ABSTRACT
BACKGROUND: Disseminated tumor cells (DTCs) in the bone marrow are observed in about 40% at primary diagnosis of breast cancer and predict poor survival. While anti-resorptive therapy with bisphosphonates was shown to eradicate minimal residue disease in the bone marrow, the effect of denosumab on DTCs, particularly in the neoadjuvant setting, is largely unknown. The recent GeparX clinical trial reported that denosumab, applied as an add-on treatment to nab-paclitaxel based neoadjuvant chemotherapy (NACT), did not improve the patient's pathologic complete response (pCR) rate. Herein, we analyzed the predictive value of DTCs for the response to NACT and interrogated whether neoadjuvant denosumab treatment may eradicate DTCs in the bone marrow. METHODS: A total of 167 patients from the GeparX trial were analyzed for DTCs at baseline by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. Initially DTC-positive patients were re-analyzed for DTCs after NACT ± denosumab. RESULTS: At baseline, DTCs were observed in 43/167 patients (25.7%) in the total cohort, however their presence did not predict response to nab-paclitaxel based NACT (pCR rates: 37.1% in DTC-negative vs. 32.6% DTC-positive; p = 0.713). Regarding breast cancer subtypes, the presence of DTCs at baseline was numerically associated with response to NACT in TNBC patients (pCR rates: 40.0% in DTC-positive vs. 66.7% in DTC-negative patients; p = 0.16). Overall, denosumab treatment did not significantly increase the given DTC-eradication rate of NACT (NACT: 69.6% DTC-eradication vs. NACT + denosumab: 77.8% DTC-eradication; p = 0.726). In TNBC patients with pCR, a numerical but statistically non-significant increase of DTC-eradication after NACT + denosumab was observed (NACT: 75% DTC-eradication vs. NACT + denosumab: 100% DTC-eradication; p = 1.00). CONCLUSION: This is the first study worldwide, demonstrating that neoadjuvant add-on denosumab over a short-term period of 24 months does not increase the DTC-eradication rate in breast cancer patients treated with NACT.
Subject(s)
Breast Neoplasms , Neoplastic Cells, Circulating , Triple Negative Breast Neoplasms , Female , Humans , Breast Neoplasms/pathology , Denosumab/therapeutic use , Neoadjuvant Therapy , Neoplastic Cells, Circulating/pathology , PrognosisABSTRACT
Immunohistochemical evaluation of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 status stratify the different subtypes of breast cancer and define the treatment course. Triple-negative breast cancer (TNBC), which does not register receptor overexpression, is often associated with worse patient prognosis. Mass spectrometry imaging transcribes the molecular content of tissue specimens without requiring additional tags or preliminary analysis of the samples, being therefore an excellent methodology for an unbiased determination of tissue constituents, in particular tumor markers. In this study, the proteomic content of 1191 human breast cancer samples was characterized by mass spectrometry imaging and the epithelial regions were employed to train and test machine-learning models to characterize the individual receptor status and to classify TNBC. The classification models presented yielded high accuracies for estrogen and progesterone receptors and over 95% accuracy for classification of TNBC. Analysis of the molecular features revealed that vimentin overexpression is associated with TNBC, supported by immunohistochemistry validation, revealing a new potential target for diagnosis and treatment.
Subject(s)
Breast Neoplasms , Triple Negative Breast Neoplasms , Humans , Female , Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Receptor, ErbB-2/metabolism , Proteomics , Biomarkers, Tumor/metabolism , Estrogens , Receptors, Progesterone/metabolism , Mass SpectrometryABSTRACT
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: Breast cancer (BC) is the most frequent female cancer and preferentially metastasizes to bone. The transcription factor TGFB-induced factor homeobox 1 (TGIF) is involved in bone metabolism. However, it is not yet known whether TGIF is associated with BC bone metastasis or patient outcome and thus of potential interest. METHODS: TGIF expression was analyzed by immunohistochemistry in 1197 formalin-fixed, paraffin-embedded tissue samples from BC patients treated in the GAIN (German Adjuvant Intergroup Node-Positive) study with two adjuvant dose-dense schedules of chemotherapy with or without bisphosphonate ibandronate. TGIF expression was categorized into negative/low and moderate/strong staining. Endpoints were disease-free survival (DFS), overall survival (OS) and time to primary bone metastasis as first site of relapse (TTPBM). RESULTS: We found associations of higher TGIF protein expression with smaller tumor size (p = 0.015), well differentiated phenotype (p < 0.001) and estrogen receptor (ER)-positive BC (p < 0.001). Patients with higher TGIF expression levels showed a significantly longer disease-free (DFS: HR 0.75 [95%CI 0.59-0.95], log-rank p = 0.019) and overall survival (OS: HR 0.69 [95%CI 0.50-0.94], log-rank p = 0.019), but no association with TTPBM (HR 0.77 [95%CI 0.51-1.16]; p = 0.213). Univariate analysis in molecular subgroups emphasized that elevated TGIF expression was prognostic for both DFS and OS in ER-positive BC patients (DFS: HR 0.68 [95%CI 0.51-0.91]; log-rank p = 0.009, interaction p = 0.130; OS: HR 0.60 [95%CI 0.41-0.88], log-rank p = 0.008, interaction p = 0.107) and in the HER2-negative subgroup (DFS:HR 0.67 [95%CI 0.50-0.88], log-rank p = 0.004, interaction p = 0.034; OS: HR 0.57 [95%CI 0.40-0.81], log-rank p = 0.002, interaction p = 0.015). CONCLUSIONS: Our results suggest that moderate to high TGIF expression is a common feature of breast cancer cells and that this is not associated with bone metastases as first site of relapse. However, a reduced expression is linked to tumor progression, especially in HER2-negative breast cancer. TRIAL REGISTRATION: This clinical trial has been registered with ClinicalTrials.gov ; registration number: NCT00196872 .
Subject(s)
Breast Neoplasms/genetics , Gene Expression , Homeodomain Proteins/genetics , Repressor Proteins/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor , Breast Neoplasms/diagnosis , Breast Neoplasms/metabolism , Breast Neoplasms/therapy , Female , Homeodomain Proteins/metabolism , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Middle Aged , Neoplasm Grading , Neoplasm Staging , Prognosis , Repressor Proteins/metabolism , Young AdultABSTRACT
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.
Subject(s)
Breast Neoplasms/epidemiology , Breast Neoplasms/pathology , Central Nervous System Neoplasms/epidemiology , Central Nervous System Neoplasms/secondary , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/therapy , Female , Follow-Up Studies , Humans , Incidence , Neoadjuvant Therapy , Neoplasm Grading , Neoplasm StagingABSTRACT
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
The E-VITA study evaluated the efficacy and tolerability of two schedules of eribulin and lapatinib in patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer. This multicenter, open-label phase II trial, randomly assigned patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer to lapatinib 1000 mg daily with eribulin 1.23 mg/m (equivalent to 1.4 mg/m eribulin mesylate) days 1+8 every 21 days (split-dose arm) or eribulin 1.76 mg/m (equivalent to 2.0 mg/m eribulin mesylate) day 1 every 21 days (3-weekly arm). Time to progression and tolerability were defined as primary end points; no sample size calculation for formal comparison of efficacy data has been performed. Secondary end points included objective response rate, clinical benefit rate, and overall survival. Overall, 43 patients of a planned number of 80 patients were recruited. At a median follow-up of 28.7 months, the median time to progression was 8.1 months [95% confidence interval (CI): 4.8-9.4] in the split-dose arm and 6.5 months (95% CI: 4.6-13.4) in the 3-weekly arm. Objective response rate was 52.4% (95% CI: 31.0-73.7) in the split-dose arm and 45.0% (95% CI: 23.2-66.8) in the 3-weekly arm, and clinical benefit rate was 71.4% (95% CI: 52.1-90.8) and 75.0% (95% CI: 56.0-94.0), respectively. Overall survival was also similar in both arms. The most frequent grade 3-4 adverse events were neutropenia (58.5%) and leukopenia (39.0%). The combination of eribulin and lapatinib showed an acceptable safety profile with less toxicity observed in the eribulin 1.23 mg/m day 1+8 group. This might be an alternative regimen when other treatment options are exhausted. Therefore, further clinical studies are warranted.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/metabolism , Breast Neoplasms/drug therapy , Receptor, ErbB-2/metabolism , Adult , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Female , Follow-Up Studies , Furans/administration & dosage , Humans , Ketones/administration & dosage , Lapatinib/administration & dosage , Middle Aged , Neoplasm Metastasis , Prognosis , Salvage Therapy , Survival Rate , Trastuzumab/administration & dosageABSTRACT
PURPOSE: The estrogen receptor (ER) is involved in control of progesterone receptor (PgR) expression and lack of PgR may be also a surrogate of altered growth factor signaling. The aim of this study was therefore to investigate PgR expression as predictive factor for response to neoadjuvant therapy and long-term outcome. METHODS: Five thousand and six hundred and thirteen patients with primary breast cancer and positive ER expression from ten German neoadjuvant trials of anthracycline and taxane-based chemotherapy were included. Pathologic complete response (pCR), disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS), and local recurrence-free survival (LRFS) were compared according to PgR expression. RESULTS: The lack of PgR expression (1172 patients) was associated with grade 3 (38.4 vs. 26.3%; p < 0.001), nodal involvement (>cN2) (6.8% vs. 4.7%; p = 0.004), and HER2 positivity (36.2 vs. 22.3%; p < 0.001). pCR rates of PgR-negative tumors were higher in the entire cohort (13.8 vs. 7.5%; p < 0.001) and in the HER2-negative subgroup (11.2 vs. 5.8%; p < 0.001). In multivariable logistic regression, PgR negativity was an independent predictive factor for pCR overall (OR 1.76; p < 0.001) and in the HER2-negative patients (OR 1.99; p < 0.001). Patients with PgR-negative disease had significantly worse outcome (p < 0.001, respectively). Multivariable Cox regression analysis revealed that PgR was an independent prognostic factor for DFS, OS, DDFS, and LRFS. CONCLUSION: ER-positive/PgR-negative breast carcinomas are associated with higher response but also worse long-term outcome after neoadjuvant therapy. PgR negativity is an independent predictive factor for pCR after neoadjuvant chemotherapy in ER-positive HER2-negative breast cancer.
Subject(s)
Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Neoplasm Recurrence, Local/genetics , Receptors, Estrogen/genetics , Adult , Aged , Breast Neoplasms/epidemiology , Breast Neoplasms/pathology , Bridged-Ring Compounds/administration & dosage , Bridged-Ring Compounds/adverse effects , Disease-Free Survival , Female , Gene Expression Regulation, Neoplastic , Humans , Middle Aged , Neoplasm Recurrence, Local/epidemiology , Neoplasm Recurrence, Local/pathology , Proportional Hazards Models , Randomized Controlled Trials as Topic , Receptor, ErbB-2/genetics , Receptors, Progesterone/genetics , Taxoids/administration & dosage , Taxoids/adverse effectsABSTRACT
PURPOSE: The GeparSepto study demonstrated that the use of nab-paclitaxel instead of paclitaxel prior to anthracycline-based chemotherapy could lead to a significantly increased pCR rate, especially in the triple negative subpopulation. We report efficacy and safety for patients treated with two different doses of nab-paclitaxel in comparison to weekly solvent-formulated paclitaxel. METHODS: Patients were treated for 12 weeks with either intravenous nab-paclitaxel 150 mg/m2 (nP150) weekly, after study amendment 125 mg/m2 (nP125) weekly or solvent-based paclitaxel 80 mg/m2 (P80) weekly followed by epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 on day 1 for four 3-week cycles. RESULTS: 229 patients received nP150, 377 nP125. Baseline characteristics were fairly balanced between these two sequential cohorts as well as compared to 601 patients receiving P80 except for hormone receptor status, HER2 status, and Ki67. Taxane treatment was discontinued in 26.8% (nP150), 16.6% (nP125), and 13.3% of (P80) patients, respectively. Median relative total dose intensity (mRTDI) based on 125 mg/m2 for nP was 103% with nP150, 95% with nP125, 99% with P80 before and 98% with P80 after the amendment. PSN grade 3-4 was observed in 14.5% of patients with nP150, 8.1% of patients with nP125 (p = 0.018), and 2.7% of patients with P80. Overall pCR before the amendment was 33.6% after nP150 and 23.5% after P80 (OR 1.65 [95% CI 1.10-2.50]; p = 0.022); pCR after the amendment was 41.4% after nP125, and 32.4% after P80 (1.48 [95% CI 1.10-1.99]; p = 0.013). CONCLUSIONS: Nab-paclitaxel 125 mg/m2 was associated with a better safety profile and compliance without compromising the efficacy compared to nab-paclitaxel 150 mg/m2.
Subject(s)
Albumins/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Paclitaxel/administration & dosage , Adult , Aged , Albumins/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/pathology , Cyclophosphamide/administration & dosage , Drug Administration Schedule , Epirubicin/administration & dosage , Female , Humans , Middle Aged , Neoadjuvant Therapy/adverse effects , Neoplasm Staging , Paclitaxel/adverse effectsABSTRACT
BACKGROUND: In metastatic breast cancer, nab-paclitaxel has been shown to significantly increase progression-free survival compared with solvent-based paclitaxel. The GeparSepto (GBG 69) trial assessed whether weekly nab-paclitaxel could increase the proportion of patients achieving pathological complete response compared with weekly solvent-based paclitaxel, both followed by epirubicin plus cyclophosphamide as neoadjuvant treatment. METHOD: In a phase 3 randomised trial, we enrolled patients with previously untreated unilateral or bilateral primary invasive breast cancer and randomly assigned them in a 1:1 ratio using dynamic allocation and Pocock minimisation by breast cancer subtype, Ki67 and SPARC expression. Patients were treated for 12 weeks with either intravenous nab-paclitaxel 150 mg/m(2) (after study amendment, 125 mg/m(2)) on days 1, 8, and 15 for four 3-week cycles, or solvent-based intravenous paclitaxel 80 mg/m(2) on days 1, 8, and 15 for four 3-week cycles. Taxane treatment was followed in both groups by intravenous epirubicin 90 mg/m(2) plus intravenous cyclophosphamide 600 mg/m(2) on day 1 for four 3-week cycles. Patients with HER2-positive tumours received concurrent trastuzumab 6 mg/kg (loading dose 8 mg/kg) and pertuzumab 420 mg (loading dose 840 mg) on day 1 of every 3-week cycle. Trastuzumab and pertuzumab were given every 3 weeks concomitantly with chemotherapy for all cycles. This report is the final analysis of the primary endpoint, pathological complete response (ypT0 ypN0), analysed for all patients who started treatment (modified intention to treat). We used a closed test procedure to test for non-inferiority, with the nab-paclitaxel group calculated as non-inferior to the solvent-based paclitaxel group if the lower 95% CI for the OR was above 0·858 (OR equivalent to pathological complete response [33%] minus a 10% non-inferiority margin [3·3%]; 29·7%). We planned to test for superiority only in case of a positive non-inferiority test, using an α of 0·05. Safety was assessed in all patients who received study drug. The trial is registered with ClinicalTrials.gov, number NCT01583426. FINDINGS: Between July 30, 2012, and Dec 23, 2013, we randomly assigned 1229 women, of whom 1206 started treatment (606 with nab-paclitaxel and 600 with solvent-based paclitaxel). The nab-paclitaxel dose was reduced after enrolment of 464 participants to 125 mg/m(2) due to increased treatment discontinuation and sensory neuropathy in this group. Pathological complete response occurred more frequently in the nab-paclitaxel group (233 [38%, 95% CI 35-42] patients) than in the solvent-based paclitaxel group (174 [29%, 25-33] patients; OR 1·53, 95% CI 1·20-1·95; unadjusted p=0·00065). The incidence of grade 3-4 anaemia (13 [2%] of 605 patients in the nab-paclitaxel group vs four [1%] of patients in the solvent-based paclitaxel group; p=0·048) and peripheral sensory neuropathy grade 3-4 (63 [10%] patients receiving any nab-paclitaxel dose; 31 [8%] of patients starting with 125 mg/m(2) and 32 [15%] of patients starting with 150 mg/m(2); vs 16 [3%] in the solvent-based paclitaxel group, p<0·001) was significantly higher for nab-paclitaxel than for solvent-based paclitaxel. Overall, 283 (23%) patients were noted to have at least one serious adverse event (based on study drug received), 156 (26%) in the nab-paclitaxel group and 127 (21%) in the solvent-based paclitaxel group (p=0·057). There were three deaths (during epirubicin plus cyclophosphamide treatment) in the nab-paclitaxel group (due to sepsis, diarrhoea, and accident unrelated to the trial) versus one in the solvent-based paclitaxel group (during paclitaxel treatment; cardiac failure). INTERPRETATION: Substituting solvent-based paclitaxel with nab-paclitaxel significantly increases the proportion of patients achieving a pathological complete response rate after anthracycline-based chemotherapy. These results might lead to an exchange of the preferred taxane, solvent-based paclitaxel, for nab-paclitaxel in therapy for primary breast cancer. FUNDING: Celgene, Roche.
Subject(s)
Albumins/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Neoadjuvant Therapy/methods , Paclitaxel/therapeutic use , Adult , Aged , Albumins/adverse effects , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Confidence Intervals , Disease-Free Survival , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Mastectomy/methods , Middle Aged , Paclitaxel/adverse effects , Prognosis , Risk Assessment , Survival Analysis , Treatment OutcomeABSTRACT
Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression-free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2-negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre-planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF-A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49-3.75), 1.20 (95% CI, 0.88-1.64) and 0.61 (95% CI, 0.34-1.12). Notably, some SNPs in VEGF-A exhibited a more pronounced effect in the triple-negative subgroup. Several SNPs in VEGF-A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Bevacizumab/therapeutic use , Breast Neoplasms/drug therapy , Neovascularization, Pathologic/genetics , Adult , Breast Neoplasms/blood supply , Breast Neoplasms/genetics , Chemotherapy, Adjuvant , Female , Genetic Association Studies , Genotype , Humans , Middle Aged , Neoadjuvant Therapy , Neovascularization, Pathologic/prevention & control , Polymorphism, Single Nucleotide , Treatment Outcome , Vascular Endothelial Growth Factor A/geneticsABSTRACT
BACKGROUND: Although greater than 40% of breast cancers occur in patients aged ≥65 years, these individuals are frequently undertreated. Taxane-based adjuvant chemotherapy is considered the treatment of choice but to the authors' knowledge has only limited evidence in elderly patients. METHODS: Patients aged ≥65 years with a Charlson comorbidity index ≤2 and pT1/2 pN0/1 disease and either human epidermal growth factor receptor 2 (HER2)-positive, hormone receptor-negative, grade 3 (according to Common Terminology Criteria for Adverse Events [version 3.0]), high uPA/PAI-1 or any stage pT3/4 pN2/3 breast cancer were randomized to receive 4 cycles of adjuvant epirubicin and cyclophosphamide (EC) (epirubicin at a dose of 90 mg/m(2) and cyclophosphamide at a dose of 600 mg/m(2) intravenously [iv] on day 1 every 3 22 days) or 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (cyclophosphamide at a dose of 500 mg/m(2), methotrexate at a dose of 40 mg/m(2), and 5-fluorouracil at a dose of 600 mg/m(2) iv on days 1 plus 8 every 29 days) versus 6 cycles of nab-paclitaxel and capecitabine (nPX) (nab-paclitaxel at a dose of 100 mg/m(2) iv on days 1, 8, and 15 every 21 days with 1 week of rest every 6 weeks plus capecitabine at a dose of 2000 mg/m(2) orally on days 1-14 every 21 days). Primary endpoints were treatment discontinuations and overall frequency of adverse events. RESULTS: Thirteen of 198 patients (6.6%) discontinued EC/CMF and 69 of 193 patients (35.8%) discontinued nPX (P<.001) with 1 and 5 deaths observed during treatment, respectively. Grade 3 to 5 adverse events were more frequent among patients treated with EC/CMF (90.9%) than among those treated with nPX (64.8%) (P<.001), with hematological toxicities being more frequent with EC/CMF (88.4% vs 22.3%; P<.001), but nonhematological toxicities (hand-foot syndrome, diarrhea, mucositis, fatigue, sensory neuropathy, thromboembolisms, and metabolic disorders) being more frequent with nPX (58.5% vs 18.7%; P<.001). None of the geriatric scores (Charlson comorbidity index, Vulnerable Elders Survey [VES-13], Instrumental Activities of Daily Living [IADL], and G8) independently predicted grade 3 to 5 toxic events or treatment discontinuations. No differences in survival between the treatment groups were observed after 22.8 months. CONCLUSIONS: Compared with EC/CMF, treatment with nPX led to more treatment discontinuations and nonhematological toxicities in elderly patients with moderate or high-risk breast cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cyclophosphamide/adverse effects , Epirubicin/adverse effects , Aged , Aged, 80 and over , Albumins/administration & dosage , Albumins/adverse effects , Capecitabine/administration & dosage , Capecitabine/adverse effects , Chemotherapy, Adjuvant/methods , Cyclophosphamide/administration & dosage , Drug Administration Routes , Drug Administration Schedule , Epirubicin/administration & dosage , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Male , Methotrexate/administration & dosage , Methotrexate/adverse effects , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Treatment OutcomeABSTRACT
BACKGROUND: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor A, has shown clinical efficacy in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. We evaluated the efficacy, measured according to the rate of pathological complete response (absence of invasive and intraductal disease in the breast and the axillary lymph nodes), and the safety of adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage breast cancer. METHODS: We randomly assigned 1948 patients with a median tumor size of 40 mm on palpation to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel, with or without concomitant bevacizumab. Patients with untreated HER2-negative breast cancer were eligible if they had large tumors, hormone-receptor-negative disease, or hormone-receptor-positive disease with palpable nodes or positive findings on sentinel-node biopsy, and no increased cardiovascular or bleeding risk. RESULTS: Overall, the rates of pathological complete response were 14.9% with epirubicin and cyclophosphamide followed by docetaxel and 18.4% with epirubicin and cyclophosphamide followed by docetaxel plus bevacizumab (odds ratio with addition of bevacizumab, 1.29; 95% confidence interval, 1.02 to 1.65; P=0.04); the corresponding rates of pathological complete response were 27.9% and 39.3% among 663 patients with triple-negative tumors (P=0.003) and 7.8% and 7.7% among 1262 patients with hormone-receptor-positive tumors (P=1.00). Breast-conserving surgery was possible in 66.6% of the patients in both groups. The addition of bevacizumab, as compared with neoadjuvant therapy alone, was associated with a higher incidence of grade 3 or 4 toxic effects (febrile neutropenia, mucositis, the hand-foot syndrome, infection, and hypertension) but with a similar incidence of surgical complications. CONCLUSIONS: The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response among patients with HER2-negative early-stage breast cancer. Efficacy was restricted primarily to patients with triple-negative tumors, in whom the pathological complete response is considered to be a reliable predictor of long-term outcome. (Funded by Sanofi-Aventis and Roche, Germany; ClinicalTrials.gov number, NCT00567554.).
Subject(s)
Angiogenesis Inhibitors/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Receptor, ErbB-2 , Adult , Aged , Angiogenesis Inhibitors/adverse effects , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab , Breast Neoplasms/surgery , Cyclophosphamide/administration & dosage , Disease Progression , Epirubicin/administration & dosage , Female , Humans , Logistic Models , Mastectomy, Segmental , Medication Adherence , Middle Aged , Neoadjuvant Therapy , Neoplasm StagingABSTRACT
Young women with breast cancer (BC) have a worse survival partly due to more aggressive tumor characteristics; however, their response to chemotherapy seems better. We investigated to what extent the prognostic factor pathological complete remission (pCR) after neoadjuvant chemotherapy is applicable to young women. 8949 patients with primary BC and follow-up from eight German neoadjuvant trials were included. A subgroup of 1453 patients <40 years was compared with women aged 40-49 and ≥50 years regarding pCR (ypT0 ypN0), as well as disease free survival (DFS), local recurrence free survival (LRFS), distant disease free survival (DDFS), and overall survival (OS) overall, according to pCR status and subtypes defined by hormone-receptor (HR) status and HER2. pCR was strongly associated with age without a clear age cut-off. The pCR rate was significantly higher in the young compared with other age groups (20.9 vs. 17.7 vs. 13.7 %; p < 0.001). This difference was confined to triple-negative breast cancer (TNBC) and HR +/HER2-. DFS, DDFS, LRFS, and OS were significantly worse for young women. Age was independently prognostic for survival in HR +/HER2-, with women <40 years without pCR having a worse DFS compared to their counterparts with pCR. Young women are more likely to achieve pCR after neoadjuvant chemotherapy, especially in HR +/HER2- and TNBC. Age is not an important prognostic factor in TNBC and HR-/HER2 + but is in HR +/HER2-. Young women with a luminal-like BC seem to benefit more from neoadjuvant chemotherapy than older women, which needs to be taken into account.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Adult , Aged , Biomarkers, Tumor , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Female , Humans , Lymphatic Metastasis , Middle Aged , Neoadjuvant Therapy , Neoplasm Grading , Neoplasm Recurrence, Local , Neoplasm Staging , Odds Ratio , Randomized Controlled Trials as Topic , Risk Factors , Survival Analysis , Treatment Outcome , Young AdultABSTRACT
Obesity is associated with an increased risk of breast cancer (BC) and poorer outcome. We assessed the impact of body mass index (BMI) on pathological complete response (pCR), disease-free (DFS), and overall survival (OS), according to BC subtypes in patients with primary BC treated with neoadjuvant chemotherapy. 8,872 patients with primary BC from eight neoadjuvant trials were categorized according to BMI: underweight (<18.5 kg/m(2)), normal weight (18.5 to <25 kg/m(2)), overweight (25 to <30 kg/m(2)), obese (30 to <40 kg/m(2)), and very obese (≥40 kg/m(2)). BC subtypes were defined as luminal-like (ER/PgR-positive and HER2-negative), HER2/luminal (ER/PgR-positive and HER2-positive), HER2-like (ER/PgR-negative and HER2-positive), and triple-negative (TNBC; ER/PgR- and HER2-negative). pCR rate was higher in normal weight patients compared with all other BMI groups (P = 0.003). Mean DFS and OS were shorter in obese (87.3 months, P = 0.014 and 94.9 months, P = 0.001, respectively) and very obese (66.6 months, P < 0.001 and 75.3 months, P < 0.001, respectively) compared with normal weight patients (91.5 and 98.8 months, respectively) which was confirmed by subpopulation treatment effect pattern plot analyses and was consistent in luminal-like and TNBC. No interaction was observed between BMI and pCR. Normal weight patients experienced less non-hematological adverse events (P = 0.002) and were more likely to receive full taxane doses (P < 0.001) compared with all other BMI groups. In multivariable analysis, the dose of taxanes was predictive for pCR (P < 0.001). Higher BMI was associated with lower pCR and a detrimental impact on survival. Normal weight patients had the best compliance to chemotherapy and received the highest taxane doses, which seems to be related with treatment outcomes.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Body Mass Index , Breast Neoplasms/drug therapy , Adult , Biomarkers, Tumor , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Neoadjuvant Therapy , Neoplasm Grading , Neoplasm Metastasis , Neoplasm Staging , Treatment OutcomeABSTRACT
Taxanes (T) plus bevacizumab (B) and taxanes plus capecitabine (X) showed better progression-free survival (PFS) compared to taxanes alone. Since life-threatening or highly symptomatic situations require polychemotherapy in metastatic breast cancer (MBC), combination of taxanes, capecitabine plus bevacizumab appears reasonable. TABEA (NCT01200212), a prospectively randomized, open-label, phase III trial compares taxanes (paclitaxel 80 mg/m(2) i.v. d1,8,15 q22 or docetaxel 75 mg/m(2) i.v. d1 q22) plus bevacizumab (15 mg/kg i.v. d1 q22) with (TBX) or without capecitabine (TB, 1800 mg/m(2) daily d1-14 q22) as first-line therapy in MBC. Histologically confirmed HER2-negative, locally advanced or MBC patients with a chemotherapy indication and measurable or non-measurable target lesions (RECIST criteria) were included. Primary objective was PFS. Secondary objectives were response rate and duration, clinical benefit rate (complete response, partial response, stable disease ≥24 weeks), 3-year overall survival, PFS in patients ≥65 years, toxicity, and compliance. We assumed 10 and 13.3 months PFS for TB and TBX, respectively (HR = 0.75), requiring 432 patients and 386 events. Preplanned interim futility and safety analyses after 100 events in 202 patients showed no efficacy benefit and higher toxicity for TBX. Recruitment and therapy were stopped following advice from the IDMC. Final analysis revealed a HR 1.13 [95 %CI 0.806-1.59], P = 0.474, for PFS. Overall grade 3-4 adverse event (77.3 vs. 62.1 %, P = 0.014) and serious adverse event (40.0 vs. 30.2 %, P = 0.127) rates were higher for TBX after 26.1 months median follow-up, with six deaths for TBX versus 1 for TB. Adding capecitabine to TB cannot be recommended as first-line therapy in MBC.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Breast Neoplasms/drug therapy , Deoxycytidine/analogs & derivatives , Fluorouracil/analogs & derivatives , Neoplasm Recurrence, Local/drug therapy , Taxoids/administration & dosage , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols , Bevacizumab , Breast Neoplasms/pathology , Capecitabine , Deoxycytidine/administration & dosage , Disease-Free Survival , Docetaxel , Drug-Related Side Effects and Adverse Reactions , Female , Fluorouracil/administration & dosage , Humans , Middle Aged , Neoplasm Recurrence, Local/pathologyABSTRACT
BACKGROUND: Preclinical data suggest that triple-negative breast cancers are sensitive to interstrand crosslinking agents, and that synergy may exist for the combination of a taxane, trastuzumab, and a platinum salt for HER2-positive breast cancer. We therefore aimed to assess the efficacy of the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive breast cancer. METHODS: Patients with previously untreated, non-metastatic, stage II-III, triple-negative breast cancer and HER2-positive breast cancer were enrolled. Patients were treated for 18 weeks with paclitaxel (80 mg/m(2) once a week) and non-pegylated liposomal doxorubicin (20 mg/m(2) once a week). Patients with triple-negative breast cancer received simultaneous bevacizumab (15 mg/kg intravenously every 3 weeks). Patients with HER2-positive disease received simultaneous trastuzumab (8 mg/kg initial dose with subsequent doses of 6 mg/kg intravenously every 3 weeks) and lapatinib (750 mg daily). Patients were randomly assigned in a 1:1 ratio with dynamic allocation and minimisation, stratified by biological subtype and Ki-67 level to receive, at the same time as the backbone regimens, either carboplatin (AUC 1·5 [2·0 for the first 329 patients] once a week) or no carboplatin. The primary endpoint the proportion of patients who achieved a pathological complete response (defined as ypT0 ypN0), analysed for all patients who started treatment; a p value of less than 0·2 was deemed significant for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01426880. FINDINGS: 296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. In this final analysis, 129 patients (43·7%, 95% CI 38·1-49·4) in the carboplatin group achieved a pathological complete response, compared with 108 patients (36·9%, 31·3-42·4) without carboplatin (odds ratio 1·33, 95% CI 0·96-1·85; p=0·107). Of the patients with triple-negative breast cancer, 84 (53·2%, 54·4-60·9) of 158 patients achieved a pathological complete response with carboplatin, compared with 58 (36·9%, 29·4-44·5) of 157 without (p=0·005). Of the patients with HER2-positive tumours, 45 (32·8%, 25·0-40·7) of 137 patients achieved a pathological complete response with carboplatin compared with 50 (36·8%, 28·7-44·9) of 136 without (p=0·581; test for interaction p=0·015). Haematological and non-haematological toxic effects that were significantly more common in the carboplatin group than in the no-carboplatin group included grade 3 or 4 neutropenia (192 [65%] vs 79 [27%]), grade 3 or 4 anaemia (45 [15%] vs one [<1%]), grade 3 or 4 thrombocytopenia (42 [14%] vs one [<1%]), and grade 3 or 4 diarrhoea (51 [17%] vs 32 [11%]); carboplatin was more often associated with dose discontinuations (141 [48%] with carboplatin and 114 [39%] without carboplatin; p=0·031). The frequency of grade 3 or 4 haematological events decreased from 82% (n=135) to 70% (n=92) and grade 3 or 4 non-haematological events from 78% (n=128) to 59% (n=77) in the carboplatin arm when the dose of carboplatin was reduced from AUC 2·0 to 1·5. INTERPRETATION: The addition of neoadjuvant carboplatin to a regimen of a taxane, an anthracycline, and targeted therapy significantly increases the proportion of patients achieving a pathological complete response. This regimen seems to increase responses in patients with triple-negative breast cancer, but not in those with HER2-positive breast cancer. FUNDING: GlaxoSmithKline, Roche, and Teva.
Subject(s)
Antineoplastic Agents/therapeutic use , Carboplatin/therapeutic use , Neoadjuvant Therapy , Receptor, ErbB-2/analysis , Triple Negative Breast Neoplasms/drug therapy , Adult , Aged , Carboplatin/adverse effects , Female , Humans , Middle Aged , Triple Negative Breast Neoplasms/chemistry , Triple Negative Breast Neoplasms/pathologyABSTRACT
Changes in cellular lipid metabolism are a common feature in most solid tumors, which occur already in early stages of the tumor progression. However, it remains unclear if the tumor-specific lipid changes can be detected at the level of systemic lipid metabolism. The objective of this study was to perform comprehensive analysis of lipids in breast cancer patient serum samples. Lipidomic profiling using an established analytical platform was performed in two cohorts of breast cancer patients receiving neoadjuvant chemotherapy. The analyses were performed for 142 patients before and after neoadjuvant chemotherapy, and the results before chemotherapy were validated in an independent cohort of 194 patients. The analyses revealed that in general the tumor characteristics are not reflected in the serum samples. However, there was an association of specific triacylglycerols (TGs) in patients' response to chemotherapy. These TGs containing mainly oleic acid (C18:1) were found in lower levels in those patients showing pathologic complete response before receiving chemotherapy. Some of these TGs were also associated with estrogen receptor status and overall or disease-free survival of the patients. The results suggest that the altered serum levels of oleic acid in breast cancer patients are associated with their response to chemotherapy.