Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study.

BACKGROUND: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. PATIENTS AND METHODS: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. RESULTS: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. CONCLUSION: Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.

Primary surgery versus no surgery in synchronous metastatic breast cancer: patient-reported quality-of-life outcomes of the prospective randomized multicenter ABCSG-28 Posytive Trial.

BACKGROUND: The ABCSG-28 trial compared primary surgery followed by systemic therapy versus primary systemic therapy without surgery in patients with de novo stage IV BC. The present report describes QoL results of this trial. METHODS: Ninety patients with primary operable MBC were randomised to surgery of the primary tumor followed by systemic therapy or to primary systemic therapy without surgery. QoL analyses covering the results at baseline, 6,12,18 and 24 months follow up of 79 (88%) patients, was assessed with the EORTC QLQ-C30 and QLQ-BR23 questionnaires. RESULTS: There were no statistically significant differences in any of the scales of the QLQ-C30 and QLQ-BR23 questionnaires between the two groups over the time. Baseline global health status and physical functioning were predictors for OS (patients with a higher score lived longer (p=0.0250, p=0.0225; p=0.0355, p=0.0355)). Global health status, social functioning scale, breast symptoms and future perspective were predictors for longer TTPd (p=0.0244; p=0.0140, p=0.020; p=0.0438, p=0.0123). Patients in both arms reported significant improvement on the emotional functioning scale. Cognitive functioning decreased over time in both groups. Younger women had clinically relevant better physical and sexual functioning scores (p=0.039 and 0.024). CONCLUSION: Primary surgery does not improve nor alter QoL of patients with de novo stage IV BC. Global health status and physical functioning were predictors for OS and could be use as additional marker for prediction of OS and TTTd in patients with de novo stage IV BC. TRIAL REGISTRATION: The trial is registered on clinicaltrial.gov (NCT01015625, date of registration:18/11/2009).

Impact of Surgical Margins in Breast Cancer After Preoperative Systemic Chemotherapy on Local Recurrence and Survival.

BACKGROUND: While "no tumour on ink" is an accepted margin width for R0 resection in primary surgery, it's unclear if it's oncologically safe after neoadjuvant chemotherapy (NAC). Only limited data demonstrate that surgery within new margins in cases of a pathological complete response (pCR) is safe. We therefore investigated the influence of different margins and pCR on local recurrence and survival rates after NAC. METHODS: We retrospectively analysed data of 406 women with invasive breast cancer, treated with NAC and breast-conserving therapy between 1994 and 2014 in two certified Austrian breast health centres. We compared R ≤ 1 mm, R > 1 mm and RX (pCR) for local recurrence-free survival (LRFS), disease-free survival (DFS) and overall survival (OS). RESULTS: After a median follow-up of 84.3 months, the 5-year LRFS (R ≤ 1 mm: 94.2%, R > 1 mm: 90.6%, RX: 95.0%; p = 0.940), the 5-year DFS (R ≤ 1 mm: 71.9%, R > 1 mm: 74.1%, RX: 87.2%; p = 0.245) and the 5-year OS (R ≤ 1 mm: 85.1%, R > 1 mm: 88.0%, RX: 96.4%; p = 0.236) did not differ significantly between narrow, wide, nor RX resections. Regarding DFS and OS, a negative nodal status reduced the hazard ratio significantly. CONCLUSION: There is no significant difference in LRFS, DFS and OS comparing close, wide or unknown margins after pCR. We suggest that resection in new margins after NAC is safe according to "no tumour on ink". Resection of the clipped area in cases of pCR is emphasized.

Dose tailoring of adjuvant chemotherapy for breast cancer based on hematologic toxicities: further results from the prospective PANTHER study with focus on obese patients.

Background: Adjuvant chemotherapy (ACT) for breast cancer improves relapse-free survival (BCRFS) and overall survival. Differences in terms of efficacy and toxicity could partly be explained by the significant interpatient variability in pharmacokinetics which cannot be captured by dosing according to body surface area. Consequently, tailored dosing was prospectively evaluated in the PANTHER trial. Patients and methods: PANTHER is a multicenter, open-label, randomized phase III trial which compared tailored, dose-dense (DD) epirubicin/cyclophosphamide (E/C) and tailored docetaxel (D) (tDD) with standard interval 5-fluorouracil/E/C and D. The primary end point was BCRFS and the primary efficacy analysis has been previously published. In this secondary analysis, we aimed to retrospectively explore the concept of dose tailoring. Our two hypotheses were that BCRFS would not vary depending on the cumulative administered epirubicin dose; and that dose tailoring would lead to appropriate dosing and improved outcomes for obese patients, who are known to have worse prognosis and increased toxicity after DD ACT. Results: Patients treated with tDD had similar BCRFS regardless of the cumulative epirubicin dose (P = 0.495), while obese patients in this group [body mass index (BMI) ≥30] had improved BCRFS compared with nonobese ones (BMI <30) [hazard ratio (HR) = 0.51, 95% confidence interval (CI) 0.30-0.89, P = 0.02]. Moreover, tDD was associated with improved BCRFS compared with standard treatment only in obese patients (HR = 0.49, 95% CI 0.26-0.90, P = 0.022) but not in nonobese ones (HR = 0.79, 95% CI 0.60-1.04, P = 0.089). The differences were not formally statistically significant (P for interaction 0.175). There were no differences in terms of toxicity across the epirubicin dose levels or the BMI groups. Conclusions: Dose tailoring is a feasible strategy that can potentially improve outcomes in obese patients without increasing toxicity and should be pursued in further clinical studies. ClinicalTrials.gov identifier: NCT00798070.

Metastatic or locally advanced breast cancer patients: towards an expert consensus on nab-paclitaxel treatment in HER2-negative tumours-the MACBETH project.

INTRODUCTION: Despite the large use of nab-paclitaxel as a treatment option in metastatic breast cancer (MBC) across different countries, no definitive data are available in particular clinical situations. AREAS COVERED: Efficacy, safety and schedule issues concerning available literature on nab-paclitaxel in advanced breast cancer and in specific subgroups of patients have been discussed and voted during an International Expert Meeting. Ten expert specialists in oncology, with extensive clinical experience on Nab-P and publications in the field of MBC have been identified. Six scientific areas of interest have been covered, generating 13 specific Statements for Nab-P, after literature review. For efficacy issues, a summary of research quality was performed adopting the GRADE algorithm for evidence scoring. The panel members were invited to express their opinion on the statements, in case of disagreement all the controversial opinions and the relative motivations have been made public. EXPERT OPINION: Consensus was reached in 30.8% of the Nab-P statements, mainly those regarding safety issues, whereas ones regarding efficacy and schedule still remain controversial areas, requiring further data originated by the literature.

Propagation and some physiological effects of Citrus bark cracking viroid and Apple fruit crinkle viroid in multiple infected hop (Humulus lupulus L.).

The hop metabolome important for the brewing industry and for medical purposes is endangered worldwide due to multiple viroid infections affecting hop physiology. Combinatorial biolistic hop inoculation with Citrus bark cracking viroid (CBCVd), Apple fruit crinkle viroid (AFCVd), Hop latent viroid, and Hop stunt viroid (HSVd) showed a low CBCVd compatibility with HSVd, while all other viroid combinations were highly compatible. Unlike to other viroids, single CBCVd propagation showed a significant excess of (-) over (+) strands in hop, tomato, and Nicotiana benthamiana, but not in citruses. Inoculation of hop with all viroids led to multiple infections with unstable viroid levels in individual plants in the pre- and post-dormancy periods, and to high plant mortality and morphological disorders. Hop isolates of CBCVd and AFCVd were highly stable, only minor quasispecies were detected. CBCVd caused a strong suppression of some crucial mRNAs related to the hop prenylflavonoid biosynthesis pathway, while AFCVd-caused effects were moderate. According to mRNA degradome analysis, this suppression was not caused by a direct viroid-specific small RNA-mediated degradation. CBCVd infection led to a strong induction of two hop transcription factors from WRKY family and to a disbalance of WRKY/WDR1 complexes important for activation of lupulin genes.

Final efficacy and updated safety results of the randomized phase III BEATRICE trial evaluating adjuvant bevacizumab-containing therapy in triple-negative early breast cancer.

BACKGROUND: The purpose of this analysis was to assess the long-term impact of adding bevacizumab to adjuvant chemotherapy for early triple-negative breast cancer (TNBC). METHODS: Patients eligible for the open-label randomized phase III BEATRICE trial had centrally confirmed triple-negative operable primary invasive breast cancer (pT1a-pT3). Investigators selected anthracycline- and/or taxane-based chemotherapy for each patient. After definitive surgery, patients were randomized 1:1 to receive ≥4 cycles of chemotherapy alone or with 1 year of bevacizumab (5 mg/kg/week equivalent). Stratification factors were nodal status, selected chemotherapy, hormone receptor status, and type of surgery. The primary end point was invasive disease-free survival (IDFS; previously reported). Secondary outcome measures included overall survival (OS) and safety. RESULTS: After 56 months' median follow-up, 293 of 2591 randomized patients had died. There was no statistically significant difference in OS between treatment arms in either the total population (hazard ratio 0.93, 95% confidence interval [CI] 0.74-1.17; P = 0.52) or pre-specified subgroups. The 5-year OS rate was 88% (95% CI 86-90%) in both treatment arms. Updated IDFS results were consistent with the primary IDFS analysis. Five-year IDFS rates were 77% (95% CI 75-79%) with chemotherapy alone versus 80% (95% CI 77-82%) with bevacizumab. From 18 months after first study dose to study end, new grade ≥3 adverse events occurred in 4.6% and 4.5% of patients in the two arms, respectively. CONCLUSION: Final OS results showed no significant benefit from bevacizumab therapy for early TNBC. Late-onset toxicities were rare in both groups. Five-year OS and IDFS rates suggest that the prognosis for patients with TNBC is better than previously thought. CLINICALTRIALS.GOV: NCT00528567.

Prognostic impact of breast cancer subtypes in elderly patients.

We aimed to analyse the impact of breast cancer (BC) subtypes on the clinical course of disease with special emphasis on the occurrence of brain metastases (BM) and outcome in an elderly BC population. A total number of 706 patients ≥65 years receiving treatment for BC from 2007 to 2011 were identified from a BC database. 62 patients diagnosed with DCIS and 73 patients with incomplete datasets were excluded, leaving 571 patients for this analysis. Patient characteristics, biological tumour subtypes, and clinical outcome including overall survival (OS) were obtained by retrospective chart review. 380/571 (66, 5 %) patients aged 65-74 years were grouped among the young-old, 182/571 (31.9 %) patients aged 75-84 years among the old-old, and 29/571 (5.1 %) patients aged ≥85 years among the oldest-old. 392/571 (68.8 %) patients presented with luminal BC, 119/571 (20.8 %) with HER2-positive, and 59/571 (10.3 %) with triple-negative BC (TNBC). At 38 months median follow-up, 115/571 (20.1 %) patients presented with distant recurrence. A higher recurrence rate was observed in the HER2-positive subtype (43/119 (36.1 %)), as compared to TNBC (15/59 (25.4 %)) and luminal BC (57/392 (14.5 %); p < 0.001). BM were detected at a significantly higher rate in HER2-positive BC patients (9/119 (7.6 %)), as compared to TNBC (2/59 (3.4 %)) and luminal BC patients (6/392 (1.5 %); p = 0.003). Diagnosis of metastatic disease (HR 7.7; 95 % CI 5.2-11.4; p < 0.001) as well as development of BM (HR 3.5; 95 % CI 1.9-6.4; p < 0.001) had a significantly negative impact on OS in a time-dependent covariate cox regression model. In contrast to younger BC patients, outcome in this large cohort of elderly patients suggests that HER2-positive disease-not TNBC-featured the most aggressive clinical course with the highest rates of metastatic spread and BM. In-depth analysis regarding a potentially distinct biology of TNBC in elderly is therefore warranted.

Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12.

BACKGROUND: Zoledronic acid (ZOL) plus adjuvant endocrine therapy significantly improved disease-free survival (DFS) at 48- and 62-month follow-up in the ABCSG-12 trial. We present efficacy results of a final additional analysis after 94.4 months. PATIENTS AND METHODS: Patients were premenopausal women who had undergone primary surgery for stage I/II estrogen-receptor-positive and/or progesterone-receptor-positive breast cancer with <10 positive lymph nodes, and were scheduled for standard goserelin therapy. All 1803 patients received goserelin (3.6 mg every 28 days) and were randomized to tamoxifen (20 mg/days) or anastrozole (1 mg/days), both with or without ZOL (4 mg every 6 months) for 3 years. The primary end point was DFS; recurrence-free survival and overall survival (OS) were secondary end points. RESULTS: After 94.4-month median follow-up (range, 0-114 months), relative risks of disease progression [hazard ratio (HR) = 0.77; 95% confidence interval (CI) 0.60-0.99; P = 0.042] and of death (HR = 0.66; 95% CI 0.43-1.02; P = 0.064) are still reduced by ZOL although no longer significant at the predefined significance level. Overall, 251 DFS events and 86 deaths were reported. Absolute risk reductions with ZOL were 3.4% for DFS and 2.2% for OS. There was no DFS difference between tamoxifen alone versus anastrozole alone, but there was a pronounced higher risk of death for anastrozole-treated patients (HR = 1.63; 95% CI 1.05-1.45; P = 0.030). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. CONCLUSION: These final results from ABCSG 12 suggest that twice-yearly ZOL enhances the efficacy of adjuvant endocrine treatment, and this benefit is maintained long-term. CLINICALTRIALSGOV: NCT00295646 (http://www.clinicaltrials.gov/ct2/results?term=00295646).

Epirubicin and docetaxel with or without capecitabine as neoadjuvant treatment for early breast cancer: final results of a randomized phase III study (ABCSG-24).

BACKGROUND: This randomized phase III trial compared pathologic complete response (pCR) rates of early breast cancer (EBC) following neoadjuvant epirubicin-docetaxel (ED)±capecitabine (C), and evaluated the addition of trastuzumab in HER2-positive tumors. PATIENTS AND METHODS: Patients with invasive breast cancer (except T4d) were randomly assigned to receive six 3-weekly cycles of ED (both 75 mg/m2)±C (1000 mg/m2, twice daily, days 1-14). Patients with HER2-positive disease were further randomized to receive trastuzumab (8 mg/kg, then 6 mg/kg every 3 weeks) or not. Primary end point: pCR rate at the time of surgery. RESULTS: Five hundred thirty-six patients were randomized to ED (n=266) or EDC (n=270); 93 patients were further randomized to trastuzumab (n=44) or not (n=49). pCR rate was significantly increased with EDC (23.0% versus 15.4% ED, P=0.027), and nonsignificantly further increased with trastuzumab (38.6% EDC versus 26.5% ED, P=0.212). Rates of axillary node involvement at surgery and breast conservation were improved with EDC versus ED, but not significantly; the addition of trastuzumab had no further impact. Hormone receptor status, tumor size, grade, and C (all P≤0.035) were independent prognostic factors for pCR. Trastuzumab added to ED±C significantly increased the number of serious adverse events (35 versus 18; P=0.020), mainly due to infusion-related reactions. CONCLUSION: These findings show that the integration of C into a neoadjuvant taxane-/anthracycline-based regimen is a feasible, safe, and effective treatment option, with incorporation of trastuzumab in HER2-positive disease. CLINICAL TRIAL NUMBER: NCT00309556, www.clinicaltrials.gov.

Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone.

BACKGROUND: PAM50 is a 50-gene test that is designed to identify intrinsic breast cancer subtypes and generate a Risk of Recurrence (ROR) score. It has been developed to be carried out in qualified routine hospital pathology laboratories. PATIENTS AND METHODS: One thousand four hundred seventy-eight postmenopausal women with estrogen receptor (ER)+ early breast cancer (EBC) treated with tamoxifen or tamoxifen followed by anastrozole from the prospective randomized ABCSG-8 trial were entered into this study. Patients did not receive adjuvant chemotherapy. RNA was extracted from paraffin blocks and analyzed using the PAM50 test. Both intrinsic subtype (luminal A/B, HER2-enriched, basal-like) and ROR score were calculated. The primary analysis was designed to test whether the continuous ROR score adds prognostic value in predicting distant recurrence (DR) over and above standard clinical variables. RESULTS: In all tested subgroups, ROR score significantly adds prognostic information to the clinical predictor (P<0.0001). PAM50 assigns an intrinsic subtype to all cases, and the luminal A cohort had a significantly lower ROR at 10 years compared with Luminal B (P<0.0001). Significant and clinically relevant discrimination between low- and high-risk groups occurred also within all tested subgroups. CONCLUSION(S): The results of the primary analysis, in combination with recently published results from the ATAC trial, constitute Level 1 evidence for clinical validity of the PAM50 test for predicting the risk of DR in postmenopausal women with ER+ EBC. A 10-year metastasis risk of <3.5% in the ROR low category makes it unlikely that additional chemotherapy would improve this outcome-this finding could help to avoid unwarranted overtreatment. CLINICAL TRIAL NUMBER: ABCSG 8: NCT00291759.

The predictive impact of body mass index on the efficacy of extended adjuvant endocrine treatment with anastrozole in postmenopausal patients with breast cancer: an analysis of the randomised ABCSG-6a trial.

BACKGROUND: We investigated whether body mass index (BMI) can be used as a predictive parameter indicating patients who benefit from extended aromatase inhibitor (AI) treatment. METHODS: The ABCSG-6a trial re-randomised event-free postmenopausal hormone receptor-positive patients from the ABCSG-6 trial to receive either 3 additional years of endocrine therapy using anastrozole vs nil. In this retrospective analysis, we investigated the prognostic and predictive impact of BMI on disease outcome and safety. RESULTS: In all, 634 patients (177 normal weight, 307 overweight, and 150 obese) patients were included in this analysis. Normal weight patients with additional 3 years of anastrozole halved their risk of disease recurrence (disease-free survival (DFS) HR 0.48; P=0.02) and death (HR 0.45; P=0.06) and had only a fifth of the risk of distant metastases (HR 0.22; P=0.05) compared with normal weight patients without any further treatment. In contrast, overweight+obese patients derived no benefit from additional 3 years of anastrozole (DFS HR 0.93; P=0.68; distant recurrence-free survival HR 0.91; P=0.78; and OS HR 0.9; P=0.68). The possible predictive impact of BMI on extended endocrine treatment could be strengthened by a Cox regression interaction model between BMI and treatment (P=0.07). CONCLUSION: Body mass index may be used to predict outcome benefit of extended AI treatment in patients with receptor-positive breast cancer.

Aromatase inhibitors with or without gonadotropin-releasing hormone analogue in metastatic male breast cancer: a case series.

BACKGROUND: Data regarding the safety and effectiveness of aromatase inhibitors (AIs) as monotherapy or combined with gonadotropin-releasing hormone (GnRH) analogue in male breast cancer are scarce. METHODS: In this retrospective chart review, cases of male breast cancer patients treated with AIs with or without a GnRH analogue were evaluated. RESULTS: Twenty-three men were included into this case series. Aromatase inhibitors in combination with or without a GnRH analogue were given as first-line therapy in 60.9% and as second-line therapy in 39.1% of patients, respectively. All patients had visceral metastases, whereas in five of them bone lesions coexisted. In all cases AIs were tolerated well, and no case of grade 3 and 4 adverse events was reported. A partial response was observed in 26.1% of patients and stable disease in 56.5%. Median overall survival (OS) was 39 months and median progression-free survival (PFS) was 13 months. Regarding OS and PFS, no significant effects of GnRH analogue co-administration or type of AI were noted. CONCLUSION: Our study shows that AIs with or without GnRH analogues may represent an effective and safe treatment option for hormone-receptor positive, pretreated, metastatic, male breast cancer patients.

Efficacy of tamoxifen ± aminoglutethimide in normal weight and overweight postmenopausal patients with hormone receptor-positive breast cancer: an analysis of 1509 patients of the ABCSG-06 trial.

BACKGROUND: There exists evidence that body mass index (BMI) impacts on the efficacy of aromatase inhibitors in patients with breast cancer. The relationship between BMI and the efficacy of tamoxifen is conflicting. We investigated the impact of BMI on the efficacy of single tamoxifen and tamoxifen plus an aromatase inhibitor in the well-defined prospective study population of the ABCSG-06 trial. METHODS: ABCSG-06 investigated the efficacy of tamoxifen vs tamoxifen plus aminoglutethimide in postmenopausal women with hormone receptor-positive breast cancer. Taking BMI at baseline, patients were classified as normal weight (BMI=18.5-24.9 kg m(-)(2)), overweight (BMI=25-29.9 kg m(-)(2)), and obese (30 kg m(-)(2)) according to WHO criteria. RESULTS: Overweight+obese patients had an increased risk for distant recurrences (hazard ratio (HR): 1.51; Cox P=0·018) and a worse overall survival (OS; HR: 1·49; Cox P=0·052) compared with normal weight patients. Analysing patients treated with single tamoxifen only, no difference between overweight+obese patients and normal weight patients regarding distant recurrence-free survival (HR: 1.35; Cox P=0·24) and OS (HR: 0.99; Cox P=0·97) could be observed. In contrast, in the group of patients treated with the combination of tamoxifen plus aminoglutethimide, overweight+obese patients had an increased risk for distant recurrences (1.67; Cox P=0·03) and a worse OS (1.47; Cox P=0·11) compared with normal weight patients. CONCLUSION: BMI impacts on the efficacy of aromatase inhibitor-based treatment but not single tamoxifen.

Brain-only metastatic breast cancer is a distinct clinical entity characterised by favourable median overall survival time and a high rate of long-term survivors.

BACKGROUND: The clinical course of breast cancer patients with brain metastases (BM) as only metastatic site (brain-only metastatic breast cancer (BO-MBC)) has been insufficiently explored. METHODS: All breast cancer patients with BM treated at our institution between 1990 and 2011 were identified. For each patient, full information on follow-up and administered therapies was mandatory for inclusion. Oestrogen receptor, progesterone receptor and Her2 status were determined according to standard protocols. Statistical analyses including computation of survival probabilities was performed. RESULTS: In total, 222 female patients (26% luminal; 47% Her2; 27% triple negative) with BM of MBC were included in this study. In all, 38/222 (17%) BM patients did not develop extracranial metastases (ECM) during their disease course and were classified as BO-MBC. Brain-only-MBC was not associated with breast cancer subtype or number of BM. The median overall survival of BO-MBC patients was 11 months (range 0-69) and was significantly longer than in patients with BM and ECM (6 months, range 0-104; P=0.007). In all, 7/38 (18%) BO-MBC patients had long-term survival of >3 years after diagnosis of BM and long-term survival was significantly more common in BO-MBC patients as compared with BM patients with ECM (P<0.001). CONCLUSIONS: Brain-only metastatic behaviour occurs in around 17% of breast cancer with BM and is not associated with breast cancer subtype. Exploitation of all multimodal treatment options is warranted in BO-MBC patients, as these patients have favourable prognosis and long-term survival is not uncommon.

Safety results from a phase III study (TURANDOT trial by CECOG) of first-line bevacizumab in combination with capecitabine or paclitaxel for HER-2-negative locally recurrent or metastatic breast cancer.

BACKGROUND: We report safety data from a randomised, phase III study (CECOG/BC.1.3.005) evaluating first-line bevacizumab plus paclitaxel or capecitabine for locally recurrent or metastatic breast cancer. PATIENTS AND METHODS: Patients aged ≥18 years with human epidermal growth factor receptor-2-negative breast adenocarcinoma were randomised to Arm A: bevacizumab 10 mg/kg days 1 and 15; paclitaxel 90 mg/m(2) days 1, 8, and 15, every 4 weeks; or Arm B: bevacizumab 15 mg/kg day 1; capecitabine 1000 mg/m(2) b.i.d., days 1-14, every 3 weeks, until disease progression, unacceptable toxicity or consent withdrawal. RESULTS: A post hoc interim safety analysis included 561 patients (Arm A: 284, Arm B: 277). The regimens demonstrated similar frequencies of all-grade and serious adverse events (SAEs), but different safety profiles. Treatment-related events occurred in 85.2% (Arm A) and 78.0% (Arm B) of patients. Fatigue was most common in Arm A (30.6% versus 23.5% Arm B), and hand-foot syndrome (HFS) most common in Arm B (49.5% versus 2.5% Arm A). Diarrhoea (Arm A: 0.4%, Arm B: 1.4%) and pulmonary embolism (Arm A: 0.7%, Arm B: 1.1%) were the most frequently reported SAEs. CONCLUSION: These findings are in-line with safety data for bevacizumab plus paclitaxel or capecitabine, reported in previous phase III trials.

Phase IB study of the EpCAM antibody adecatumumab combined with docetaxel in patients with EpCAM-positive relapsed or refractory advanced-stage breast cancer.

BACKGROUND: Targeted therapy options in HER2-negative breast cancer are limited. This open-label, multicenter phase IB dose-escalation trial was conducted to determine safety, tolerability, and antitumor activity of a combination of docetaxel (Taxotere) and increasing doses of adecatumumab, a human IgG1 antibody targeting epithelial cell adhesion molecule (EpCAM), in EpCAM-positive relapsed or primary refractory advanced-stage breast cancer. PATIENTS AND METHODS: Patients pretreated with up to four prior chemotherapy regimens received increasing adecatumumab doses either every 3 weeks (q3w) or weekly (qw) combined with docetaxel (100 mg/m(2) q3w). Primary end points were safety and tolerability. Antitumor activity was evaluated according to RECIST. Clinical benefit was defined as complete or partial response or stable disease for ≥24 weeks. RESULTS: Thirty-one evaluable patients were treated. Most adverse events were mild to moderate in severity. Neutropenia, leukocytopenia, lymphopenia, and diarrhea (dose-limiting) were the most frequent toxic effects. Maximum tolerated doses of adecatumumab given in combination with docetaxel were 550 mg/m(2) q3w and 360 mg/m(2) qw. Clinical benefit was observed in 44% of patients treated with q3w adecatumumab and docetaxel, increasing to 63% in patients with high EpCAM-expressing tumors. CONCLUSION: Combination therapy of adecatumumab and docetaxel is safe, feasible, and potentially active in heavily pretreated advanced-stage breast cancer.

Brain metastases free survival differs between breast cancer subtypes.

BACKGROUND: Brain metastases (BM) are frequently diagnosed in patients with HER-2-positive metastatic breast cancer; in addition, an increasing incidence was reported for triple-negative tumours. We aimed to compare brain metastases free survival (BMFS) of breast cancer subtypes in patients treated between 1996 until 2010. METHODS: Brain metastases free survival was measured as the interval from diagnosis of extracranial breast cancer metastases until diagnosis of BM. HER-2 status was analysed by immunohistochemistry and reanalysed by fluorescent in situ hybridisation if a score of 2+ was gained. Oestrogen-receptor (ER) and progesterone-receptor (PgR) status was analysed by immunohistochemistry. Brain metastases free survival curves were estimated with the Kaplan-Meier method and compared with the log-rank test. RESULTS: Data of 213 patients (46 luminal/124 HER-2/43 triple-negative subtype) with BM from breast cancer were available for the analysis. Brain metastases free survival differed significantly between breast cancer subtypes. Median BMFS in triple-negative tumours was 14 months (95% CI: 11.34-16.66) compared with 18 months (95% CI: 14.46-21.54) in HER-2-positive tumours (P=0.001) and 34 months (95% CI: 23.71-44.29) in luminal tumours (P=0.001), respectively. In HER-2-positive patients, co-positivity for ER and HER-2 prolonged BMFS (26 vs 15 m; P=0.033); in luminal tumours, co-expression of ER and PgR was not significantly associated with BMFS. Brain metastases free survival in patients with lung metastases was significantly shorter (17 vs 21 months; P=0.014). CONCLUSION: Brain metastases free survival in triple-negative breast cancer, as well as in HER-2-positive/ER-negative, is significantly shorter compared with HER-2/ER co-positive or luminal tumours, mirroring the aggressiveness of these breast cancer subtypes.

Impact of anti-HER2 therapy on overall survival in HER2-overexpressing breast cancer patients with brain metastases.

BACKGROUND: Trastuzumab-based therapy after diagnosis of brain metastases (BM) may improve survival due to prolonged systemic disease control. We investigated whether lapatinib may yield additional survival benefit. METHODS: Eighty patients with BM from HER2-positive breast cancer were identified. Karnofsky Performance Score (KPS) of at least 70 was required. We included a control group of 37 patients treated before 2003, when continuation of trastuzumab after diagnosis of BM was not yet recommended. Remainders received either trastuzumab or lapatinib and trastuzumab (either concomitantly or sequentially) with or without chemotherapy. RESULTS: Median overall survival (OS) in patients receiving trastuzumab after diagnosis of BM was 13 months; corresponding numbers were 9 months in patients treated with chemotherapy, and 3 months with radiotherapy alone. Median OS was not reached in the lapatinib group. Addition of lapatinib prolonged OS over trastuzumab alone (P=0.002). After correction for potential confounders, lapatinib therapy remained an independent positive predictor for survival (HR 0.279; P=0.012). INTERPRETATION: This retrospective single-centre study suggests that the introduction of lapatinib improved survival in patients with BM from HER2-positive breast cancer. Patients with KPS ≥70 may benefit when treated with lapatinib in addition to trastuzumab after completion of local therapy.