Initial experience with CDK4/6 inhibitor-based therapies compared to antihormone monotherapies in routine clinical use in patients with hormone receptor positive, HER2 negative breast cancer - Data from the PRAEGNANT research network for the first 2 years of drug availability in Germany.

PURPOSE: Treatment with CDK4/6 inhibitors and endocrine therapy (CDK4/6i + ET) is a standard for patients with advanced hormone receptor-positive, HER2-negative (HR + HER2-) breast cancer (BC). However, real-world data on the implementation of therapy usage, efficacy, and toxicity have not yet been reported. METHODS: The PRAEGNANT registry was used to identify advanced HR + HER2- BC patients (n = 1136). The use of chemotherapy, ET, everolimus + ET, and CDK4/6i + ET was analyzed for first-line, second-line, and third-line therapy. Progression-free survival (PFS) and overall survival (OS) were also compared between patients treated with CDK4/6i + ET and ET monotherapy. Also toxicity was assessed. RESULTS: CDK4/6i + ET use increased from 38.5% to 62.7% in the first 2 years after CDK4/6i treatment became available (November 2016). Chemotherapy and ET monotherapy use decreased from 2015 to 2018 from 42.2% to 27.2% and from 53% to 9.5%, respectively. In this early analysis no statistically significant differences were found comparing CDK4/6i + ET and ET monotherapy patients with regard to PFS and OS. Leukopenia was was seen in 11.3% of patients under CDK4/6i + ET and 0.5% under ET monotherapy. CONCLUSIONS: In clinical practice, CDK4/6i + ET has been rapidly implemented. A group of patients with a more unfavorable prognosis was possibly treated in the real-world setting than in the reported randomized clinical trials. The available data suggest that longer follow-up times and a larger sample size are required in order to identify differences in survival outcomes. Studies should be supported that investigate whether chemotherapy can be avoided or delayed in this patient population by using CDK4/6i + ET.

Therapy Landscape in Patients with Metastatic HER2-Positive Breast Cancer: Data from the PRAEGNANT Real-World Breast Cancer Registry.

This study presents comprehensive real-world data on the use of anti-human epidermal growth factor receptor 2 (HER2) therapies in patients with HER2-positive metastatic breast cancer (MBC). Specifically, it describes therapy patterns with trastuzumab (H), pertuzumab + trastuzumab (PH), lapatinib (L), and trastuzumab emtansine (T-DM1). The PRAEGNANT study is a real-time, real-world registry for MBC patients. All therapy lines are documented. This analysis describes the utilization of anti-HER2 therapies as well as therapy sequences. Among 1936 patients in PRAEGNANT, 451 were HER2-positive (23.3%). In the analysis set (417 patients), 53% of whom were included in PRAEGNANT in the first-line setting, 241 were treated with H, 237 with PH, 85 with L, and 125 with T-DM1 during the course of their therapies. The sequence PH → T-DM1 was administered in 51 patients. Higher Eastern Cooperative Oncology Group (ECOG) scores, negative hormone receptor status, and visceral or brain metastases were associated with more frequent use of this therapy sequence. Most patients received T-DM1 after treatment with pertuzumab. Both novel therapies (PH and T-DM1) are utilized in a high proportion of HER2-positive breast cancer patients. As most patients receive T-DM1 after PH, real-world data may help to clarify whether the efficacy of this sequence is similar to that in the approval study.

Treatment landscape of advanced breast cancer patients with hormone receptor positive HER2 negative tumors - Data from the German PRAEGNANT breast cancer registry.

PURPOSE: This study describes comprehensive data from a breast cancer registry concerning the use of endocrine treatment (ET) and chemotherapy in the first, second and higher therapy lines in hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC). METHODS: The PRAEGNANT study is a real-time registry for patients with MBC. Therapies were categorized into the following categories: chemotherapy, aromatase inhibitor (AI), tamoxifen, fulvestrant, or everolimus plus ET and reported for first, second and third line or higher therapy use. Also treatment sequences for the first, second and third therapy line were analyzed. RESULTS: This analysis includes 958 patients with HR positive, HER2 negative MBC. 42.7% were treated with a chemotherapy in the first therapy line compared to 45.9% receiving an ET. A total of 25.9% were treated with everolimus plus anti-hormone therapy in any therapy line. 34.1% were treated with fulvestrant as single agent therapy. Analyzing therapy sequences, the administration of three different chemotherapies in a row was the most frequently used pattern. CONCLUSIONS: This analysis shows that across all three first therapy lines chemotherapy is a dominant therapy for HR positive, HER2 negative MBC patients. Education about the efficacy of ET might help to increase its use and decrease the possible burden of chemotherapy related toxicities.

First-line Bevacizumab-containing Therapy for HER2-negative Metastatic Breast Cancer: Final Results from a Prospective German Study.

AIM: The German ML21165 study evaluated bevacizumab-containing therapy for metastatic breast cancer (mBC) in routine oncology practice. PATIENTS AND METHODS: Patients received bevacizumab with chemotherapy until disease progression, unacceptable toxicity or consent withdrawal. Pre-specified end-points were safety and efficacy [response rate, progression-free survival (PFS) and overall survival (OS)]. RESULTS: Between May 2007 and September 2009, 865 patients received first-line bevacizumab plus paclitaxel for mBC, of whom 16% were aged ≥70 years and 9% had ECOG performance status of 2 or more. At data cut-off (median of 15.9 months' follow-up), the median PFS was 9.6 months [95% confidence interval (CI)=9.0-10.4 months] and the median OS was 21.6 months (95% CI=19.4-23.5 months). The most common non-haematological adverse drug reactions of grade 3 or more were pain (9%), hypertension (5%), sensory neuropathy (3%) and proteinuria (3%). Prolonged bevacizumab was well-tolerated. CONCLUSION: The efficacy and safety of first-line bevacizumab-paclitaxel in routine oncology practice is consistent with results from randomized trials.

Everolimus plus exemestane as first-line therapy in HR⁺, HER2⁻ advanced breast cancer in BOLERO-2.

The present exploratory analysis examined the efficacy, safety, and quality-of-life effects of everolimus (EVE) + exemestane (EXE) in the subgroup of patients in BOLERO-2 whose last treatment before study entry was in the (neo)adjuvant setting. In BOLERO-2, patients with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer recurring/progressing after a nonsteroidal aromatase inhibitor (NSAI) were randomly assigned (2:1) to receive EVE (10 mg/day) + EXE (25 mg/day) or placebo (PBO) + EXE. The primary endpoint was progression-free survival (PFS) by local assessment. Overall, 137 patients received first-line EVE + EXE (n = 100) or PBO + EXE (n = 37). Median PFS by local investigator assessment nearly tripled to 11.5 months with EVE + EXE from 4.1 months with PBO + EXE (hazard ratio = 0.39; 95 % CI 0.25-0.62), while maintaining quality of life. This was confirmed by central assessment (15.2 vs 4.2 months; hazard ratio = 0.32; 95 % CI 0.18-0.57). The marked PFS improvement in patients receiving EVE + EXE as first-line therapy for disease recurrence during or after (neo)adjuvant NSAI therapy supports the efficacy of this combination in the first-line setting. Furthermore, the results highlight the potential benefit of early introduction of EVE + EXE in the management of HR(+), HER2(-) advanced breast cancer in postmenopausal patients.

Practical management of everolimus-related toxicities in patients with advanced solid tumors.

Everolimus is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), an intracellular protein kinase downstream of the phosphatidylinositol 3-kinase/AKT pathway involved in key components of tumorigenesis, including cell growth, proliferation, and angiogenesis. In the advanced cancer setting, based on favorable results from phase III trials, everolimus is indicated for the treatment of advanced renal cell carcinoma, advanced neuroendocrine tumors of pancreatic origin, and advanced hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Additional oncology indications for everolimus include renal angiomyolipoma with tuberous sclerosis complex and subependymal giant-cell astrocytoma. Although it is generally well tolerated, with most adverse events of mild to moderate severity and manageable, everolimus exhibits a distinct adverse event profile that warrants guidance for proper diagnostic and medical management. This guidance is particularly important given the potential for widespread long-term use of everolimus. This review will focus on the most relevant toxicities associated with mTOR inhibitors and on their management. Practical treatment recommendations are presented for stomatitis, noninfectious pneumonitis, rash, selected metabolic abnormalities, and infections. Provided these events are rapidly identified and treated, the vast majority should resolve with minimal effect on treatment outcomes and patients' quality of life.

Effect of everolimus on bone marker levels and progressive disease in bone in BOLERO-2.

BACKGROUND: Breast Cancer Trials of Oral Everolimus 2 (BOLERO-2), a phase III study in postmenopausal women with estrogen receptor-positive breast cancer progressing despite nonsteroidal aromatase inhibitor therapy, showed statistically significant benefits with adding everolimus to exemestane. Moreover, in preclinical studies, mammalian target of rapamycin inhibition was associated with decreased osteoclast survival and activity. Exploratory analyses in BOLERO-2 evaluated the effect of everolimus on bone marker levels and progressive disease in bone. METHODS: Patients were treated with exemestane (25mg/day) and randomized (2:1) to everolimus (10mg/day; combination) or placebo (exemestane only). Exploratory endpoints included changes in bone turnover marker levels vs baseline and progressive disease in bone, defined as unequivocal progression of a preexisting bone lesion or the appearance of a new bone lesion. RESULTS: Baseline disease characteristics were well balanced between arms (N = 724); baseline bisphosphonate use was not (43.9% combination vs 54.0% exemestane only). At a median of 18 months of follow-up, median progression-free survival (primary endpoint) was statistically significantly longer with the combination vs exemestane only (Cox proportional hazard ratio = 0.45, 95% confidence interval = 0.38 to 0.54; log-rank, 1-sided P < .0001). Bone marker levels at 6 and 12 weeks increased with exemestane only, as expected, but decreased with the combination. The cumulative incidence rate of progressive disease in bone was lower in the combination arm. Bone-related adverse events occurred with similar frequency in both arms (3.3% combination vs 4.2% exemestane only). CONCLUSION: These exploratory analyses suggest that everolimus has beneficial effects on bone turnover and progressive disease in bone in patients receiving exemestane for hormone receptor-positive breast cancer progressing during/after nonsteroidal aromatase inhibitor therapy.

A randomised trial of goserelin versus control after adjuvant, risk-adapted chemotherapy in premenopausal patients with primary breast cancer - GABG-IV B-93.

GABG-IV B-93 is a prospective, randomised study comparing goserelin (n=384) with no further treatment (n=392) in hormone receptor (HR)-negative breast cancer patients (n=465) after 3 cycles cyclophosphamide, methotrexate, 5-fluorouracil (CMF) for patients with 0-3 positive lymph nodes (LN) or 4 cycles epirubicin, cyclophosphamide (EC) followed by 3 cycles CMF for patients with 4-9 positive LN. After completion of the ZEBRA trial the study was amended to enrol also HR-positive patients with 1-9+LN (n=311). After a median follow-up of 4.7 years neither HR-negative nor HR-positive patients showed a benefit for goserelin. The adjusted estimated hazard ratio for event-free survival in HR-negative patients was 1.01 (goserelin versus control, 95% confidence interval [CI] 0.72-1.42, P=0.97) and 0.77 in HR-positive patients (95% CI 0.47-1.24, P=0.27). These results do not support the general use of goserelin after adjuvant chemotherapy in this group of premenopausal patients.

CMF versus goserelin as adjuvant therapy for node-negative, hormone-receptor-positive breast cancer in premenopausal patients: a randomised trial (GABG trial IV-A-93).

Gonadotrophin-releasing hormone analogues were investigated as adjuvant treatment for patients with node-negative, hormone-sensitive, premenopausal breast cancer. Patients were randomised to either three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy (n=378) or goserelin every 28 d for 2 years (n=393). During a median follow-up of 4.9 years, 123 events were observed. The first-failure event of CMF versus goserelin, respectively, was ipsilateral locoregional recurrence (18 versus 20), contralateral breast cancer (7 versus 6), distant failure (35 versus 24) and death without recurrence (2 versus 2). Forty-two (23 versus 19) deaths of any cause occurred. The estimated adjusted hazard ratio for goserelin versus CMF (intention-to-treat analysis) was 0.79 (95% CI=0.54-1.14; P=0.19). It is concluded that medical ovarian ablation with goserelin represents a valid option for premenopausal patients with node-negative breast cancer.

Tamoxifen versus control after adjuvant, risk-adapted chemotherapy in postmenopausal, receptor-negative patients with breast cancer: a randomized trial (GABG-IV D-93)--the German Adjuvant Breast Cancer Group.

PURPOSE: To investigate the effect of adjuvant sequential tamoxifen after chemotherapy in postmenopausal patients with hormone receptor-negative breast cancer. METHODS: Patients were randomly assigned to oral tamoxifen (30 mg daily for 5 years; n = 421) or no additional treatment (n = 408) after risk-adapted polychemotherapy consisting of three 28-day cycles of CMF (cyclophosphamide, 500 mg/m(2), methotrexate, 40 mg/m(2), and fluorouracil, 600 mg/m(2)) in patients with negative or one to three positive lymph nodes and four 21-day cycles of epirubicin 90 mg/m(2), cyclophosphamide 600 mg/m(2) followed by three cycles of CMF in patients with four to nine positive lymph nodes. RESULTS: Thirty-six percent of the patients included were older than 60 years, 63% were node negative, 13% had four to nine positive nodes, 55% had tumor grade 3, and 41% received breast-preserving surgery. At 5.3 years' median follow-up, the first event of failure (recurrence, secondary tumor, or death) had occurred in 123 patients in the tamoxifen group and 107 patients of the control group. Event-free survival rates after 5 years were 70.3% (95% CI, 65.5% to 75.0%) and 72.8% (95% CI, 68.2% to 77.5%) for the tamoxifen and control groups, respectively. The estimated hazard ratio of tamoxifen versus control was 1.13 (95% CI, 0.87 to 1.48; P = .34), which gives no indication of an additional benefit of tamoxifen in these patients. CONCLUSION: This study contributes substantially to finalization of the presently emerging evidence that tamoxifen does not benefit women with receptor-negative breast cancer after chemotherapy.

Only grading has independent impact on breast cancer survival after adjustment for pathological response to preoperative chemotherapy.

Our objective was to determine pretreatment factors with an independent impact on survival after adjusting for response to preoperative chemotherapy and to describe parameters predictive for achieving a pathological complete remission (pCR) after preoperative chemotherapy containing an anthracycline. We performed univariate and multivariate analyses to describe the impact of the following pretreatment characteristics of 240 primary breast cancer patients who received preoperative chemotherapy containing an anthracycline at our institution on disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS): age, stage, clinical tumor size, clinical nodal status, grading, and expression of estrogen receptor, progesterone receptor, Her2/neu, Ki67, Bcl-2 and p53. Afterwards, the response to preoperative chemotherapy was added to the multivariate model in order to evaluate which pretreatment parameters retained their prognostic impact. In addition, univariate analysis was performed to describe pretreatment variables predictive for achieving a pCR. With a median follow-up of 6.4 years (range 0-10.4), only grading retained its independent impact on DFS, DDFS and OS [hazard ratio (HR) 1.5, 1.7 and 2.9, respectively; p<0.05] after adjusting for the strongest independent prognostic factors pathological T category at surgery (HR 1.6, 1.8 and 1.7, respectively; p<0.001) and pathological N category at surgery (HR 2.3, 2.4 and 2.1, respectively; p<0.001). Predictive factors for the achievement of pCR (p<0.05) were age under 35 years, lower stage or smaller clinical tumor size and higher expression of Bcl-2 at diagnosis. We conclude that only grading retained its independent prognostic impact on DFS, DDFS and OS after adjusting for pathological response of breast tumor and axillary lymph node metastases to preoperative chemotherapy. According to our data, it could be hypothesized that young patients with early tumor stage and small primary tumors might profit most from preoperative chemotherapy.