Metastasis and bone loss: Advancing treatment and prevention

Tumor metastasis to the skeleton affects over 400,000 individuals in the United States annually, more than any other site of metastasis, including significant proportions of patients with breast, prostate, lung and other solid tumors. Research on the bone microenvironment and its role in metastasis suggests a complex role in tumor growth. Parallel preclinical and clinical investigations into the role of adjuvant bone-targeted agents in preventing metastasis and avoiding cancer therapy-induced bone loss have recently reported exciting and intriguing results. A multidisciplinary consensus conference convened to review recent progress in basic and clinical research, assess gaps in current knowledge and prioritize recommendations to advance research over the next 5 years. The program addressed three topics: advancing understanding of metastasis prevention in the context of bone pathophysiology; developing therapeutic approaches to prevent metastasis and defining strategies to prevent cancer therapy-induced bone loss. Several priorities were identified: (1) further investigate the effects of bone-targeted therapies on tumor and immune cell interactions within the bone microenvironment; (2) utilize and further develop preclinical models to study combination therapies; (3) conduct clinical studies of bone-targeted therapies with radiation and chemotherapy across a range of solid tumors; (4) develop biomarkers to identify patients most likely to benefit from bone-targeted therapies; (5) educate physicians on bone loss and fracture risk; (6) define optimal endpoints and new measures of efficacy for future clinical trials; and (7) define the optimum type, dose and schedule of adjuvant bone-targeted therapy

The Lancet Breast Cancer Commission: tackling a global health, gender, and equity challenge

Breast cancer is an increasing global health, gender, socioeconomic, and equity challenge. In 2020, 2·3 million women were diagnosed with breast cancer and there were 685 000 deaths worldwide.1 Not only is breast cancer the highest incident cancer globally, but it is also the most prevalent, causing more disability-adjusted life-years lost than any other malignancy. Tackling breast cancer is a formidable task for health-care systems, policy makers, and other stakeholders. The numbers of people with metastatic breast cancer who go uncounted are concerning. Cancer registries record patients initially presenting with de-novo metastatic breast cancer, but data on those who develop metastases after a diagnosis of early breast cancer are scarce. In a world focused on breast cancer cure, these uncounted people living with metastatic disease face abandonment and stigma

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years

The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment

Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

Background Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer. Methods We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs). Findings We received data on 18 766 women (18 206 [97%] in trials of 2–5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87–1·01; 2p=0·08), distant recurrence (0·92, 0·85–0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83–0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73–0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78–0·94; 2p=0·002), distant recurrence (0·82, 0·74–0·92; 2p=0·0003), bone recurrence (0·72, 0·60–0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73–0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75–0·97; 2p=0·02). Interpretation Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began. Funding Cancer Research UK, Medical Research Council

Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials

Background Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials. Methods We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality). Findings Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5–14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21·4% for NACT versus 15·9% for adjuvant chemotherapy (5·5% increase [95% CI 2·4–8·6]; rate ratio 1·37 [95% CI 1·17–1·61]; p=0·0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38·2% for NACT vs 38·0% for adjuvant chemotherapy; rate ratio 1·02 [95% CI 0·92–1·14]; p=0·66), breast cancer mortality (34·4% vs 33·7%; 1·06 [0·95–1·18]; p=0·31), or death from any cause (40·9% vs 41·2%; 1·04 [0·94–1·15]; p=0·45). Interpretation Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered—eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy