MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer.

Purpose Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer previously treated with endocrine therapy. Methods MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events. Results Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%). Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.

Tissue confirmation of disease recurrence in breast cancer patients: pooled analysis of multi-centre, multi-disciplinary prospective studies.

BACKGROUND: Treatment decisions in recurrent breast cancer are usually based on the estrogen (ER), progesterone (PgR) and HER2 receptor status of the primary tumour. Retrospective studies suggest that discordance between receptor expression of primary and recurrent breast cancer exists. METHODS: A pooled analysis of individual patient data from two large prospective studies comprising biopsy of recurrent lesions obtained from consenting patients was undertaken. Tissue was analyzed for ER, PgR by immunohistochemistry and HER2 by FISH. Receptor status of recurrent disease was compared with that of the primary tumour. Recruiting clinicians assessed whether or not receptor discordance affected subsequent systemic treatment. RESULTS: Two hundred and eighty-nine patients underwent biopsy. Recurrent biopsy specimens were obtained from locoregional recurrence in 48.1% and from distant metastases in 51.9%. Distant sites included skin/soft tissue (25.0%), bone/bone marrow (19.2%) and liver (15.8%). Benign disease or second primary cancer was observed in 7.6% of biopsies. Discordance in ER, PgR or HER2 between confirmed primary and recurrent breast cancer was 12.6%, 31.2% and 5.5%, respectively (all p<0.001). Biopsy results altered management in 14.2% of patients undergoing biopsy (95% confidence intervals 10.4-18.8%, p≤0.0001). The duration between primary and recurrent disease, the site of recurrence and the receptor profile of the primary tumour did not affect discordance rates. CONCLUSIONS: There is substantial discordance in receptor status between primary and recurrent breast cancer. The number needed to biopsy in order to alter treatment was 7.1. Patients with recurrent breast cancer should have tissue confirmation of receptor status of recurrent disease.

Assessing women at high risk of breast cancer: a review of risk assessment models.

Women who are at high risk of breast cancer can be offered more intensive surveillance or prophylactic measures, such as surgery or chemoprevention. Central to decisions regarding the level of prevention is accurate and individualized risk assessment. This review aims to distill the diverse literature and provide practicing clinicians with an overview of the available risk assessment methods. Risk assessments fall into two groups: the risk of carrying a mutation in a high-risk gene such as BRCA1 or BRCA2 and the risk of developing breast cancer with or without such a mutation. Knowledge of breast cancer risks, taken together with the risks and benefits of the intervention, is needed to choose an appropriate disease management strategy. A number of models have been developed for assessing these risks, but independent validation of such models has produced variable results. Some models are able to predict both mutation carriage risks and breast cancer risk; however, to date, all are limited by only moderate discriminatory accuracy. Further improvements in the knowledge of how to best integrate both new risk factors and newly discovered genetic variants into these models will allow clinicians to more accurately determine which women are most likely to develop breast cancer. These steady and incremental improvements in models will need to undergo revalidation.

A phase 2 trial exploring the effects of high-dose (10,000 IU/day) vitamin D(3) in breast cancer patients with bone metastases.

BACKGROUND: Vitamin D deficiency has potential roles in breast cancer etiology and progression. Vitamin D deficiency has also been associated with increased toxicity from bisphosphonate therapy. The optimal dose of vitamin D supplementation is unknown, but daily sunlight exposure can generate the equivalent of a 10,000-IU oral dose of vitamin D(3). This study therefore aimed to assess the effect of this dose of vitamin D(3) in patients with bone metastases from breast cancer. METHODS: Patients with bone metastases treated with bisphosphonates were enrolled into this single-arm phase 2 study. Patients received 10,000 IU of vitamin D(3) and 1000 mg of calcium supplementation each day for 4 months. The effect of this treatment on palliation, bone resorption markers, calcium metabolism, and toxicity were evaluated at baseline and monthly thereafter. RESULTS: Forty patients were enrolled. No significant changes in bone resorption markers were seen. Despite no change in global pain scales, there was a significant reduction in the number of sites of pain. A small but statistically significant increase in serum calcium was seen, as was a significant decrease in serum parathyroid hormone. Treatment unmasked 2 cases of primary hyperparathyroidism, but was not associated with direct toxicity. CONCLUSIONS: Daily doses of 10,000 IU vitamin D(3) for 4 months appear safe in patients without comorbid conditions causing hypersensitivity to vitamin D. Treatment reduced inappropriately elevated parathyroid hormone levels, presumably caused by long-term bisphosphonate use. There did not appear to be a significant palliative benefit nor any significant change in bone resorption.

The role of palliative care in the lung cancer patient: can we improve quality while limiting futile care?

PURPOSE OF REVIEW: Lung cancer is the leading cause of cancer death worldwide, and is diagnosed in the advanced stage in 70% of patients. This study will summarize the most up-to-date strategies in supportive care for patients with metastatic lung cancer. RECENT FINDINGS: Two recent systematic reviews concluded that longer-course radiation treatment offers a survival and symptom benefit over short-course treatment in patients with good performance status. Whereas several meta-analyses have demonstrated the benefit of palliative chemotherapy for quality of life and survival, the optimal drug combination and number of courses remain under study, and proper stratification of patients is essential. Clinical practice guidelines are available for evidence-based management of symptoms common in patients with lung cancer. Early integration of specialized palliative care shows promise as a means of improving patient care and limiting unnecessary treatment. SUMMARY: Supportive care for the patient with advanced lung cancer should involve consideration and discussion of all therapeutic options that could provide benefit. Depending on the clinical situation, these could include chemotherapy or radiation, and should always include appropriate symptom management and family support. Research incorporating symptom and quality-of-life measures is challenging, but is also essential to inform excellent supportive care.

Adjuvant bisphosphonate therapy for breast cancer patients: Standard of care or future direction?

Bone is the most common site of metastatic spread in breast cancer patients. The use of bisphosphonates (BPs) in women with bone metastases from breast cancer has been shown to reduce the incidence, and delay the onset of, skeletal-related events. Indeed, BPs are now an established standard of care in treating patients with bone metastases. As with many new therapies, once efficacy in the metastatic setting is demonstrated, therapies are tested in the adjuvant setting. There are a number of trials that have tested the hypothesis that BP therapy in women with early breast cancer may not only reduce the development of skeletal metastases but also improve both disease-free and overall survival; recent randomized trials have demonstrated intriguing results regarding the possible anticancer effects of adjuvant BP therapy. Furthermore, interesting signals are filtering through from trials evaluating the role of BPs to prevent cancer-treatment induced bone loss. Many of these trials will be reported in the near future. In this article we review possible subgroups that may benefit from adjuvant treatment with BPs, and ongoing trials that may offer more definitive answers.

Overcoming endocrine resistance in breast cancer: are signal transduction inhibitors the answer?

Endocrine therapy is probably the most important systemic therapy for hormone receptor positive breast cancer. Hormonal manipulation was the first targeted treatment employed in breast cancer therapy even before the role of the estrogen (ER) and progesterone receptors (PR) had been elucidated. Unfortunately, a substantial proportion of patients, despite being ER and/or PR positive, are either primarily resistant to hormone therapies or will develop hormone resistance during the course of their disease. Signaling through complex growth factor receptor pathways, which activate the ER are emerging as important causes of endocrine resistance. Targeted therapies, such as signal transduction inhibitors (STIs), are being explored as agents to be able to potentially overcome this crosstalk and thus, resistance to hormone treatment. This article reviews the biology of the ER, the proposed mechanisms of endocrine resistance, and ongoing clinical trials with STIs in combination with hormonal manipulation as a means to overcome endocrine resistance.