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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.

Preoperative and perioperative aromatase inhibitor (POAI) therapy has the potential to improve outcomes in women with operable oestrogen receptor-positive primary breast cancer. It has also been suggested that tumour Ki67 values after 2 weeks (Ki672W) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67B). The POETIC trial aimed to test these two hypotheses. POETIC was an open-label, multicentre, parallel-group, randomised, phase 3 trial (done in 130 UK hospitals) in which postmenopausal women aged at least 50 years with WHO performance status 0–1 and hormone receptor-positive, operable breast cancer were randomly assigned (2:1) to POAI (letrozole 2·5 mg per day orally or anastrozole 1 mg per day orally) for 14 days before and following surgery or no POAI (control). Adjuvant treatment was given as per UK standard local practice. Randomisation was done centrally by computer-generated permuted block method (variable block size of six or nine) and was stratified by hospital. Treatment allocation was not masked. The primary endpoint was time to recurrence. A key second objective explored association between Ki67 (dichotomised at 10%) and disease outcomes. The primary analysis for clinical endpoints was by modified intention to treat (excluding patients who withdrew consent). For Ki67 biomarker association and endpoint analysis, the evaluable population included all randomly assigned patients who had paired Ki67 values available. This study is registered with ClinicalTrials.gov, NCT02338310; the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN registry, ISRCTN63882543. Recruitment is complete and long-term follow-up is ongoing. Between Oct 13, 2008, and April 16, 2014, 4480 women were recruited and randomly assigned to POAI (n=2976) or control (n=1504). On Feb 6, 2018, median follow-up was 62·9 months (IQR 58·1–74·1). 434 (10%) of 4480 women had a breast cancer recurrence (280 [9%] POAI; 154 [10%] control), hazard ratio 0·92 (95% CI 0·75–1·12); p=0·40 with the proportion free from breast cancer recurrence at 5 years of 91·0% (95% CI 89·9–92·0) for patients in the POAI group and 90·4% (88·7–91·9) in the control group. Within the POAI-treated HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67B and Ki672W (low–low) was 4·3% (95% CI 2·9–6·3), 8·4% (6·8–10·5) with high Ki67B and low Ki672W (high–low) and 21·5% (17·1–27·0) with high Ki67B and Ki672W (high–high). Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in the low–low group was 10·1% (95% CI 3·2–31·3), 7·7% (3·4–17·5) in the high–low group, and 15·7% (10·1–24·4) in the high–high group. The most commonly reported grade 3 adverse events were hot flushes (20 [1%] of 2801 patients in the POAI group vs six [<1%] of 1400 in the control group) and musculoskeletal pain (29 [1%] vs 13 [1%]). No treatment-related deaths were reported. POAI has not been shown to improve treatment outcome, but can be used without detriment to help select appropriate adjuvant therapy based on tumour Ki67. Most patients with low Ki67B or low POAI-induced Ki672W do well with adjuvant standard endocrine therapy (giving consideration to clinical–pathological factors), whereas those whose POAI-induced Ki672W remains high might benefit from further adjuvant treatment or trials of new therapies. Cancer Research UK.

The endothelin pathway has a role in bone metastases, which are characteristic of advanced prostate cancer. Atrasentan, an endothelin receptor antagonist, has shown activity in prostate cancer. We therefore assessed its effect on survival in patients with castration-resistant prostate cancer with bone metastases. In a double-blind phase 3 trial, men with metastatic castration-resistant prostate cancer, stratified for progression type (prostate-specific antigen or radiological), baseline pain, extraskeletal metastases, and bisphosphonate use, were randomly assigned in a 1:1 ratio to docetaxel (75 mg/m2 every 21 days, intravenously) with atrasentan (10 mg/day, orally) or placebo for up to 12 cycles and treated until disease progression or unacceptable toxicity. Patients who did not progress on treatment were permitted to continue atrasentan or placebo for up to 52 weeks. Coprimary endpoints were progression-free survival (PFS) and overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00134056. 498 patients were randomly assigned to the atrasentan group and 496 to the placebo group. The trial was halted early for futility in April, 2011, after a planned interim analysis. Median PFS was 9·2 months (95% CI 8·5–9·9) in the atrasentan group and 9·1 months (8·4–10·2) in the placebo group (hazard ratio 1·02, 0·89–1·16; p=0·81). Median overall survival was 17·8 months (16·4–19·8) in the atrasentan group versus 17·6 months (16·4–20·1) in the placebo group (1·04, 0·90–1·19; p=0·64). 278 (57%) of 492 patients in the atrasentan group had grade 3 and greater toxicity compared with 294 (60%) of 486 in the placebo group (p=0·22). Three deaths in the atrasentan group and seven in the placebo group were judged to be possibly or probably due to protocol treatment. Atrasentan, when added to docetaxel, does not improve overall survival or PFS in men with castration-resistant prostate cancer and bone metastases; therefore, single-agent docetaxel should remain as one of the standard treatments. National Cancer Institute, Sanofi-Aventis, and Abbott Laboratories.

Background In recent years, there is increasing evidence showing a beneficial outcome (e.g. progression free survival; PFS) after metastases-directed therapy (MDT) with external beam radiotherapy (EBRT) or targeted surgery for oligometastatic hormone sensitive prostate cancer (oHSPC). However, many patients do not qualify for these treatments due to prior interventions or tumor location. Such oligometastatic patients could benefit from radioligand therapy (RLT) with 177 Lu-PSMA; a novel tumor targeting therapy for end-stage metastatic castration-resistant prostate cancer (mCRPC). Especially because RLT could be more effective in low volume disease, such as the oligometastatic status, due to high uptake of radioligands in smaller lesions. To test the hypothesis that 177 Lu-PSMA is an effective treatment in oHSPC to prolong PFS and postpone the need for androgen deprivation therapy (ADT), we initiated a multicenter randomized clinical trial. This is globally, the first prospective study using 177 Lu-PSMA-I&T in a randomized multicenter setting. Methods & design This study compares 177 Lu-PSMA-I&T MDT to the current standard of care (SOC); deferred ADT. Fifty-eight patients with oHSPC (≤5 metastases on PSMA PET) and high PSMA uptake (SUVmax > 15, partial volume corrected) on 18 F-PSMA PET after prior surgery and/or EBRT and a PSA doubling time of < 6 months, will be randomized in a 1:1 ratio. The patients randomized to the interventional arm will be eligible for two cycles of 7.4GBq 177 Lu-PSMA-I&T at a 6-week interval. After both cycles, patients are monitored every 3 weeks (including adverse events, QoL- and xerostomia questionnaires and laboratory testing) at the outpatient clinic. Twenty-four weeks after cycle two an end of study evaluation is planned together with another 18 F-PSMA PET and (whole body) MRI. Patients in the SOC arm are eligible to receive 177 Lu-PSMA-I&T after meeting the primary study objective, which is the fraction of patients who show disease progression during the study follow up. A second primary objective is the time to disease progression. Disease progression is defined as a 100% increase in PSA from baseline or clinical progression. Discussion This is the first prospective randomized clinical study assessing the therapeutic efficacy and toxicity of 177 Lu-PSMA-I&T for patients with oHSPC. Trial registration Clinicaltrials.gov identifier: NCT04443062 .

Insulin-like growth factors (IGF-1 and IGF-2) bind to the IGF-1 receptor (IGF-1R), increasing cell proliferation and survival. Ganitumab is a monoclonal IgG1 antibody that blocks IGF-1R. We tested the efficacy and safety of adding ganitumab to endocrine treatment for patients with hormone-receptor-positive breast cancer. We did this phase 2 trial in outpatient clinics and hospitals. We enrolled postmenopausal women with hormone-receptor-positive, locally advanced or metastatic breast cancer previously treated with endocrine treatment. They were randomly assigned (2:1) with a central randomisation schedule to receive intravenous ganitumab 12 mg per kg bodyweight or placebo in combination with open-label intramuscular fulvestrant (500 mg on day 1, then 250 mg on days 15, 29, and every 28 days) or oral exemestane (25 mg once daily) on a 28-day cycle. Patients, investigators, study monitors, and the sponsor staff were masked to treatment allocation. Response was assessed every 8 weeks. The primary endpoint was median progression-free survival in the intention-to-treat population. We analysed overall survival as one of our secondary endpoints. The study is registered at ClinicalTrials.gov, number NCT00626106. We screened 189 patients and enrolled 156 (106 in the ganitumab group and 50 in the placebo group). Median progression-free survival did not differ significantly between the ganitumab and placebo groups (3·9 months, 80% CI 3·6–5·3 vs 5·7 months, 4·4–7·4; hazard ratio [HR] 1·17, 80% CI 0·91–1·50; p=0·44). However, overall survival was worse in the the ganitumab group than in the placebo group (HR 1·78, 80% CI 1·27–2·50; p=0·025). With the exception of hyperglycaemia, adverse events were generally similar between groups. The most common grade 3 or higher adverse event was neutropenia—reported by six of 106 (6%) patients in the ganitumab group and one of 49 (2%) in the placebo group. Hyperglycaemia was reported by 12 of 106 (11%) patients in the ganitumab group (with six patients having grade 3 or 4 hyperglycaemia) and none of 49 in the placebo group. Serious adverse events were reported by 27 of 106 (25%) patients in the ganitumab group and nine of 49 (18%) patients in the placebo group. Addition of ganitumab to endocrine treatment in women with previously treated hormone-receptor-positive locally advanced or metastatic breast cancer did not improve outcomes. Our results do not support further study of ganitumab in this subgroup of patients. Amgen.

In this study, women 70 years of age or older who had early, estrogen-receptor–positive breast cancer underwent lumpectomy and were then randomly assigned to receive tamoxifen alone or with local irradiation. The only significant difference in outcome was in the probability of local recurrence at five years (4 percent in the tamoxifen group and 1 percent in the combined-treatment group). For women 70 years of age or older, lumpectomy plus adjuvant treatment with tamoxifen (without local irradiation) is a reasonable choice. Multiple trials of breast-conserving surgery for breast cancer 1 – 5 have shown that postoperative irradiation decreases the rate of ipsilateral recurrence but offers no survival benefit. However, the high rate of recurrence with surgery alone (10 to 40 percent) has suggested that the only two appropriate treatments are modified radical mastectomy and breast-conserving surgery plus adjuvant radiation therapy. Since tamoxifen, with 3 or without 4 radiation therapy, decreases the risk of recurrence, and given the cost and adverse effects of breast irradiation 5 – 12 and its negative effect on the quality of life, 6 , 7 we designed a trial to determine whether women 70 years . . .

This randomized trial compared local radiotherapy plus tamoxifen with tamoxifen alone in women 50 years of age or older who had undergone breast-conserving surgery for breast cancer. As compared with tamoxifen alone, radiotherapy plus tamoxifen substantially lowered the rate of local relapse. Overall survival at five years did not differ significantly between the two groups. The results support the use of tamoxifen with radiotherapy for women 50 years of age or older who have undergone lumpectomy for invasive breast cancer. In most women with breast cancer, breast-conserving surgery plus local radiotherapy reduces the risk of recurrence in the ipsilateral breast and results in long-term survival similar to that after mastectomy. 1 – 4 Adjuvant treatment with tamoxifen also reduces the risk of local relapse. 5 , 6 Since mammographic screening is capable of detecting relatively small tumors and salvage therapy is successful in many women who have a relapse in the breast, 3 , 7 there is interest in identifying patients at low risk who could avoid radiotherapy. They are likely to have a small tumor and negative axillary nodes. 8 Postmenopausal patients have a lower risk . . .

Aromatase inhibitors have shown increased efficacy compared with tamoxifen in postmenopausal early breast cancer. We aimed to assess the efficacy and safety of anastrozole versus tamoxifen in premenopausal women receiving goserelin for early breast cancer in the neoadjuvant setting. In this phase 3, randomised, double-blind, parallel-group, multicentre study, we enrolled premenopausal women with oestrogen receptor (ER)-positive, HER2-negative, operable breast cancer with WHO performance status of 2 or lower. Patients were randomly assigned (1:1) to receive goserelin 3·6 mg/month plus either anastrozole 1 mg per day and tamoxifen placebo or tamoxifen 20 mg per day and anastrozole placebo for 24 weeks before surgery. Patients were randomised sequentially, stratified by centre, with randomisation codes. All study personnel were masked to study treatment. The primary endpoint was best overall tumour response (complete response or partial response), assessed by callipers, during the 24-week neoadjuvant treatment period for the intention-to-treat population. The primary endpoint was analysed for non-inferiority (with non-inferiority defined as the lower limit of the 95% CI for the difference in overall response rates between groups being 10% or less); in the event of non-inferiority, we assessed the superiority of the anastrozole group versus the tamoxifen group. We included all patients who received study medication at least once in the safety analysis set. We report the primary analysis; treatment will also continue in the adjuvant setting for 5 years. This trial is registered with ClinicalTrials.gov, number NCT00605267. Between Oct 2, 2007, and May 29, 2009, 204 patients were enrolled. 197 patients were randomly assigned to anastrozole (n=98) or tamoxifen (n=99), and 185 patients completed the 24-week neoadjuvant treatment period and had breast surgery (95 in the anastrazole group, 90 in the tamoxifen group). More patients in the anastrozole group had a complete or partial response than did those in the tamoxifen group during 24 weeks of neoadjuvant treatment (anastrozole 70·4% [69 of 98 patients] vs tamoxifen 50·5% [50 of 99 patients]; estimated difference between groups 19·9%, 95% CI 6·5–33·3; p=0·004). Two patients in the anastrozole group had treatment-related grade 3 adverse events (arthralgia and syncope) and so did one patient in the tamoxifen group (depression). One serious adverse event was reported in the anastrozole group (benign neoplasm, not related to treatment), compared with none in the tamoxifen group. Given its favourable risk–benefit profile, the combination of anastrozole plus goserelin could represent an alternative neoadjuvant treatment option for premenopausal women with early-stage breast cancer. AstraZeneca.

In a randomized comparison of letrozole with tamoxifen for the adjuvant treatment of early-stage, hormone-receptor–positive breast cancer in more than 8000 postmenopausal women, disease-free survival was significantly longer in the letrozole group. The five-year survival rates were 84.0 percent in the letrozole group and 81.4 percent in the tamoxifen group. In more than 8000 postmenopausal women with early breast cancer, disease-free survival was significantly longer in the letrozole group. The five-year survival rates were 84.0 percent in the letrozole group and 81.4 percent in the tamoxifen group. Adjuvant endocrine therapy with tamoxifen significantly prolongs disease-free and overall survival in postmenopausal women with early-stage breast cancer. Five years of treatment with tamoxifen reduces the risk of breast-cancer recurrence by 47 percent and the risk of death by 26 percent among patients with hormone-receptor–positive breast cancer. 1 Despite these benefits, about half the women so treated relapse. Tamoxifen treatment is associated with rare but serious adverse effects, including endometrial cancer and thromboembolism. 1 In contrast to tamoxifen, which inhibits the activity of estrogen by competitively binding to the estrogen receptor, aromatase inhibitors block the conversion of androgens to estrogens and reduce . . .

Treatment of breast cancer with aromatase inhibitors is associated with damage to bones. NCIC CTG MA.27 was an open-label, phase 3, randomised controlled trial in which women with breast cancer were assigned to one of two adjuvant oral aromatase inhibitors—exemestane or anastrozole. We postulated that exemestane—a mildly androgenic steroid—might have a less detrimental effect on bone than non-steroidal anastrozole. In this companion study to MA.27, we compared changes in bone mineral density (BMD) in the lumbar spine and total hip between patients treated with exemestane and patients treated with anastrozole. In MA.27, postmenopausal women with early stage hormone (oestrogen) receptor-positive invasive breast cancer were randomly assigned to exemestane 25 mg versus anastrozole 1 mg, daily. MA.27B recruited two groups of women from MA.27: those with BMD T-scores of −2·0 or more (up to 2 SDs below sex-matched, young adult mean) and those with at least one T-score (hip or spine) less than −2·0. Both groups received vitamin D and calcium; those with baseline T-scores of less than −2·0 also received bisphosphonates. The primary endpoints were percent change of BMD at 2 years in lumbar spine and total hip for both groups. We analysed patients according to which aromatase inhibitor and T-score groups they were allocated to but BMD assessments ceased if patients deviated from protocol. This study is registered with ClinicalTrials.gov, NCT00354302. Between April 24, 2006, and May 30, 2008, 300 patients with baseline T-scores of −2·0 or more were accrued (147 allocated exemestane, 153 anastrozole); and 197 patients with baseline T-scores of less than −2·0 (101 exemestane, 96 anastrozole). For patients with T-scores greater than −2·0 at baseline, mean change of bone mineral density in the spine at 2 years did not differ significantly between patients taking exemestane and patients taking anastrozole (−0·92%, 95% CI −2·35 to 0·50 vs −2·39%, 95% CI −3·77 to −1·01; p=0·08). Respective mean loss in the hip was −1·93% (95% CI −2·93 to −0·93) versus −2·71% (95% CI −4·32 to −1·11; p=0·10). Likewise for those who started with T-scores of less than −2·0, mean change of spine bone mineral density at 2 years did not differ significantly between the exemestane and anastrozole treatment groups (2·11%, 95% CI −0·84 to 5·06 vs 3·72%, 95% CI 1·54 to 5·89; p=0·26), nor did hip bone mineral density (2·09%, 95% CI −1·45 to 5·63 vs 0·0%, 95% CI −3·67 to 3·66; p=0·28). Patients with baseline T-score of −2·0 or more taking exemestane had two fragility fractures and two other fractures, those taking anastrozole had three fragility fractures and five other fractures. For patients who had baseline T-scores of less than −2·0 taking exemestane, one had a fragility fracture and four had other fractures, whereas those taking anastrozole had five fragility fractures and one other fracture. Our results demonstrate that adjuvant treatment with aromatase inhibitors can be considered for breast cancer patients who have T-scores less than −2·0. Canadian Cancer Society Research Institute, Pfizer, Canadian Institutes of Health Research.