Clinical effectiveness and safety of olaparib in BRCA-mutated, HER2-negative metastatic breast cancer in a real-world setting: final analysis of LUCY

Breast cancer; Olaparib; Progression-free survivalCàncer de mama; Olaparib; Supervivència lliure de progressióCáncer de mama; Olaparib; Supervivencia libre de progresiónPurpose The interim analysis of the phase IIIb LUCY trial demonstrated the clinical effectiveness of olaparib in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC), with median progression-free survival (PFS) of 8.11 months, which was similar to that in the olaparib arm of the phase III OlympiAD trial (7.03 months). This prespecified analysis provides final overall survival (OS) and safety data. Methods The open-label, single-arm LUCY trial of olaparib (300 mg, twice daily) enrolled adults with gBRCAm or somatic BRCA-mutated (sBRCAm), HER2-negative mBC. Patients had previously received a taxane or anthracycline for neoadjuvant/adjuvant or metastatic disease and up to two lines of chemotherapy for mBC. Results Of 563 patients screened, 256 (gBRCAm, n = 253; sBRCAm, n = 3) were enrolled. In the gBRCAm cohort, median investigator-assessed PFS (primary endpoint) was 8.18 months and median OS was 24.94 months. Olaparib was clinically effective in all prespecified subgroups: hormone receptor status, previous chemotherapy for mBC, previous platinum-based chemotherapy (including by line of therapy), and previous cyclin-dependent kinase 4/6 inhibitor use. The most frequent treatment-emergent adverse events (TEAEs) were nausea (55.3%) and anemia (39.2%). Few patients (6.3%) discontinued olaparib owing to a TEAE. No deaths associated with AEs occurred during the study treatment or 30-day follow-up. Conclusion The LUCY patient population reflects a real-world population in line with the licensed indication of olaparib in mBC. These findings support the clinical effectiveness and safety of olaparib in patients with gBRCAm, HER2-negative mBC. Clinical trial registration Clinical trials registration number: NCT03286842This study was funded by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. The funding source was involved in the study design, analysis, data interpretation, writing of the manuscript, and the decision to submit the article for publication

Efficacy of Neratinib Plus Capecitabine in the Subgroup of Patients with Central Nervous System Involvement from the NALA Trial

Capecitabina; Neoplàsies del sistema nerviós central; Neratinibcapecitabina; Neoplasias del sistema nervioso central; NeratinibCapecitabine; Central nervous system neoplasms; NeratinibBackground Neratinib has efficacy in central nervous system (CNS) metastases from HER2-positive metastatic breast cancer (MBC). We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (N + C) versus lapatinib plus capecitabine (L + C). Materials and Methods NALA was a randomized, active-controlled trial in patients who received two or more previous HER2-directed regimens for HER2-positive MBC. Patients with asymptomatic/stable brain metastases (treated or untreated) were eligible. Patients were assigned to N + C (neratinib 240 mg per day, capecitabine 750 mg/m2 twice daily) or L + C (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m2 twice daily) orally. Independently adjudicated progression-free survival (PFS), overall survival (OS), and CNS endpoints were considered. Results Of 621 patients enrolled, 101 (16.3%) had known CNS metastases at baseline (N + C, n = 51; L + C, n = 50); 81 had received prior CNS-directed radiotherapy and/or surgery. In the CNS subgroup, mean PFS through 24 months was 7.8 months with N + C versus 5.5 months with L + C (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.41–1.05), and mean OS through 48 months was 16.4 versus 15.4 months (HR, 0.90; 95% CI, 0.59–1.38). At 12 months, cumulative incidence of interventions for CNS disease was 25.5% for N + C versus 36.0% for L + C, and cumulative incidence of progressive CNS disease was 26.2% versus 41.6%, respectively. In patients with target CNS lesions at baseline (n = 32), confirmed intracranial objective response rates were 26.3% and 15.4%, respectively. No new safety signals were observed. Conclusion These analyses suggest improved PFS and CNS outcomes with N + C versus L + C in patients with CNS metastases from HER2-positive MBC.Funded by Puma Biotechnology, Inc. Medical writing support was also funded by Puma Biotechnology Inc. and provided by Miller Medical Communications

A multicenter randomized phase II study of sequential epirubicin/cyclophosphamide followed by docetaxel with or without celecoxib or trastuzumab according to HER2 status, as primary chemotherapy for localized invasive breast cancer patients

International audienceTo assess anti-tumor activity of sequential epirubicin/cyclophosphamide followed by docetaxel with the randomized addition of celecoxib in HER2 negative patients or trastuzumab in HER2 positive patients. From May 2004 till October 2007, 340 patients with stage II and III breast adenocarcinoma, ineligible for breast conserving surgery, received eight sequential three weekly cycles of EC-D [epirubicin (75 mg/m)–cyclophosphamide (750 mg/m) for four cycles followed by docetaxel (100 mg/m) for four cycles]. HER2-negative patients ( = 220) were randomized to receive concomitantly with docetaxel celecoxib 800 mg/day during cycles 5–8 or no additional treatment, while HER2-positive patients confirmed by FISH ( = 120) were randomized to trastuzumab concomitant to docetaxel (8 mg/kg then 6 mg/kg IV every 3 weeks) or no additional preoperative treatment. In the HER2 negative group, pCR (grade 1 and 2 of Chevallier's classification) was observed in 11.5 and 13% of patients treated without and with neoadjuvant Celecoxib, respectively. In the HER2 positive group, pCR rate reached 26% in those who received neoadjuvant trastuzumab versus 19% in the others. There was no unexpected toxicity, no cardiac toxicity, and no toxic death. Triple negative breast cancers experience the highest pCR rate of 30%. Celecoxib is not likely to improve pCR rates in addition to EC-D in patients with HER2-negative tumor. In HER2-positive tumor patients, trastuzumab added to ECD leads to increased pCR rates. It was the only combination to deserve further study according to the two-stage Fleming's design used in this trial

Higher Toxicity with 42 Gy in 10 Fractions as a Total Dose for 3D-Conformal Accelerated Partial Breast Irradiation: Results from a Dose Escalation Phase II Trial

Objective: Recent recommendations regarding indications of accelerated partial breast irradiation (APBI) have been put forward for selected breast cancer (BC) patients. However, some treatment planning parameters, such as total dose, are not yet well defined. The Institut Gustave Roussy has initiated a dose escalation trial at the 40 Gy/10 fractions/5 days and at a further step of total dose (TD) of 42 Gy/10 fractions/5 days. Here, we report early results of the latest step compared with the 40 Gy dose level. Methods and materials: From October 2007 to March 2010, a total of 48 pT1N0 BC patients were enrolled within this clinical trial: 17 patients at a TD of 42 Gy/10f/5d and 31 at a TD of 40 Gy/10f/5d. Median follow-up was 19 months (min-max, 12–26). All the patients were treated by APBI using a technique with 2 minitangents and an “enface” electrons delivering 20% of the total dose. Toxicities were systematically assessed at 1; 2; 6 months and then every 6 months. Results: Patients’ recruitment of 42 Gy step was ended owing to persistent grade 3 toxicity 6 months after APBI completion (n = 1). Early toxicities were statistically higher after a total dose of 42 Gy regarding grade ≥2 dry (p = 0.01) and moist (p = 0.05) skin desquamation. Breast pain was also statistically higher in the 42 Gy step compared to 40 Gy step (p = 0.02). Other late toxicities (grade ≥2 fibrosis and telangectasia) were not statistically different between 42 Gy and 40 Gy. Conclusions: Early toxicities were more severe and higher rates of late toxicities were observed after 42 Gy/10 fractions/5 days when compared to 40 Gy/10 fractions/5 days. This data suggest that 40 Gy/10 fractions/5 days could potentially be the maximum tolerance for PBI although longer follow-up is warranted to better assess late toxicities

Safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive advanced breast cancer: Primary results from the KAMILLA study cohort 1

Abstract Background Many patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) are candidates for trastuzumab emtansine (T-DM1) treatment sometime in their disease history. KAMILLA evaluated safety of T-DM1 in patients with previously treated HER2-positive locally advanced or metastatic BC (advanced BC). Methods KAMILLA (NCT01702571) is a single-arm, open-label, international, phase IIIb safety study of patients with HER2-positive advanced BC with progression after prior treatment with chemotherapy and a HER2-directed agent for MBC or within 6 months of completing adjuvant therapy. Patients received T-DM1 (3.6 mg/kg every 3 weeks) until unacceptable toxicity, withdrawal or disease progression. Results Among 2002 treated patients, median age was 55 years (range, 26–88; 373 [18.6%] aged ≥65 years), 1321 (66.0%) received ≥2 prior metastatic treatment lines and 398 (19.9%) had baseline central nervous system metastases. Adverse events (AEs) and serious AEs occurred in 1862 (93.0%) and 427 (21.3%) patients, respectively. Grade ≥3 AEs occurred in 751 (37.5%) patients; the three most common (individual Medical Dictionary for Regulatory Activity terms) were anaemia (3.0%), thrombocytopaenia (2.7%) and fatigue (2.5%). Median progression-free survival (PFS) was 6.9 months (95% confidence interval [CI], 6.0–7.6). Median overall survival (OS) was 27.2 months (95% CI, 25.5–28.7). With increasing lines of prior advanced therapy (0–1 versus 4+), median PFS and OS decreased numerically from 8.3 to 5.6 months and from 31.3 to 22.5 months, respectively. Conclusions KAMILLA is the largest cohort of T-DM1–treated patients studied to date. Results are consistent with prior randomised studies, thereby supporting T-DM1 as safe, tolerable and efficacious treatment for patients with previously treated HER2-positive advanced BC

Olaparib for metastatic breast cancer in patients with a germline BRCA mutation

BACKGROUND Olaparib is an oral poly(adenosine diphosphate-ribose) polymerase inhibitor that has promising antitumor activity in patients with metastatic breast cancer and a germline BRCA mutation. METHODS We conducted a randomized, open-label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation and human epidermal growth factor receptor type 2 (HER2)-negative metastatic breast cancer who had received no more than two previous chemotherapy regimens for metastatic disease. Patients were randomly assigned, in a 2: 1 ratio, to receive olaparib tablets (300 mg twice daily) or standard therapy with single-agent chemotherapy of the physician's choice (capecitabine, eribulin, or vinorelbine in 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review and was analyzed on an intention-to-treat basis. RESULTS Of the 302 patients who underwent randomization, 205 were assigned to receive olaparib and 97 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the olaparib group than in the standardtherapy group (7.0 months vs. 4.2 months; hazard ratio for disease progression or death, 0.58; 95% confidence interval, 0.43 to 0.80; P<0.001). The response rate was 59.9% in the olaparib group and 28.8% in the standard-therapy group. The rate of grade 3 or higher adverse events was 36.6% in the olaparib group and 50.5% in the standard-therapy group, and the rate of treatment discontinuation due to toxic effects was 4.9% and 7.7%, respectively. CONCLUSIONS Among patients with HER2-negative metastatic breast cancer and a germline BRCA mutation, olaparib monotherapy provided a significant benefit over standard therapy; median progression-free survival was 2.8 months longer and the risk of disease progression or death was 42% lower with olaparib monotherapy than with standard therapy. (Funded by AstraZeneca; OlympiAD ClinicalTrials.gov number, NCT02000622.

Validation of a new fully automated software for 2D digital mammographic breast density evaluation in predicting breast cancer risk.

We compared accuracy for breast cancer (BC) risk stratification of a new fully automated system (DenSeeMammo-DSM) for breast density (BD) assessment to a non-inferiority threshold based on radiologists' visual assessment. Pooled analysis was performed on 14,267 2D mammograms collected from women aged 48-55 years who underwent BC screening within three studies: RETomo, Florence study and PROCAS. BD was expressed through clinical Breast Imaging Reporting and Data System (BI-RADS) density classification. Women in BI-RADS D category had a 2.6 (95% CI 1.5-4.4) and a 3.6 (95% CI 1.4-9.3) times higher risk of incident and interval cancer, respectively, than women in the two lowest BD categories. The ability of DSM to predict risk of incident cancer was non-inferior to radiologists' visual assessment as both point estimate and lower bound of 95% CI (AUC 0.589; 95% CI 0.580-0.597) were above the predefined visual assessment threshold (AUC 0.571). AUC for interval (AUC 0.631; 95% CI 0.623-0.639) cancers was even higher. BD assessed with new fully automated method is positively associated with BC risk and is not inferior to radiologists' visual assessment. It is an even stronger marker of interval cancer, confirming an appreciable masking effect of BD that reduces mammography sensitivity

ESMO Management and treatment adapted recommendations in the COVID-19 era : Breast Cancer

The global preparedness and response to the rapid escalation to severe acute respiratory syndrome coronavirus (SARS-CoV)-2-related disease (COVID-19) to a pandemic proportion has demanded the formulation of a reliable, useful and evidence-based mechanism for health services prioritisation, to achieve the highest quality standards of care to all patients. The prioritisation of high value cancer interventions must be embedded in the agenda for the pandemic response, ensuring that no inconsistency or discrepancy emerge in the health planning processes. The aim of this work is to organise health interventions for breast cancer management and research in a tiered framework (high, medium, low value), formulating a scheme of prioritisation per clinical cogency and intrinsic value or magnitude of benefit. The public health tools and schemes for priority setting in oncology have been used as models, aspiring to capture clinical urgency, value in healthcare, community goals and fairness, while respecting the principles of benevolence, non-maleficence, autonomy and justice. We discuss the priority health interventions across the cancer continuum, giving a perspective on the role and meaning to maintain some services (undeferrable) while temporarily abrogate some others (deferrable). Considerations for implementation and the essential link to pre-existing health services, especially primary healthcare, are addressed, outlining a framework for the development of effective and functional services, such as telemedicine. The discussion covers the theme of health systems strategising, and why oncology care, in particular breast cancer care, should be maintained in parallel to pandemic control measures, providing a pragmatic clinical model within the broader context of public healthcare schemes

70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer.

The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy. In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher. A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease. Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. (Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31.)