Combined Therapies Increase Adverse Events in Patients With Hormone Receptor–Positive Metastatic Breast Cancer


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In patients with hormone receptor–positive metastatic breast cancer, the combination of targeted agents and hormone therapy is associated with a significantly increased risk of severe adverse events, according to research presented by Matteo Lambertini, MD, European Society for Medical Oncology (ESMO) Fellow at the Institut Jules Bordet in Brussels; Samuel Martel, MD, at CISSS Montérégie Centre/Hôpital Charles-Lemoyne, Université de Sherbrooke in Québec; and colleagues, in a poster at the European School of Oncology (ESO)–ESMO 4th International Consensus Conference for Advanced Breast Cancer (ABC4) in Lisbon1 and simultaneously published in Cancer Treatment Review.2 

Previous studies have shown that combining targeted agents and endocrine therapy improves outcomes in patients with hormone receptor–positive metastatic breast cancer but increases the risk of adverse events. Until now, a more precise estimation of the specific additional toxicity burden caused by these agents has remained uncertain. Though most of the side effects evaluated in the study are treatable and potentially preventable, the information gained from this research will enable physicians and patients to make more informed choices, the investigators maintain.


The results of our study can potentially serve as a basis for designing future trials of co-medications for preventing and treating adverse events.
— Matteo Lambertini, MD

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Study Details

The researchers analyzed data from 8,529 patients who took part in 16 randomized controlled trials. They conducted a systematic literature search of MEDLINE, EMBASE, and Cochrane Library and evaluated proceedings from major conferences up to July 17, 2017, to identify randomized controlled trials that investigated endocrine therapy plus cyclin-dependent kinase (CDK) 4/6 inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and anti-HER2 agents—as compared to endocrine therapy alone—in patients with advanced hormone receptor–positive breast cancer. 

Overall, the addition of targeted agents to hormonal therapy was associated with a significantly higher risk of grade 3 or 4 adverse events, the investigators reported. CDK4/6 inhibitors increased the risk of grade 3 or 4 adverse side effects almost threefold, anti-HER2 agents increased the risk 2.5-fold, PI3K inhibitors doubled the risk, and mTOR inhibitors nearly doubled the risk. 

TREATMENT COMBINATIONS AND ADVERSE EVENTS

  • Combining targeted agents with endocrine therapy in patients with advanced hormone receptor–positive breast cancer increases the risk of grade 3–4 adverse events.
  • Most of these adverse events are treatable and potentially avoidable, underlining the need for open and effective health professional/patient communication as well as accurate and easy-to-understand patient information/education, before starting a combination regimen. 
  • Incorporating patient-reported outcomes into clinical trials could better inform treatment decisions. 

Grade 3 or 4 adverse events with the highest risk by class of drug were neutropenia for CDK4/6 inhibitors, stomatitis for mTOR inhibitors, hyperglycemia for P13K inhibitors, and diarrhea for anti-HER2 agents (this last mainly due to the fact that lapatinib [Tykerb] was the anti-HER2 agent used in three of the four studies investigating anti-HER2 agents with hormone therapy). Anti-HER2 agents, CDK4/6 inhibitors, and PI3K inhibitors significantly increased the risk of grade 3 and 4 fatigue, but mTOR inhibitors did not, whereas anti-HER2 agents, PI3K inhibitors, and mTOR inhibitors significantly increased the risk of grade 3 and 4 diarrhea, but CDK4/6 inhibitors did not. 

Although the results show that CDK4/6 inhibitors were associated with the highest risk of developing grade 3 and 4 adverse events, Dr. Lambertini explained in a press release that this is mainly due to the increased risk of developing grade 3 or 4 blood toxicities, mainly neutropenia. However, CDK4/6 inhibitors are known to be better tolerated than mTOR or PI3K inhibitors, and their side effects can be managed relatively easily with early detection and dose delay or reduction; nevertheless, this could not be illustrated in the study, which focused only on adverse events registered in the trials and not on patient-reported outcomes. Based on this observation, he and his team maintain that going forward, the use of patient-reported outcomes should be implemented in clinical trials, as they more accurately measure the frequency, severity, and impact of cancer treatment on a patient’s quality of life. 

How These Findings Can Be Used 

Since the majority of patients with advanced hormone receptor–positive breast cancer are candidates to receive a combined treatment with targeted agents and hormone therapy at some point during their treatment, effective communication between patients and physicians is key, the researchers added. The potential for specific toxicities should be taken into account and discussed with patients when choosing whether or not to opt for a combination regimen. 

“The results of our study can potentially serve as a basis for designing future trials of co-medications for preventing and treating adverse events; such studies are to be considered a research priority, as more patients are likely to be managed with these new treatments in the coming years,” Dr. Lambertini continued. 

Fatima Cardoso, MD

Fatima Cardoso, MD

Chair of the ABC4 conference, Fatima Cardoso, MD, Director of the Breast Unit of the Champalimaud Cancer Centre in Lisbon, said in a press release, “This study clearly highlights that combined treatment with endocrine therapy and targeted agents is substantially more toxic than endocrine therapy alone. This is very important when making decisions in clinical practice. So far, with the exception of anti-HER2 therapies, none of the other agents have been shown to improve survival of patients; therefore, the benefit provided must be balanced with their added toxicity, and some patients will be very well treated with endocrine therapy alone. Furthermore, efforts must be made to use the correct quality-of-life tools and patient-reported outcomes to evaluate the impact of new treatments on patients’ lives.” ■

DISCLOSURE: Dr. Lambertini reported no conflicts of interest. Dr. Cardoso is a consultant for and on the advisory board of Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, -Merck Sharp & Dohme, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, Roche, Sanofi, Seattle Genetics, and Teva.

REFERENCES

1. Lambertini M, Bruzzone M, Ceppi M, et al: Adverse events of targeted agents added to endocrine therapy in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis. ESO-ESMO Advanced Breast Cancer 4th International Consensus Conference. Abstract PO66. Presented November 3, 2017. 

2. Martel S, Bruzzone M, Ceppi M, et al: Risk of adverse events with the addition of targeted agents to endocrine therapy in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis. Cancer Treat Rev. October 28, 2017 (early release online).


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