Trastuzumab or lapatinib with standard chemotherapy for HER2-positive breast cancer: results from the GEICAM/2006-14 trial.

BACKGROUND: The addition of trastuzumab (T) and lapatinib (L) to neoadjuvant chemotherapy increases the pathological complete response (pCR) rate in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We investigated the efficacy of T or L with neoadjuvant chemotherapy and specific efficacy biomarkers. METHODS: Patients with stages I-III (including inflammatory) HER2-positive breast cancer were randomised to receive epirubicin (E) plus cyclophosphamide (C) × 4 cycles followed by docetaxel (D) plus either T (EC-DT) or L (EC-DL). End points included pCR (primary), clinical response, toxicity, and pCR-predictive biomarkers. RESULTS: We randomised 102 patients to EC-DT (50) and EC-DL (52). Median age was 48, 56% were premenopausal and 58% had oestrogen receptor (ER)-positive tumours. Pathological complete response in breast was 52.1% (95% CI:38.0-66.2%) for EC-DT and 25.5% (95% CI:13.5-37.5%) for EC-DL (P=0.0065). Pathological complete response in breast and axilla was 47.9% for EC-DT and 23.5% for EC-DL (P=0.011). Grade 3-4 toxicity did not differ across treatments, except for diarrhoea (2% in EC-DT vs 13.5% in EC-DL, P=0.030). Multivariate analyses showed that treatment (P=0.036) and ER (P=0.014) were the only predictors of pCR in both groups. CONCLUSION: EC-DT exhibited higher efficacy and lower toxicity than EC-DL. Of the different biomarkers studied, only the absence of ER expression was associated with increased pCR.

Chemotherapy (CT) and hormonotherapy (HT) as neoadjuvant treatment in luminal breast cancer patients: results from the GEICAM/2006-03, a multicenter, randomized, phase-II study.

BACKGROUND: Luminal breast cancer is a highly endocrine responsive disease. However, the therapeutic benefit of chemotherapy (CT) in this population is not fully characterized. This study investigates the value of CT and hormone therapy (HT) in luminal breast cancer patients in the neoadjuvant setting. PATIENTS AND METHODS: Patients with operable breast cancer and immunophenotypically defined luminal disease (ER+/PR+/HER2-/cytokeratin 8/18+) were recruited. Patients were randomized to CT (epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) 4 cycles followed by docetaxel 100 mg/m(2 )4 cycles [EC-T]) or HT (exemestane 25 mg daily 24 weeks [combined with goserelin in premenopausal patients]). The primary end point was the clinical response measured by magnetic resonance imaging. RESULTS: Ninety-five patients were randomized (47 CT, 48 HT). The clinical response rate was 66% for CT and 48% for HT (P = 0.075). We performed an unplanned analysis based on Ki67 levels (cut-off of 10%). Similar clinical response was seen between arms in patients with low Ki67 (CT: 63%, HT: 58%; P = 0.74); patients with high Ki67 had a better response with CT (67 versus 42%; P = 0.075). Grade 3/4 toxicity was more frequent with CT. CONCLUSIONS: Luminal immunophenotype is not enough to identify patients who do not benefit from neoadjuvant CT. Luminal patients with low proliferation index could potentially avoid CT.

Electronic health records and patient registries in medical oncology departments in Spain.

PURPOSE: We aimed to evaluate the current situation of electronic health records (EHRs) and patient registries in the oncology departments of hospitals in Spain. METHODS: This was a cross-sectional study conducted from December 2018 to September 2019. The survey was designed ad hoc by the Outcomes Evaluation and Clinical Practice Section of the Spanish Society of Medical Oncology (SEOM) and was distributed to all head of medical oncology department members of SEOM. RESULTS: We invited 148 heads of oncology departments, and 81 (54.7%) questionnaires were completed, with representation from all 17 Spanish autonomous communities. Seventy-seven (95%) of the respondents had EHRs implemented at their hospitals; of them, over 80% considered EHRs to have a positive impact on work organization and clinical practice, and 73% considered that EHRs improve the quality of patient care. In contrast, 27 (35.1%) of these respondents felt that EHRs worsened the physician-patient relationship and conveyed an additional workload (n = 29; 37.6%). Several drawbacks in the implementation of EHRs were identified, including the limited inclusion of information on both outpatients and inpatients, information recorded in free text data fields, and the availability of specific informed consent. Forty-six (56.7%) respondents had patient registries where they recorded information from all patients seen in the department. CONCLUSION: Our study indicates that EHRs are almost universally implemented in the hospitals surveyed and are considered to have a positive impact on work organization and clinical practice. However, EHRs currently have several drawbacks that limit their use for investigational purposes. CLINICAL TRIAL REGISTRATION: Not applicable.

A retrospective, multicenter study of the efficacy of lapatinib plus trastuzumab in HER2-positive metastatic breast cancer patients previously treated with trastuzumab, lapatinib, or both: the Trastyvere study.

PURPOSE: To evaluate the efficacy and safety of lapatinib (L) and trastuzumab (T) combination in HER2-positive metastatic breast cancer (MBC) patients previously treated with T and/or L. MATERIALS AND METHODS: We conducted a retrospective, post-authorized, multicenter study including patients with HER2-positive MBC or locally advanced breast cancer (ABC) treated with the combination of L-T. Concomitant endocrine therapy, as well as brain metastasis and/or prior exposure to L, were allowed. RESULTS: One hundred and fifteen patients from 14 institutions were included. The median age was 59.8 years. The median number of prior T regimens in the advanced setting was 3 and 73 patients had received a prior L regimen. The clinical benefit rate (CBR) was 34.8% (95% CI 26.1-43.5). Among other efficacy endpoints, the overall response rate was 21.7%, and median progression-free survival (PFS) and overall survival were 3.9 and 21.6 months, respectively. Heavily pretreated and ≥ 3 metastatic organ patients showed lower CBR and PFS than patients with a low number of previous regimens and < 3 metastatic organs. Moreover, CBR did not significantly change in L-pretreated compared with L-naïve patients (31.5% versus 40.5% for L-pretreated versus L-naïve). Grade 3/4 adverse events were reported in 19 patients (16.5%). CONCLUSION: The combination of L-T is an effective and well-tolerated regimen in heavily pretreated patients and remains active among patients progressing on prior L-based therapy. Our study suggests that the L-T regimen is a safe and active chemotherapy-free option for MBC patients previously treated with T and/or L.

Non-pegylated liposomal doxorubicin combined with gemcitabine as first-line treatment for metastatic or locally advanced breast cancer. Final results of a phase I/II trial.

Doxorubicin and gemcitabine are active as single agents in breast cancer, have different mechanisms of action, and mainly have non-overlapping side effects. Dose-dependent doxorubicin-related cardiac toxicity is the principal limitation in the metastatic setting. This open, multicenter, single-arm phase I/II study assessed the safety and activity of gemcitabine in combination with non-pegylated liposomal doxorubicin (Myocet), a more cardiac-friendly anthracycline, in the first-line treatment of patients with advanced breast cancer. We aimed to determine the optimal recommended dose (RD) of gemcitabine combined with Myocet in a population, with performance status >or=2 and LVEF >or=50%. A formal phase II study was performed afterwards. A total of 53 patients were recruited. Gemcitabine 900 mg/m(2) intravenously day 1 and 8 combined with Myocet 55 mg/m(2) intravenously day 1, every 21 days, was the final RD. The principal toxicity observed was hematological, and 48% of patients developed grade 3-4 neutropenia. Other toxicities were mild and infrequent, including nausea and vomiting. There were no symptomatic cardiac events despite the fact that 36% of the patients had received prior treatment with adjuvant anthracyclines. Objective responses were observed in 51.1% of 47 evaluable patients (95% CI: 36-66%), including two complete response. In addition, 14 patients (29.8%) demonstrated stable disease. The combination of Myocet and gemcitabine at the RD is safe and has encouraging clinical activity in patients with advanced breast cancer, without apparent cardiac toxicity in anthracycline-pretreated patients. These data support further development of this combination.

GSTP1 and MTHFR polymorphisms are related with toxicity in breast cancer adjuvant anthracycline-based treatment.

We have analyzed several members of drug-metabolizing enzymes (DMEs) and other polymorphisms in genes implicated in tumor aggressivity regarding possible links between specific genetic variability in systemic drug bioavailability and toxicity in breast cancer patients treated with adjuvant anthracycline-based treatment. PCR-RFLP and sequencing analyses technique were used for evaluating fourteen previously identified polymorphisms in 94 patients. GSTP1A>G and MTHFR 1298A>C genotypes remained as significant predictors in a multivariate logistic regression analysis. GSTP1 polymorphism was linked to haematological GIII-IV toxicity (P = 0.044, HR= 6.4, 95% CI = 1.05 to 39. Increased and significant HR was obtained for MTHFR-1298 AC+CC group when non-haematological toxicities GIII-IV toxicities were evaluated (HR = 24; 95% CI = 2.3 to 254), P = 0.008. Our results suggest that GSTP1 and MTHFR genotypes may be consider relevant and independent factors of toxicity in adjuvant anthracycline-based treatment of breast cancer.

A definition for aggressive disease in patients with HER-2 negative metastatic breast cancer: an expert consensus of the Spanish Society of Medical Oncology (SEOM).

PURPOSE: To converge on an expert opinion to define aggressive disease in patients with HER2-negative mBC using a modified Delphi methodology. METHODS: A panel of 21 breast cancer experts from the Spanish Society of Medical Oncology agreed upon a survey which comprised 47 questions that were grouped into three sections: relevance for defining aggressive disease, aggressive disease criteria and therapeutic goals. Answers were rated using a 9-point Likert scale of relevance or agreement. RESULTS: Among the 88 oncologists that were invited to participate, 81 answered the first round (92%), 70 answered the second round (80%), and 67 answered the third round (76%) of the survey. There was strong agreement regarding the fact that identifying patients with aggressive disease needs to be adequately addressed to help practitioners to decide the best treatment options for patients with HER2-negative mBC. The factors that were considered to be strongly relevant to classifying patients with aggressive HER2-negative mBC were a high tumor burden, a disease-free interval of less than 12-24 months after surgery, the presence of progressive disease during adjuvant or neoadjuvant chemotherapy and having a triple-negative phenotype. The main therapeutic goals were controlling symptoms, improving quality of life and increasing the time to progression and overall survival. CONCLUSIONS: High tumor burden, time to recurrence after prior therapy and having a triple-negative phenotype were the prognostic factors for which the greatest consensus was found for identifying patients with aggressive HER2-negative mBC. Identifying patients with aggressive disease leads to different therapeutic approaches.

Potential application of GSTT1-null genotype in predicting toxicity associated to 5-fluouracil irinotecan and leucovorin regimen in advanced stage colorectal cancer patients.

Our aim was to evaluate the role of C-69T in GSTA1, Ile105Val in GSTP1, null allele in GSTT1 and GSTM1 in the prediction of toxicity in patients treated with 5-Fu/CPT-11/Lv regimens in metastatic CRC patients. Fifty-one patients with CRC metastatic disease were analysed. All patients had bidimensionally measurable disease according to WHO criteria. The gender distribution was 37 (74%) males and 13 (26%) females; age ranged from 41 to 71 years; performance status was in all patients > or = 80 (Karnofsky index). The analysis of gene polymorphism was performed in lymphocytes by using PCR-RFLP (GSTA1, GSTP1), PCR (GSTT1, GSTM1) and sequencing analysis (UGT1A1 *28). An appreciable significant association was observed between the GSTT1-null and toxicity: 57% developed gastrointestinal toxicity grade III versus 23% of patients with GSTT1-present genotype (p = 0.053). The other polymorphisms analysed did not show any significant relation with toxicity. Our data suggest that GSTT1-null is associated with a greater probability of developing toxicity to 5-Fu/CPT-11/Lv treatments, indicating a potential application of this genetic analysis in predicting adverse effects of this regimen.

Final results of a phase II study of paclitaxel, bevacizumab, and gemcitabine as first-line therapy for patients with HER2-negative metastatic breast cancer.

BACKGROUND: Efficacy and safety data for combining bevacizumab, gemcitabine, and paclitaxel for locally advanced/metastatic breast cancer are limited. PATIENTS AND METHODS: AVALUZ trial evaluates the combination of bevacizumab 10 mg/kg, gemcitabine 2,000 mg/m(2) plus paclitaxel 150 mg/m(2), on days 1 and 15 of each 28-day course in previously untreated HER-2 negative patients. RESULTS: Median progression-free survival (PES): 12.3 months. The overall response and clinical benefit rate (CR + PR + SD) were 72 % (95 % CI 60.9-82.0 %) and 89 % (95 % CI 80.3-95.3 %), respectively. Median overall survival: 27.4 mo. Baseline circulating tumor cell (CTCs) ≥2 versus CTCs <2 was associated with lower PFS, p = 0.046. Overall response was significantly greater in patients with intense angiotensin type 1 receptor (AGTR1) expression (99 vs. 60 % [p = 0.021]). The most frequent grade 3/4 adverse events were: neutropenia (10 %); febrile neutropenia (1 %); sensory neuropathy (13 %); and asthenia (6 %). Grade 3 adverse events of interest with bevacizumab included bleeding (1 %) and hypertension (4 %). One patient developed cardiac ischemia (1 %). CONCLUSIONS: Adding bevacizumab to chemotherapy appeared feasible and well tolerated, producing toxicity comparable to other effective combined first-line regimens. Baseline circulating endothelial cells and AGTR1 expression are predictive of PFS and response.

The quotient of number of nodes and tumour size (N/T) from primary breast cancer predicts the clinical course after diagnosis of distant relapse.

INTRODUCTION: Breast cancer is a disease with a very variable progression. Primary tumour size and metastatic lymph node involvement are the best indicators of the likelihood of relapse. However, their value in predicting progression following relapse is not clear. AIM: The aim of this study was to asses whether the relationship between tumour size and the number of lymph nodes involved had any value as predictive factors of post-relapse progression. METHOD: We established an index defined as the quotient between the number of diseased lymph nodes and the tumour size (in cm). RESULTS: Applying this index in 230 consecutive patients with metastatic breast cancer, we observed that there was a significant inverse relation between the index and post-relapse progression. CONCLUSION: We conclude that, at the time of initial diagnosis, the quotient of tumour size and the number of diseased lymph nodes could be a good predictor of time-to-progression following the diagnosis of the metastatic disease.

Epirubicin-cyclophosphamide adjuvant chemotherapy plus tamoxifen administered concurrently versus sequentially: randomized phase III trial in postmenopausal node-positive breast cancer patients. A GEICAM 9401 study.

BACKGROUND: A prospective randomized clinical trial was implemented to assess whether the concomitant or the sequential addition of tamoxifen to chemotherapy provides improved clinical benefit in the adjuvant treatment of breast cancer in postmenopausal patients. PATIENTS AND METHODS: Four-hundred and eighty-five patients with node-positive operable disease were randomized to receive tamoxifen (20 mg/day) concomitantly (CON) or sequentially (SEQ) to EC chemotherapy (epirubicin 75 mg/m(2) + cyclophosphamide 600 mg/m(2) on day 1, every 21 days for four cycles). RESULTS: In the 474 fully evaluable patients there were 96 events; eight being second neoplasms and 88 being related to the breast cancer. Of these, 48 of 88 occurred in the CON arm and 40 of 88 in the SEQ arm. The Kaplan-Meier estimation of disease-free survival (DFS) at 5 years was 70% in the CON and 75% in the SEQ group (log-rank test, P = 0.43). Adjusted hazard ratio for treatment was 1.11 (95% confidence interval 0.71-1.73; P = 0.64). CONCLUSION: This study fails to show an advantage of one treatment arm over the other, but a trend, albeit non-significant, appears to favor the sequential addition of tamoxifen to epirubicin + cyclophosphamide and, as such, warrants further investigation.