Search

Background We report long-term efficacy and cardiac safety outcomes in patients with HER2-positive early breast cancer treated with neoadjuvant pertuzumab plus trastuzumab with anthracycline-containing or anthracycline-free chemotherapy. Methods Descriptive efficacy analyses were conducted in patients randomised to group A (cycles 1–6: trastuzumab [8 mg/kg loading dose and 6 mg/kg maintenance] plus pertuzumab [840 mg loading dose and 420 mg maintenance], plus 5-fluorouracil, epirubicin and cyclophosphamide [FEC] [cycles 1–3; 500 mg/m 2 5-fluorouracil/100 mg/m 2 epirubicin/600 mg/m 2 cyclophosphamide] then docetaxel [cycles 4–6; 75 mg/m 2 , escalated to 100 mg/m 2 if well tolerated]), B (cycles 1–3: FEC, cycles 4–6: trastuzumab plus pertuzumab plus docetaxel as mentioned previously) or C (cycles 1–6: trastuzumab plus pertuzumab plus docetaxel [75 mg/m 2 , without dose escalation], and carboplatin [AUC 6]), five years after randomisation of the last patient. This study is registered with ClinicalTrials.gov , number NCT00976989 . Results Three-year Kaplan–Meier survival estimates for disease-free survival (DFS) were 87% (95% confidence interval: 79–95), 88% (80–96) and 90% (82–97) in groups A–C, respectively. Progression-free survival (PFS) rates were 89% (81–96), 89% (81–96) and 87% (80–95). DFS hazard ratio for total pathological complete response (tpCR) versus no tpCR was 0.27 (0.11–0.64). During post-treatment follow-up, 2/72 (2.8%), 3/75 (4.0%) and 4/76 (5.4%) patients in groups A–C had any-grade left ventricular systolic dysfunction; eight (11.1%), 12 (16.0%) and nine (11.8%) patients experienced left ventricular ejection fraction declines ≥10% from baseline to <50%. Conclusions Long-term DFS and PFS were similar between groups. Patients who achieved tpCR had improved DFS. No new safety signals were identified. [ABSTRACT FROM AUTHOR]

Background Bone metastases are common in women with breast cancer and often result in skeletal related events (SREs). As the angiogenic factor vascular endothelial growth factor (VEGF) regulates osteoclast activity and is associated with more extensive bone metastases and SRE risk in metastatic breast cancer, we hypothesized that blockade of VEGF signaling could be a therapeutic strategy for inhibiting bone metastases progression and possibly prolonging overall (OS) or progression-free survival (PFS). The Zamboney trial was a randomized placebo-controlled study designed to assess whether patients with bone predominant metastatic breast cancer benefited from addition of the VEGF receptor (VEGFR) targeting agent, vandetanib, to endocrine therapy with fulvestrant. As a companion study, evaluation of biomarkers and their potential association with response to vandetanib or SRE risk was performed. Methods Baseline overnight fasted serum from enrolled patients was analyzed for levels of various putative biomarkers including; VEGF-A, soluble (s)VEGFR2, sVEGFR3, transforming growth factor (TGF)-β1 and activinA by ELISA. Spearman correlation coefficients and Wilcoxon rank sum tests were used to investigate potential relationships between biomarker values and baseline clinical parameters. Prognostic and predictive ability of each marker was investigated using Cox proportional hazards regression with adjustments for treatment and baseline strata of serum CTx (<400 versus ≥400 ng/L). Results Of 129 enrolled patients, serum was available for analysis in 101; 51 in vandetanib and 50 in placebo arm. Mean age amongst consenting patients was 59.8 years. Clinical characteristics were not significantly different between patients with or without serum biomarker data and serum markers were similar for patients by treatment arm. Baseline sVEGFR2 was prognostic for OS (HR=0.77, 95% CI=0.61–0.96, p =0.020), and although a modest association was observed, it was not significant for PFS (HR=0.90, 95% CI=0.80–1.01, p =0.085) nor time to first SRE (HR=0.82, 95% CI=0.66–1.02, p =0.079). When interaction terms were evaluated, sVEGFR2 was not found to be predictive of response to vandetanib, although a modest association remained with respect to PFS (interaction p =0.085). No other marker showed any significant prognostic or predictive ability with any measured outcome. Conclusions In this clinical trial, sVEGFR2 appeared prognostic for OS, hence validation of sVEGFR2 should be conducted. Moreover, the role of sVEGFR2 in breast cancer bone metastasis progression should be elucidated. [ABSTRACT FROM AUTHOR]

Background: Axillary lymph node involvement remains the most important prognostic factor in early-stage breast cancer. We hypothesized that molecular classification based on breast cancer biology would predict the presence of nodal involvement at diagnosis, which might aid treatment decisions regarding the axilla. Patients and Methods: From a clinically annotated tissue microarray of 4444 early-stage breast cancers, expression of estrogen receptor (ER), progesterone receptor (PgR), HER2, epidermal growth factor receptor, and cytokeratin 5/6 was determined by immunohistochemistry. Cases were classified by published criteria into molecular subtypes of luminal, luminal/HER2 positive, HER2 positive/ER negative/PgR negative, and basal. Risk of axillary nodal involvement at diagnosis was determined in 2 multivariable logistic regression models: a "core biopsy model" including molecular subtype, age, grade, and tumor size and a "lumpectomy model," which also included lymphovascular invasion. Luminal was used as the reference group. After internal validation of findings in 2 independent sets, we conducted combined analysis of both. Results: In the core biopsy model, the molecular subtypes had a predictive effect for nodal involvement (P = .000001), with the basal subtype having an odds ratio for axillary lymph node involvement of 0.53 (95% CI, 0.41-0.69). Tumor grade (P = 5.43 × 10–12) and size (P = 8.52 × 10–35) were also predictive for nodal involvement. Similar results were found in the lumpectomy model, where lymphovascular invasion was also predictive (P = 2.74 × 10–115). Conclusion: These results indicate that the basal breast cancer molecular subtype predicts a lower incidence of axillary nodal involvement, and including biomarker profiles to predict nodal status at diagnosis could help stratification for decisions regarding axillary surgery and locoregional radiation. [ABSTRACT FROM AUTHOR]

Abstract: With the aromatase inhibitors (AIs) replacing tamoxifen as the first-line treatment for postmenopausal women with hormone receptor-positive early and advanced breast cancer, there is a need to evaluate appropriate endocrine treatment options following AI failure. However, until recently, there were no Phase III trial data in this area. Fulvestrant (Faslodex™) is an oestrogen receptor antagonist utilised for the treatment of postmenopausal women with locally advanced or metastatic breast cancer following progression or recurrence on anti-oestrogen therapy. Fulvestrant has a mode of action that is distinct from the AIs and the selective oestrogen receptor modulators, and thus may offer an effective treatment option in the post-AI setting. The Evaluation of Faslodex and Exemestane Clinical Trial (EFECT) is the first Phase III trial to evaluate the efficacy and tolerability of fulvestrant and the steroidal AI, exemestane, in patients with locally advanced or metastatic breast cancer who have progressed or recurred while receiving a non-steroidal AI. EFECT confirmed that fulvestrant and exemestane offer effective treatment options in this setting. Similar efficacy was seen in both treatment groups and there were no significant differences in reported adverse events between fulvestrant and exemestane. The EFECT data provide further evidence for the activity of fulvestrant in the treatment of advanced breast cancer. Other ongoing fulvestrant trials will further define its full role, including the potential for a high-dose regimen, combination of fulvestrant with an AI, and identification of clinical and biological markers to help in targeting those patients who are most likely to respond to treatment. [Copyright &y& Elsevier]

Purpose: Randomized clinical trials have shown that regional nodal irradiation (RNI) in patients with unselected N1 breast cancer improves breast cancer-specific survival. However, the benefit of RNI in women with biologically low-risk N1 breast cancer is uncertain. We conducted a population-based study to determine whether RNI is associated with improved breast cancer recurrence-free interval (BCRFI) in this population.Methods and Materials: Patients aged 40 to 79 years with pT1-2 pN1 (node-positive) breast cancer diagnosed between 2005 and 2014 were identified. The inclusion criteria were modeled off of the TAILOR RT study, which is a randomized noninferiority clinical trial designed to assess the value of RNI in patients with low-risk N1 disease. Eligible patients had breast-conserving surgery or mastectomy and axillary lymph node dissection with 1 to 3 positive nodes, breast-conserving surgery and sentinel lymph node biopsy with 1 to 2 positive nodes, or mastectomy and sentinel lymph node biopsy with 1 positive node. Additionally, patients had luminal A breast cancers, as approximated by estrogen receptor positive (Allred 6-8/8), progesterone receptor (PR) positive (Allred 6-8/8), human epidermal growth factor receptor 2-negative, and grade 1 to 2 immunohistochemical testing. All patients were prescribed hormonal treatment. The primary endpoint of BCRFI, the time to any breast cancer recurrence or breast cancer-related death, was analyzed using a multivariate competing risks analysis.Results: The cohort included 1169 women with a median follow-up of 9.2 years. Radiation treatments were not performed in 151 women treated with mastectomy alone, were delivered to the breast only in 133 women, and were delivered locoregionally in 885 women. Patients undergoing RNI were younger (median age: 58 vs 62 years), more likely to have 2 to 3 macroscopic lymph nodes involved, and more often received chemotherapy (all P < .05). The 10-year estimate of BCRFI was 90% without RNI versus 90% with RNI (P = .5). On multivariable analysis, RNI was not a significant predictor of BCRFI (hazard ratio: 1.0; P = .9).Conclusions: In this retrospective analysis, RNI was not associated with improved BCRFI for women with biologically low-risk N1 breast cancer. We advocate accrual to the ongoing TAILOR RT study. [ABSTRACT FROM AUTHOR]

Background: Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A.Methods: This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755.Findings: Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5-15·9). 61 (50·4%; 95% CI 41·2-59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported.Interpretation: BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor.Funding: Novartis Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Thymidine kinase 1 (TK1) plays a critical role in DNA synthesis and cell proliferation. Recent studies have shown potential for serum TK1 activity (sTKa) as a prognostic marker and indicator of early response to endocrine therapy in advanced breast cancer. The aim of this study is to assess the correlation between sTKa and patient outcome. The Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) was a double-blind, double-dummy, randomised trial of fulvestrant versus exemestane after progression on non-steroidal aromatase inhibitor therapy, in postmenopausal women with advanced breast cancer. Retrospective analyses of serum archived from EFECT were conducted. sTKa was assessed using the DiviTum® assay on samples collected at baseline, after three and six months of endocrine therapy, and at disease progression. The median time to progression (mTTP) for patients with low baseline sTKa levels was 5.03 months (95% confidence interval [CI]: 3.91–5.89) versus 2.57 months (95% CI: 2.04–3.52) in patients with high sTKa baseline levels (P < 0.0001). On treatment, patients whose sTKa increased from baseline had a significantly shorter mTTP (3.39 months, 95% CI: 2.14–4.11) than those without an sTKa increase (5.39 months, 95% CI: 4.01–6.68) (P = 0.0045). Similar results were observed in the separate EFECT treatment arms. After adjusting for major prognostic factors, sTKa remained an independent marker. sTKa is a potential circulating prognostic marker in patients with advanced breast cancer treated with endocrine therapy. It may also represent a tool for upfront identification of endocrine therapy resistance and early positive response to therapy. Independent validation of these results is warranted. • Retrospective analyses of sera from the Evaluation of Faslodex versus Exemestane Clinical Trial to assess the association between serum thymidine kinase 1 activity (sTKa) and outcome. • Low baseline sTKa correlated with longer median time to progression (mTTP). • Stable or decreased sTKa while on endocrine treatment correlated with longer mTTP. • After adjusting for prognostic factors, sTKa remained an independent marker. • sTKa may identify early endocrine resistance and monitor response in sensitive disease. [ABSTRACT FROM AUTHOR]

Background: The optimal duration of extended therapy with aromatase inhibitors in patients with postmenopausal breast cancer is unknown. In the NSABP B-42 study, we aimed to determine whether extended letrozole treatment improves disease-free survival after 5 years of aromatase inhibitor-based therapy in women with postmenopausal breast cancer.Methods: This randomised, double-blind, placebo-controlled, phase 3 trial was done in 158 centres in the USA, Canada, and Ireland. Postmenopausal women with stage I-IIIA hormone receptor-positive breast cancer, who were disease-free after about 5 years of treatment with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor, were randomly assigned (1:1) to receive 5 years of letrozole (2·5 mg orally per day) or placebo. Randomisation was stratified by pathological node status, previous tamoxifen use, and lowest bone mineral density T score in the lumbosacral spine, total hip, or femoral neck. The primary endpoint was disease-free survival, defined as time from randomisation to breast cancer recurrence, second primary malignancy, or death, and was analysed by intention to treat. To adjust for previous interim analyses, the two-sided statistical significance level for disease-free survival was set at 0·0418. This study is registered with ClinicalTrials.gov, number NCT00382070, is active, and is no longer enrolling patients.Findings: Between Sept 28, 2006, and Jan 6, 2010, 3966 patients were randomly assigned to receive letrozole (n=1983) or placebo (n=1983). Follow-up information was available for 3903 patients for the analyses of disease-free survival. Median follow-up was 6·9 years (IQR 6·1-7·5). Letrozole treatment did not significantly improve disease-free survival (339 disease-free survival events were reported in the placebo group and 292 disease-free survival events were reported in the letrozole group; hazard ratio 0·85, 95% CI 0·73-0·999; p=0·048). 7-year disease-free survival estimate was 81·3% (95% CI 79·3-83·1) in the placebo group and 84·7% (82·9-86·4) in the letrozole group. The most common grade 3 adverse events were arthralgia (47 [2%] of 1933 patients in the placebo group vs 50 [3%] of 1941 patients in the letrozole group) and back pain (44 [2%] vs 38 [2%]). The most common grade 4 adverse event in the placebo group was thromboembolic event (eight [<1%]) and the most common grade 4 adverse events in the letrozole group were urinary tract infection, hypokalaemia, and left ventricular systolic dysfunction (four [<1%] each).Interpretation: After 5 years of aromatase inhibitor-based therapy, 5 years of letrozole therapy did not significantly prolong disease-free survival compared with placebo. Careful assessment of potential risks and benefits is required before recommending extended letrozole therapy to patients with early-stage breast cancer.Funding: National Cancer Institute, Korea Health Technology R&D Project, Novartis. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To examine the acute cardiotoxicity of internal mammary chain (IMC) irradiation with concurrent trastuzumab. Materials and Methods: Clinical and cardiac function data were collected on 59 patients with early breast cancer who were treated with adjuvant trastuzumab and chemotherapy with or without radiotherapy (often including IMC) at BC Cancer Agency in 2005. Results: Forty-four of fifty-nine patients received adjuvant radiotherapy (RT). Thirteen had left-sided IMC RT. For left-sided RT, IMC inclusion increased the mean percentage dose to 5% of the heart, but the mean doses to 50% and 90% of the heart were similar. Median baseline left ventricular ejection fraction (LVEF) was 62% and similar in all groups. Median absolute decrease in LVEF after RT was 4%, which was not significantly different according to side or inclusion of IMCs. Trastuzumab was stopped in 11 of 59 patients (18.6%) due to decrease in LVEF. After median follow up of 15 months, three patients developed clinical congestive heart failure, none of whom received left-sided IMC RT. Conclusions: There was no excess acute cardiotoxicity observed with the combination of left-sided IMC irradiation and concurrent trastuzumab. [Copyright &y& Elsevier]