 [48·0%] of 767, p=0·21). Patients with HER2-low-positive tumours had significantly longer survival than did patients with HER2-zero tumours (3-year disease-free survival: 83·4% [95% CI 80·5-85·9] vs 76·1% [72·9-79·0]; stratified log-rank test p=0·0084; 3-year overall survival: 91·6% [84·9-93·4] vs 85·8% [83·0-88·1]; stratified log-rank test p=0·0016). Survival differences were also seen in patients with hormone receptor-negative tumours (3-year disease-free survival: 84·5% [95% CI 79·5-88·3] vs 74·4% [70·2-78.0]; stratified log-rank test p=0·0076; 3-year overall survival: 90·2% [86·0-93·2] vs 84·3% [80·7-87·3], stratified log-rank test p=0·016), but not in patients with hormone receptor-positive tumours (3-year disease-free survival 82·8% [79·1-85·9] vs 79·3% [73·9-83·7]; stratified log-rank test p=0·39; 3-year overall survival 92·3% [89·6-94·4] vs 88·4% [83·8-91·8]; stratified log-rank test p=0·13). INTERPRETATION: Our results show that HER2-low-positive tumours can be identified as new subgroup of breast cancer by standardised IHC, distinct from HER2-zero tumours. HER2-low-positive tumours have a specific biology and show differences in response to therapy and prognosis, which is particularly relevant in therapy-resistant, hormone receptor-negative tumours. Our results provide a basis for a better understanding of the biology of breast cancer subtypes and the refinement of future diagnostic and therapeutic strategies. FUNDING: German Cancer Aid (Deutsche Krebshilfe).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Receptor, ErbB-2/genetics , Adult , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Chemotherapy, Adjuvant/methods , Female , Humans , Middle Aged , Neoadjuvant Therapy/methods , Treatment OutcomeABSTRACT
BACKGROUND: Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) is associated with superior survival. This association is strongest in triple-negative breast cancer (TNBC). The CPS + EG system, based on pre-treatment clinical (CS) and post-treatment pathological stage (PS), oestrogen-receptor status (E) and grade (G), leads to a refined estimate of prognosis after NACT in all-comers and hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Here, we investigate if CPS + EG scoring provides a superior estimate of prognosis in TNBC to select patients for postneoadjuvant therapy. METHODS: We calculated the CPS + EG score for 1795 patients with TNBC from 8 prospective German trials. Five-year disease-free survival (DFS) and overall survival estimates were calculated using the Kaplan-Meier method. RESULTS: In TNBC, patients with pCR (ypT0/is ypN0, n = 822, 45.8%) had a 5-year DFS of 86%, whereas patients with residual American Joint Committee on Cancer stage I disease (n = 383; 21.3%) had a 5-year DFS of 77.5%.CPS + EG led to superior prognostic information compared with that provided by the clinical stage, but it was inferior to the prognostic information provided by the pathological stage (c-index statistics, p < 0.001). CPS + EG did not discriminate prognosis within the two best prognostic groups (score 1 and 2; n = 362; 37.2%). In contrast, pCR status added prognostic information beyond CPS + EG. Patients with a CPS + EG score of 3 had a 5-year DFS rate of 64% overall, but those with pCR had a 5-year DFS rate of 84%, and those without pCR had a 5-year DFS rate of only 49.7%. CONCLUSIONS: In TNBC, CPS + EG scoring provided inferior prognostic information compared with the pathological stage and was unable to identify patients without pCR and with a sufficiently good prognosis, who could avoid postneoadjuvant therapy. pCR remains the strongest and most clinically useful prognostic factor after NACT. Other biologic factors beyond pCR are needed in TNBC.
Subject(s)
Neoadjuvant Therapy/methods , Triple Negative Breast Neoplasms/drug therapy , Adult , Aged , Female , Humans , Middle Aged , Neoplasm Staging , Prognosis , Triple Negative Breast Neoplasms/pathology , Young AdultABSTRACT
AIM: To evaluate HER2-negative breast cancer (BC) with a low hormone receptor (HR) expression, with regard to pathological complete response (pCR) and survival, in comparison to triple-negative BC (TNBC) and strong HR-positive BC. METHODS: We compared negative [oestrogen (ER) and progesterone receptor (PR) <1%], low-positive (ER and/or PR 1-9%) and strong-positive (ER or PR 10-100%) HR-expression in neoadjuvant clinical trial cohorts (n = 2765) of BC patients. End-points were disease-free survival (DFS), distant-disease free survival (DDFS) and overall survival (OS). We performed RNA sequencing on available tumour tissue samples from patients with low-HR expression (n = 38). RESULTS: Ninety-four (3.4%) patients had low HR-positive tumours, 1769 (64.0%) had strong HR-positive tumours, and 902 (32.6%) had TNBC. There were no significant differences in pCR rates between women with low HR-positive tumours (27.7%) and women with TNBC (35.5%). DFS and DDFS were also not different [for DFS, hazard ratio 1.26, 95%-CI (confidence interval) : 0.87-1.83, log-rank test p = 0.951; for DDFS, hazard ratio 1.17, 95%-CI: 0.78-1.76, log-rank test p = 0.774]. Patients with strong HR-positive tumours had a significantly lower pCR rate (pCR 9.4%; odds ratio 0.38, 95%-CI: 0.23-0.63), but better DFS (hazard ratio 0.48, 95%-CI: 0.33-0.70) and DDFS (hazard ratio 0.49, 95%-CI: 0.33-0.74) than patients with low HR-positive tumours. Molecular subtyping (RNA sequencing) of low HR-positive tumours classified these predominantly into a basal subtype (86.8%). CONCLUSION: Low HR-positive, HER2-negative tumours have a similar clinical behaviour to TNBC showing high pCR rates and poor survival and also a basal-like gene expression signature. Patients with low HR-positive tumours should be regarded as candidates for therapy strategies targeting TNBC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Chemotherapy, Adjuvant/mortality , Neoadjuvant Therapy/mortality , Triple Negative Breast Neoplasms/mortality , Adult , Aged , Female , Follow-Up Studies , Gene Expression Profiling , Humans , Middle Aged , Prognosis , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Remission Induction , Survival Rate , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathologyABSTRACT
PURPOSE: We evaluated mRNA signatures to predict response to neoadjuvant PD-L1 inhibition in combination with chemotherapy in early triple-negative breast cancer. EXPERIMENTAL DESIGN: Targeted mRNA sequencing of 2,559 transcripts was performed in formalin-fixed, paraffin-embedded samples from 162 patients of the GeparNuevo trial. We focused on validation of four predefined gene signatures and differential gene expression analyses for new predictive markers. RESULTS: Two signatures [GeparSixto signature (G6-Sig) and IFN signature (IFN-Sig)] were predictive for treatment response in a multivariate model including treatment arm [G6-Sig: OR, 1.558; 95% confidence interval (CI), 1.130-2.182; P = 0.008 and IFN-Sig: OR, 1.695; 95% CI, 1.234-2.376; P = 0.002), while the CYT metric predicted pathologic complete response (pCR) in the durvalumab arm, and the proliferation-associated gene signature in the placebo arm. Expression of PD-L1 mRNA was associated with better response in both arms, indicating that increased levels of PD-L1 are a general predictor of neoadjuvant therapy response. In an exploratory analysis, we identified seven genes that were higher expressed in responders in the durvalumab arm, but not the placebo arm: HLA-A, HLA-B, TAP1, GBP1, CXCL10, STAT1, and CD38. These genes were associated with cellular antigen processing and presentation and IFN signaling. CONCLUSIONS: Immune-associated signatures are associated with pCR after chemotherapy, but might be of limited use for the prediction of response to additional immune checkpoint blockade. Gene expressions related to antigen presentation and IFN signaling might be interesting candidates for further evaluation.
Subject(s)
Biomarkers, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Immune Checkpoint Inhibitors/pharmacology , Immunity/genetics , Triple Negative Breast Neoplasms/etiology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Clinical Trials, Phase II as Topic , Computational Biology/methods , Disease Management , Disease Susceptibility , Female , Gene Expression Profiling , Humans , Immune Checkpoint Inhibitors/administration & dosage , Middle Aged , Multicenter Studies as Topic , Neoadjuvant Therapy , Neoplasm Staging , Randomized Controlled Trials as Topic , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathologyABSTRACT
BACKGROUND: BRCA1 and BRCA2 play a central role in DNA repair. Therefore, patients harbouring germline (g) BRCA1/2 mutations (m) treated with chemotherapy might be at higher risk of haematological toxicities. METHODS: Patients from German Breast Group (GBG) and Arbeitsgemeinschaft Gynäkologische Onkologie-breast group studies with early triple-negative breast cancer (TNBC) and known gBRCA1/2m status treated with anthracycline-taxane-based neoadjuvant chemotherapy were analysed. Primary objective was the rate of neutropenia grade (G)III-IV in cycle 1 (C1). Secondary objectives included effects on overall and other haematological toxicities GIII-IV in C1, cumulative haematological toxicity across all cycles, relative total dose intensity, and granulocyte-colony stimulating factor prophylaxis. Haematological toxicities under taxanes, carboplatin, and cyclophosphamide were explored. RESULTS: Two hundred nine of 1171 (17.8%) evaluated patients had gBRCA1/2m. In C1, 37.4% gBRCA1/2m versus 35.7% wild-type patients had neutropenia GIII-IV (P = 0.683). For C1, gBRCA1/2m predicted neither for neutropenia GIII-IV (odds ratio [OR]: 1.26, 95% confidence intervals [CI]: 0.87-1.82, P = 0.226) nor for other haematological toxicities GIII-IV (OR: 0.91, 95% CI: 0.64-1.31, P = 0.625) in multivariable regression models. Analyses of cumulative toxicities across all cycles yielded similar results except thrombocytopaenia GIII-IV, which was increased in gBRCA1m patients. In patients treated with taxanes, the rate of haematological toxicities GIII-IV was higher in gBRCA1/2m compared with wild-type (59.5% versus 43.1%; p < 0.001). No difference was seen under cyclophosphamide or platinum-containing chemotherapies. CONCLUSIONS: gBRCA1/2m was not associated with higher risk of overall severe haematological toxicities in the first cycle or cumulatively across all cycles under standard chemotherapy for TNBC. Under taxane, patients with gBRCA1/2m might have a higher risk of haematological toxicities GIII-IV, requiring further research.
Subject(s)
Anthracyclines/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Germ-Line Mutation , Hematologic Diseases/chemically induced , Neoadjuvant Therapy/adverse effects , Taxoids/adverse effects , Triple Negative Breast Neoplasms/drug therapy , Adult , Carboplatin/adverse effects , Chemotherapy, Adjuvant/adverse effects , Chemotherapy-Induced Febrile Neutropenia/etiology , Cyclophosphamide/adverse effects , Female , Germany , Hematologic Diseases/diagnosis , Humans , Middle Aged , Randomized Controlled Trials as Topic , Risk Assessment , Risk Factors , Thrombocytopenia/chemically induced , Treatment Outcome , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathologyABSTRACT
BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer (BC). Due to the absence of targets such as HER2 or hormone receptors, early TNBC is treated with surgery and chemotherapy. Since TNBC is also considered the most immunogenic type of BC with tumor infiltrating lymphocytes that are predictive for chemotherapy response and prognostic for patients' survival, many different immunotherapeutic strategies are currently explored in clinical trials for the treatment of this disease. In order to efficiently combine chemotherapy with immunotherapy, it is important to evaluate the effect of chemotherapy on immune cells in vivo. METHODS: Peripheral blood was taken from 56 patients with TNBC undergoing neoadjuvant chemotherapy with nanoparticle albumin-bound paclitaxel (Nab-Pac) followed by epirubicin and cyclophosphamide (EC) at three different time points. Multicolor flow cytometry was used to characterize the immune cell composition and functional properties along neoadjuvant chemotherapy. RESULTS: Whereas the first phase of the neoadjuvant chemotherapy did not significantly alter the patients' immune cell composition, after the second phase of chemotherapeutic administration most B cells (>90%) were lost and the frequency of natural killer (NK) cells and CD4+ T lymphocytes decreased approximately to 50%. In contrast, the frequency of CD8+ T cells were less affected. CONCLUSIONS: Despite late consequences of Nab-Pac cannot be ruled out, these data suggest that different chemotherapeutics might have distinct effects on the immune cell repertoire and that different immune cell populations exhibit a specific susceptibility to these chemotherapies with B and NK cells being more affected than T cells. This might also have an impact on the combination of chemotherapies with immunotherapies. TRIAL REGISTRATION NUMBER: NCT02685059.
Subject(s)
Neoadjuvant Therapy/methods , Triple Negative Breast Neoplasms/drug therapy , Adult , Aged , Female , Humans , Middle AgedABSTRACT
AIM: This pooled analysis aimed to evaluate locoregional recurrence (LRR) rates of breast cancer (BC) after neoadjuvant chemotherapy (NACT) and to identify independent LRR predictors. METHODS: 10,075 women with primary BC from nine neoadjuvant trials were included. The primary outcome was the cumulative incidence rate of LRR as the first event after NACT. Distant recurrence, secondary malignancy or death were defined as competing events. For identifying LRR predictors, surgery type, pathological complete response (pCR), BC subtypes and other potential risk factors were evaluated. RESULTS: Median followup was 67 months (range 0-215), overall LRR rate was 9.5%, 4.1% in pCR versus 9.5% in non-pCR patients. Younger age, clinically positive lymph nodes, G3 tumours, non-pCR and TNBC but not surgery type were independent LRR predictors in multivariate analysis. Among BC subtypes, 5-year cumulative LRR rates were associated with higher risk in non-pCR versus pCR patients, which was significant for HR+/HER2- (5.9% vs 3.9%; HR = 2.32 [95%CI 1.22-4.43]; p = 0.011); HR-/HER2+ (14.8% vs 3.1%; HR = 4.26 [94%CI 2.35-7.71]; p < 0.001) and TNBC (18.5% vs 4.2%; HR = 4.10 [95%CI 2.88-5.82]; p < 0.001) but not for HR+/HER2+ (8.1% vs 4.8%; HR = 1.56 [95%CI 0.85-2.85]; p = 0.150). Within non-pCR subgroup, LRR risk was higher for HR-/HER2+ and TNBC vs HR+/HER2- (HR = 2.05 [95%CI 1.54-2.73]; p < 0.001 and HR = 2.77 [95%CI 2.27-3.39]; p < 0.001, respectively). CONCLUSIONS: This pooled analysis demonstrated that young age, node-positive and G3 tumours, as well as TNBC, and non-pCR significantly increased the risk of LRR after NACT. Hence, there is a clear need to investigate better multimodality therapies in the post-neoadjuvant setting for high-risk patients.
Subject(s)
Neoadjuvant Therapy/methods , Adult , Aged , Aged, 80 and over , Clinical Trials as Topic , Female , Humans , Middle Aged , Neoplasm Recurrence, Local , Prospective Studies , Risk Factors , Young AdultABSTRACT
Importance: The GeparOcto randomized clinical trial compared the efficacy of 2 neoadjuvant breast cancer (BC) treatment regimens: sequential intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) vs weekly paclitaxel and nonpegylated liposomal doxorubicin (PM) in patients with different biological BC subtypes. Patients with triple-negative BC (TNBC) randomized to the PM arm received additional carboplatin (PMCb). Overall, no difference in pathologic complete response (pCR) rates was observed between study arms. It remained elusive whether the germline variant status of BRCA1/2 and further BC predisposition genes are associated with treatment outcome. Objective: To determine treatment outcome for BC according to germline variant status. Design, Setting, and Participants: This retrospective biomarker study is a secondary analysis of the GeparOcto multicenter prospective randomized clinical trial conducted between December 2014 and June 2016. Genetic analyses assessing for variants in BRCA1/2 and 16 other BC predisposition genes in 914 of 945 women were performed at the Center for Familial Breast and Ovarian Cancer, Cologne, Germany, from August 2017 through December 2018. Main Outcomes and Measures: Proportion of patients who achieved pCR (ypT0/is ypN0 definition) after neoadjuvant treatment according to germline variant status. Results: In the study sample of 914 women with different BC subtypes with a mean (range) age at BC diagnosis of 48 (21-76) years, overall higher pCR rates were observed in patients with BRCA1/2 variants than in patients without (60.4% vs 46.7%; odds ratio [OR], 1.74; 95% CI, 1.13-2.68; P = .01); variants in non-BRCA1/2 BC predisposition genes were not associated with therapy response. Patients with TNBC with BRCA1/2 variants achieved highest pCR rates. In the TNBC subgroup, a positive BRCA1/2 variant status was associated with therapy response in both the PMCb arm (74.3% vs 47.0% without BRCA1/2 variant; OR, 3.26; 95% CI, 1.44-7.39; P = .005) and the iddEPC arm (64.7% vs 45.0%; OR, 2.24; 95% CI, 1.04-4.84; P = .04). A positive BRCA1/2 variant status was also associated with elevated pCR rates in patients with ERBB2-negative, hormone receptor-positive BC (31.8% vs 11.9%; OR, 3.44; 95% CI, 1.22-9.72; P = .02). Conclusions and Relevance: Effective chemotherapy for BRCA1/2-mutated TNBC is commonly suggested to be platinum based. With a pCR rate of 64.7%, iddEPC may also be effective in these patients, though further prospective studies are needed. The elevated pCR rate in BRCA1/2-mutated ERBB2-negative, hormone receptor-positive BC suggests that germline BRCA1/2 testing should be considered prior to treatment start. Trial Registration: ClinicalTrials.gov Identifier: NCT02125344.
Subject(s)
Breast Neoplasms/genetics , Germ-Line Mutation/genetics , Adult , Aged , Female , Humans , Middle Aged , Neoplasm Staging , Retrospective Studies , Young AdultABSTRACT
PURPOSE: In breast cancer, bevacizumab increased pCR rate but not long-term survival and no predictive markers are available to identify patients with long-term benefit from the drug. EXPERIMENTAL DESIGN: We profiled 289 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) biopsies of HER2-negative patients from the GeparQuinto trial of neoadjuvant chemotherapy ± bevacizumab by exome-capture RNA-sequencing (RNA-seq). In a prospectively planned study, we tested molecular signatures for response prediction. IHC validation was performed using tissue microarrays. RESULTS: We found strong agreement of molecular and pathologic parameters as hormone receptors, grading, and lymphocyte infiltration in 221 high-quality samples. Response rates (49.3% pCR overall) were higher in basal-like (68.9%) and HER2-enriched (45.5%) than in luminal B (35.7%), luminal A (17.9%), and normal-like (20.0%) subtypes. T-cell (OR = 1.60; 95% confidence interval, 1.21-2.12; P = 0.001), proliferation (OR = 2.88; 95% CI, 2.00-4.15; P < 0.001), and hypoxia signatures (OR = 1.92; 95% CI, 1.41-2.60; P < 0.001) significantly predicted pCR in univariate analysis. In a prespecified multivariate logistic regression, a small hypoxia signature predicted pCR (OR = 2.40; 95% CI, 1.28-4.51; P = 0.006) with a significant interaction with bevacizumab treatment (P = 0.020). IHC validation using NDRG1 as marker revealed highly heterogenous expression within tissue leading to profound loss of sensitivity in TMA analysis, still a significant predictive value for pCR was detected (P = 0.025). CONCLUSIONS: Exome-capture RNA-seq characterizes small FFPE core biopsies by reliably detecting factors as for example ER status, grade, and tumor-infiltrating lymphocytes levels. Beside molecular subtypes and immune signatures, a small hypoxia signature predicted pCR to bevacizumab, which could be validated by IHC. The signature can have important applications for bevacizumab treatment in different cancer types and might also have a role for novel combination therapies of bevacizumab with immune checkpoint inhibition.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Biomarkers, Tumor/genetics , Breast Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Hypoxia/genetics , Lymphocytes, Tumor-Infiltrating/immunology , Angiogenesis Inhibitors/therapeutic use , Biopsy, Large-Core Needle , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Female , Humans , Hypoxia/metabolism , Middle Aged , Prospective Studies , RNA-Seq/methods , Treatment OutcomeABSTRACT
BACKGROUND: The impact of locoregional radiotherapy (RT) after neoadjuvant chemotherapy (NACT) and mastectomy in breast cancer patients is currently unclear. Several publications have suggested that patients with a favorable response to NACT might not benefit from RT after mastectomy. METHODS: A retrospective analysis of three prospective randomized NACT trials was performed. Information on the use of RT was available for 817 breast cancer patients with non-inflammatory breast cancer who underwent mastectomy after NACT within the GeparTrio, GeparQuattro, and GeparQuinto-trials. RT was administered to 676 of these patients (82.7%). RESULTS: The 5-year cumulative incidence of locoregional recurrence (LRR) was 15.2% (95% confidence interval [CI] 9.0-22.8%) in patients treated without RT and 11.3% in patients treated with RT (95% CI 8.7-14.3%). In the multivariate analysis, RT was associated with a lower risk of LRR (hazard ratio 0.51, 95% CI 0.27-1.0; p = 0.05). This effect was shown especially in patients with cT3/4 tumors, as well as in patients who were cN+ before neoadjuvant therapy, including those who converted to ypN0 after neoadjuvant therapy. In the bivariate analysis, disease-free survival was significantly worse in patients who received RT, however this was not confirmed in the multivariate analysis. CONCLUSIONS: Our results suggest that RT reduces the LRR rates in breast cancer patients who receive a mastectomy after NACT without an improvement in DFS. Prospective randomized controlled trials such as the National Surgical Adjuvant Breast and Bowel Project B-51/RTOG 1304 trial will analyze whether RT has any benefit in patients who have a favorable response after NACT.
Subject(s)
Breast Neoplasms/mortality , Carcinoma, Ductal, Breast/mortality , Carcinoma, Lobular/mortality , Mastectomy/mortality , Neoadjuvant Therapy/mortality , Neoplasm Recurrence, Local/mortality , Radiotherapy/mortality , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Carcinoma, Ductal, Breast/pathology , Carcinoma, Ductal, Breast/therapy , Carcinoma, Lobular/pathology , Carcinoma, Lobular/therapy , Combined Modality Therapy , Female , Follow-Up Studies , Germany/epidemiology , Humans , Incidence , Middle Aged , Neoplasm Recurrence, Local/epidemiology , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Prognosis , Prospective Studies , Retrospective Studies , Survival Rate , Young AdultABSTRACT
BACKGROUND: Information on deaths occurring during oncological clinical trials has never been systematically assessed. Here, we examine the incidence of death and the profile of patients who died during randomized clinical breast cancer (BC) trials. METHODS: Information on fatal events during German Breast Group (GBG) led BC trials was prospectively captured. Data were derived from the trial databases and death narratives. All deaths were evaluated for possible causes, underlying conditions, treatment relatedness, time point and rate of autopsies. RESULTS: From 12/1996 to 01/2017, 23,387 patients were treated within 32 trials. Of those 88 (0.4%) died on therapy within 17 trials. Median age was 64 [range 35-84] years, 63.2% of patients had a body mass index (BMI) ≥ 25 kg/m2; 65.9% 1-3 and 22.7% ≥ 4 comorbidities; 61.4% 1-2 cardiovascular risk factors (CRFs); 26.4% took > 3 drugs; 81.7% had ECOG 0; 50.0% stage III, 76.7% luminal BC. The main causes of death were infection (38.6%; of those, 82.3% sepsis, 17.6% pneumonia), heart failure (14.8%), and pulmonary embolism (13.6%). Fatal events mainly occurred within the first 4 therapy cycles (55.7%), in the investigational arm (66.7%) and under anthracycline-taxane-based chemotherapy (51.1%). A relationship with the treatment was declared in 27.3% of the cases. An autopsy was performed in 13.6% of patients. CONCLUSIONS: Death during study treatment was mainly related to infections, and patients with advanced disease, high BMI, underlying comorbidities, CRFs and concomitant medications. If considered for study participation these patients need careful monitoring due to their higher risk for death on study.
Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Randomized Controlled Trials as Topic , Adult , Aged , Aged, 80 and over , Anthracyclines/adverse effects , Anthracyclines/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Autopsy , Body Mass Index , Breast Neoplasms/pathology , Bridged-Ring Compounds/adverse effects , Bridged-Ring Compounds/therapeutic use , Comorbidity , Female , Germany , Heart Failure/complications , Humans , Middle Aged , Patient Safety , Pneumonia/complications , Prospective Studies , Pulmonary Embolism/complications , Risk Factors , Sepsis/complications , Taxoids/adverse effects , Taxoids/therapeutic useABSTRACT
BACKGROUND: The incidence of central nervous system (CNS) metastases in breast cancer patients is rising and has become a major clinical challenge. Only few data are published concerning risk factors for the development of CNS metastases as a first site of metastatic disease in breast cancer patients. Moreover, the incidence of CNS metastases after modern neoadjuvant treatment is not clear. METHODS: We analyzed clinical factors associated with the occurrence of CNS metastases as the first site of metastatic disease in breast cancer patients after neoadjuvant treatment in the trials GeparQuinto and GeparSixto (n = 3160) where patients received targeted treatment in addition to taxane and anthracycline-based chemotherapy. RESULTS: After a median follow-up of 61 months, 108 (3%) of a total of 3160 patients developed CNS metastases as the first site of recurrence and 411 (13%) patients had metastatic disease outside the CNS. Thirty-six patients (1%) developed both CNS metastases and other distant metastases as the first site of metastatic disease. Regarding subtypes of the primary tumor, 1% of luminal A-like (11/954), 2% of luminal B-like (7/381), 4% of HER2-positive (34/809), and 6% of triple-negative patients (56/1008) developed CNS metastases as the first site of metastatic disease. In multivariate analysis, risk factors for the development of CNS metastases were larger tumor size (cT3-4; HR 1.63, 95% CI 1.08-2.46, p = 0.021), node-positive disease (HR 2.57, 95% CI 1.64-4.04, p < 0.001), no pCR after neoadjuvant chemotherapy (HR 2.29, 95% CI 1.32-3.97, p = 0.003), and HER2-positive (HR 3.80, 95% CI 1.89-7.64, p < 0.001) or triple-negative subtype (HR 6.38, 95% CI 3.28-12.44, p < 0.001). CONCLUSIONS: Especially patients with HER2-positive and triple-negative tumors are at risk of developing CNS metastases despite effective systemic treatment. A better understanding of the underlying mechanisms is required in order to develop potential preventive strategies.