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Background Limited data are available regarding the use of nab-paclitaxel in older patients with breast cancer. A weekly schedule is recommended, but there is a paucity of evidence regarding the optimal dose. We evaluated the efficacy of two different doses of weekly nab-paclitaxel, with a specific focus on their corresponding impact on patient function, in order to address the lack of data specifically relating to the older population. Methods EFFECT is an open-label, phase II trial wherein 160 women with advanced breast cancer aged ≥ 65 years were enrolled from 15 institutions within Italy. Patients were randomly assigned 1:1 to receive nab-paclitaxel 100 mg/m 2 (arm A) or 125 mg/m 2 (arm B) on days 1, 8, and 15 on a 28-day cycle, as first-line treatment for advanced disease. The primary endpoint was event-free survival (EFS), wherein an event was defined as disease progression (PD), functional decline (FD), or death. In each arm, the null hypothesis that the median EFS would be ≤ 7 months was tested against a one-sided alternative according to the Brookmeyer Crowley test. Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. Results After a median follow-up of 32.6 months, 140 events were observed in 158 evaluable patients. Median EFS was 8.2 months (90% CI, 5.9–8.9; p  = 0.188) in arm A vs 8.3 months (90% CI, 6.2–9.7, p  = 0.078) in arm B. Progression-free survival, overall survival, and response rates were similar in both groups. A higher percentage of dose reductions and discontinuations due to adverse events (AEs) was noted in arm B. The most frequently reported non-haematological AEs were fatigue (grade [G] 2–3 toxicity occurrence in arm A vs B, 43% and 51%, respectively) and peripheral neuropathy (G2–3 arm A vs B, 19% and 38%, respectively). Conclusion Pre-specified outcomes were similar in both treatment arms. However, 100 mg/m 2 was significantly better tolerated with fewer neurotoxicity-related events, representing a more feasible dose to be recommended for older patients with advanced disease. Trial registration EudraCT, 2012-002707-18 . Registered on June 4, 2012. NIH ClinicalTrials.gov, NCT02783222 . Retrospectively registered on May 26, 2016.

Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB–IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0–2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin–carboplatin, or 15 mg/kg every 21 days combined with gemcitabine–carboplatin or paclitaxel–carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4–9·3) in the standard chemotherapy group and 11·8 months (10·8–12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41–0·65; log-rank p<0·0001). Most common grade 3–4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. Hoffmann–La Roche and Associazione Italiana per la Ricerca sul Cancro.

Lapatinib is a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR/ErbB1) and human epidermal growth factor receptor 2 (HER2/ErbB2). EGFR and HER2 overexpression is associated with aggressive breast cancer with a high risk of disease relapse and death. Although lapatinib targets both EGFR and HER2, its effects on HER2 appear to be more critical. The role of lapatinib in the first-line setting remains unclear. A phase II first-line monotherapy lapatinib trial in HER2-therapy-naïve metastatic breast cancer (MBC) patients confirms efficacy in HER2-positive tumors. Retrospective analysis of a phase III, first-line MBC study confirmed incremental benefit from lapatinib and paclitaxel over paclitaxel alone in HER2-positive disease. A prospective phase III study confirms superiority of letrozole and lapatinib over letrozole alone in HER2-positive MBC. Further investigation is required to define the potential first-line role for lapatinib. Particular strengths appear to be its manageable toxicity profile, lack of cross resistance with trastuzumab, activity in central nervous system disease, and synergy in combination with other anticancer therapy. Current limitations are lack of dosing recommendations from early trials, lack of predictive biomarkers beyond HER2 status, and lack of large prospective phase III trials for HER2-positive disease in the first-line setting. The role of lapatinib in HER2-negative disease is unclear.

Management of older breast cancer patients is challenging due to a lack of good quality evidence regarding the role of adjuvant chemotherapy. Older women can benefit as much from adjuvant chemotherapy as younger women, although they have an increased risk of toxicities. Decisions regarding adjuvant chemotherapy should be made based on tumor biology and biological age, rather than chronological age. Geriatrician assessment can detect subtle functional deficits that may impact on the ability of the patient to tolerate chemotherapy; however, implementation of comprehensive geriatric assessment in the oncology setting is challenging. Instead, numerous frailty screening tools are in development. Future advances should incorporate more accurate and efficient means for determining the biological age of elderly breast cancer patients, which will better define the risk:benefit ratio of adjuvant chemotherapy.

Very recently, Dr. Kathy Albain presented data suggesting the predictive value of the 21 -gene recurrence score (RS) assay in patients with node-positive breast cancer. [4] RS was calculated for postmenopausal patients with ER-positive, nodepositive breast cancer randomized to receive tamoxifen or six cycles of anthracycline-based chemotherapy plus tamoxifen, in The Breast Cancer Intergroup of North America 0100 trial. The additive benefit of chemotherapy observed in the clinical trial was seen in patients with a high RS, whereas no benefit was apparent in patients with a low RS, and no statistical benefit was observed in patients with an intermediate RS. These data reproduce what was already observed in applying the 21 -gene RS assay to node-negative patients entered in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B20 trial.[5] Of note, Dr. Albain also showed that for patients with a high-risk RS, chemotherapy was beneficial regardless of age. Upfront AIs should be considered for patients at risk of early relapse (ie, patients with at least four positive nodes) and/or large tumors. Tamoxifen remains a valuable option for early breast cancers at low risk of relapse (ie, grade 1 tumors < 1 cm, with a low proliferative index). Patients falling between these two categories might be good candidates for sequential treatment. An extended adjuvant treatment might be proposed to healthy elderly women with high-risk breast cancer after completing 5 years of adjuvant tamoxifen. Careful evaluation of concomitant comorbidities and the different spectrum of toxicity of tamoxifen vs aromatase inhibitors (cardiovascular events, lipid metabolism, préexistent osteoporosis, cognitive functions) must also be taken into account when recommending adjuvant endocrine therapy in the elderly population. Despite the paucity of data from randomized trials or meta-analyses investigating the role of adjuvant chemotherapy in elderly patients, the general consensus is that fit elderly women with endocrine-resistant breast cancer should be offered adjuvant chemotherapy. Much less clear is the role of adjuvant chemotherapy in patients with estrogen receptor (ER)- and/or progesterone receptor (PR)-positive breast cancer.

Background: Limited data are available regarding the use of nab-paclitaxel in older patients with breast cancer. A weekly schedule is recommended, but there is a paucity of evidence regarding the optimal dose. We evaluated the efficacy of two different doses of weekly nab-paclitaxel, with a specific focus on their corresponding impact on patient function, in order to address the lack of data specifically relating to the older population. Methods: EFFECT is an open-label, phase II trial wherein 160 women with advanced breast cancer aged ≥ 65 years were enrolled from 15 institutions within Italy. Patients were randomly assigned 1:1 to receive nab-paclitaxel 100 mg/m2 (Arm A) or 125 mg/m2 (Arm B) on days 1,8,15 on a 28-day cycle, as first-line treatment for advanced disease. The primary endpoint was event-free survival (EFS), wherein an event was defined as disease progression (PD), functional decline (FD) or death. In each arm, the null hypothesis that the median EFS would be ≤7 months was tested against a one-sided alternative according to the Brookmeyer Crowley test. Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. Results: After a median follow-up of 32.6 months, 140 events were observed in 158 evaluable patients. Median EFS was 8.2 months (90% CI, 5.9-8.9; p=0.188) in Arm A, versus 8.3 months (90% CI, 6.2-9.7; p=0.078) in Arm B. Progression-free survival, overall survival and response rates were similar in both groups. A higher percentage of dose reductions and discontinuations due to adverse events (AEs) was noted in Arm B. The most frequently reported non-hematological AEs were fatigue (grade [G] 2-3 toxicity occurrence in Arm A versus B: 43% and 51%, respectively) and peripheral neuropathy (G2-3 Arm A versus B: 19% and 38%, respectively). Conclusion: Pre-specified outcomes were similar in both treatment arms. However, 100 mg/m2 was significantly better tolerated with fewer neurotoxicity-related events, representing a more feasible dose to be recommended for older patients with advanced disease. Trial registration EudraCT identifier: 2012-002707-18, registered June 4 2012 - https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-002707-18/IT#E . NIH ClinicalTrials.gov identifier: NCT02783222, registered May 26 2016 – retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02783222