[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Management of BM mainly relies on local treatment approaches including whole brain radiotherapy (WBRT), radiosurgery,
and neurosurgery depending on number and size of BM. Of note, WBRT is associated with severe late-toxicity. Recently, lapatinib
plus capecitabine (LapCap) as primary systemic treatment in oligosymptomatic patients (pts) with multiple Her2-positive BM
was shown to achieve considerable response and delay the need for WBRT. T-DM1 (trastuzumab-emtansine) is an antibody-drug
conjugate linking trastuzumab (T) to an anti-microtubule agent. T-DM1 provides activity in pts progressing upon T and has
lower toxicity as compared to LapCap. Here, we investigated the activity of T-DM1 in newly diagnosed or progressive BM. PATIENTS
AND METHODS: Six pts (median age 55 years) with Her2-positive breast cancer and BM were treated with T-DM1. Two asymptomatic
pts received T-DM1 as first line therapy for brain metastatic disease, while four pts received local therapy before and had
documented CNS progression at inclusion. T-DM1 was administered intravenously at a dose of 3.6 mg/kg body weight every three
weeks; re-assessment of disease status was performed every three cycles. At baseline and restaging, MRI was performed. CNS
response was defined as a reduction of lesion size of ≥50%. RESULTS: Median follow-up was 6 months (m). All pts had received
prior T, 3/6 (50%) had already received LapCap, and 2/6 (33.3%) pertuzumab. Currently, 4/6 pts (66.6%) are assessable for
CNS response. Two/4 pts (50%) had partial remission, while one patient progressing upon prior local therapy had stable disease.
One/6 (16.6%) patient had minor response on MRI but no reduction of pre-existing brain oedema and increasing cortisol doses
and was therefore deemed PD. A significant LVEF drop was observed in one heavily pretreated patient. CONCLUSION: This prospective
case series again indicates that systemic therapy offers activity in Her2-positive BM. Currently, primary systemic treatment
with LapCap remains the standard of care. Still, T-DM1 is well tolerated and offers relevant clinical activity; therefore,
the role of T-DM1 in BM should be investigated in larger studies.
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Dec 2013 · Annals of Oncology
[Show abstract][Hide abstract] ABSTRACT: 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.
In this retrospective chart review, cases of male breast cancer patients treated with AIs with or without a GnRH analogue were evaluated.
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.
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.
Full-text · Article · May 2013 · British Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
BMI impacts on the efficacy of aromatase inhibitor-based treatment but not single tamoxifen.
Full-text · Article · Mar 2013 · British Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
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.
Full-text · Article · Oct 2012 · British Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: 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 ⩾18years with human epidermal growth factor receptor-2-negative breast adenocarcinoma were randomised to Arm A: bevacizumab 10mg/kg days 1 and 15; paclitaxel 90mg/m(2) days 1, 8, and 15, every 4weeks; or Arm B: bevacizumab 15mg/kg day 1; capecitabine 1000mg/m(2) b.i.d., days 1-14, every 3weeks, 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.
No preview · Article · May 2012 · European journal of cancer (Oxford, England: 1990)
[Show abstract][Hide abstract] ABSTRACT: Background
Denosumab was superior to zoledronic acid (ZA) in reducing the risk of a first on-study skeletal-related event (SRE; HR, 0.82; 95% confidence interval (CI) 0.71, 0.95; p = 0.01) in patients with breast cancer and bone metastases (BMs; Stopeck et al., 2010). All patients who remained on treatment after the primary analysis were offered open-label (OL) denosumab for a pre-specified 2-year extension phase.
Women with BMs secondary to breast cancer (N = 2046) were randomly assigned to subcutaneous denosumab 120 mg or IV ZA 4 mg (adjusted for renal function) Q4W. Patients who completed this double-blind, double-dummy treatment phase were offered OL denosumab Q4W. Patients who did not participate in the OL phase were followed up for survival every 12 weeks for up to 2 years after their last dose of investigational drug.
Of the 752 patients who completed the double-blind phase, 667 (89%) chose to receive OL denosumab: 325 initially randomly assigned to denosumab (DD) and 342 to ZA (ZD). Total median (Q1, Q3) cumulative denosumab exposure in DD patients was 19.3 months (9.2, 32.2) (range 0.9–59.8 months). Adverse events (AEs) were comparable between groups (n = 283/318 [89%] for DD; n = 303/334 [91%] ZD) during the OL phase; 20 and 18 patients, respectively, reported osteonecrosis of the jaw; cumulative incidence was 4.7% in DD patients and 3.5% in ZD patients for the entire study duration of 5 years. Hypocalcaemia was comparable between groups (n = 12 DD; n = 9 ZD). Serious AEs were reported in 126 (39.6%) DD patients and 133 (39.8%) ZD patients. Overall survival was similar between the groups for the entire study: median 34.4 months (95% CI 31.5, 39.3) and 34.2 months (95% CI 31.0, 37.6), respectively.
This OL extension treatment phase confirmed the safety profile of denosumab in patients with breast cancer with BMs receiving up to 5 years of monthly denosumab therapy or switching to denosumab after up to 3 years of ZA.
Funding was provided by Amgen Inc.
A.T. Stopeck is a consultant for Amgen and Novartis; A. Lipton is a member of the speakers’ bureau, is a consultant, has received research support from Amgen and Novartis, and has provided expert testimony for Novartis; M. Martín is a consultant for Amgen; J-J. Body is a consultant for and has received lecture fees from both Amgen and Novartis; A. Paterson has received honoraria for speaking from Amgen, Roche, and Novartis; G.G. Steger has received travel grants and attended advisory boards for Amgen and Novartis; K. Tonkin has no disclosures; R.H. de Boer has no disclosures; Y. Fujiwara, Chugai Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma KK, Janssen Pharmaceutical KK, and Takeda Bio Development Center Limited; D. Yardley has no disclosures; J. Jassem has no disclosures; T. Takano is a medical consultant for Daiichi Sankyo; P. Solal-Céligny has no disclosures; and M. Fan and A. Braun are employed by Amgen and own stock.
[Show abstract][Hide abstract] ABSTRACT: 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 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.
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.
Combination therapy of adecatumumab and docetaxel is safe, feasible, and potentially active in heavily pretreated advanced-stage breast cancer.
No preview · Article · Feb 2012 · Annals of Oncology
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
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.
Full-text · Article · Jan 2012 · British Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
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.
Full-text · Article · Nov 2011 · British Journal of Cancer