Doctors prescribe drugs known as CDK inhibitors to treat some women with estrogen-receptor-positive (ER+) metastatic breast cancer. Research into these drugs is ongoing, and new, promising CDK inhibitor options are on the horizon. Here, I address the current outlook for CDK inhibitors in ER+ breast cancer.
First, some background: ER+ breast cancers comprise about 70% of all breast cancers. The name reflects the fact that cells of these cancers express estrogen receptors (ERs), which are protein features targeted by many treatment strategies for this cancer type. The estrogen receptor (ER) protein is a treatment target not only because “it is there,” but mainly because it drives tumor cell proliferation in ER+ breast cancer. The activity of the ER depends on its binding to the hormone estrogen, and treatments known as endocrine drugs aim to prevent this interaction. Some endocrine drugs inhibit the synthesis of estrogen in the body (e.g., aromatase inhibitors, such as letrozole and anastrozole), and others prevent the interaction of estrogen with ERs (e.g., ER modulators such as tamoxifen, or the pure anti-estrogen drug fulvestrant). The problem of course is that, in metastatic breast cancer, resistance develops to each and every endocrine drug used. Continue reading…
“Results of an initial study of tumors from patients with lung cancer or head and neck cancer suggest that the widespread acquired resistance to immunotherapy drugs known as checkpoint inhibitors may be due to the elimination of certain genetic mutations needed to enable the immune system to recognize and attack malignant cells. The study, conducted by researchers on the cells of five of their patients treated at the Johns Hopkins Kimmel Cancer Center, is described online Dec. 28 in Cancer Discovery.”
“The first phase III study of PD-L1 inhibitor atezolizumab in previously-treated non-small-cell lung cancer has seen significant improvements in survival compared to standard chemotherapy, researchers reported at the ESMO 2016 Congress in Copenhagen.
“PD-L1 inhibitors are of a class of cancer immunotherapies called checkpoint inhibitors, and work by inhibiting one of the mechanisms of resistance developed by cancer cells in order to evade the immune system.”
“A new type of cancer drug designed to unleash the immune system is revolutionizing treatment for advanced melanoma, lung cancer and other malignancies. But some patients who initially respond to the therapy relapse, and researchers are anxious to figure out how and why the delayed resistance occurs.
” ‘Does the immune system stop working, or does the cancer change so that it’s no longer responding to the immune system?’ said Antoni Ribas, director of the Jonsson Comprehensive Cancer Center Tumor Immunology Program at the University of California at Los Angeles.
“New research by Ribas and others, published online Wednesday in the New England Journal of Medicine, provides some answers. The study, which outlines key mechanisms in how melanoma becomes resistant to immunotherapy, found that genetic changes in tumors allowed them to avoid recognition by the immune system or become less sensitive to its attacks.”
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“The use of drugs that target genetic mutations driving the growth of tumors has revolutionized treatment for several serious forms of cancer, but in almost every case, tumors become resistant to the drugs’ therapeutic effects and resume growth, often through the emergence of new mutations, which has spurred the development of more powerful drugs that can overcome resistance mutations. In the Dec. 24 issue of New England Journal of Medicine, Massachusetts General Hospital (MGH) physicians report their study examining the evolution of drug resistance in a lung cancer patient treated with multiple different targeted therapies. When resistance developed to the third targeted therapy, the new mutation actually restored the cancer’s response to the very first targeted therapy drug used to treat the patient.”
“The ALK inhibitor alectinib was highly active and well-tolerated in patients with ALK-rearranged, crizotinib-refractory, advanced non–small-cell lung cancer (NSCLC), according to results of a phase II trial.
“In this trial, 138 patients with crizotinib-refractory ALK-positive NSCLC were treated with alectinib; 122 of these patients were evaluable for response, and 61% had central nervous system (CNS) metastases at baseline. The results were published in the Journal of Clinical Oncology.
“ ‘Almost all patients invariably experience progression on crizotinib, and approximately 40% of the patients with ALK-rearranged NSCLC develop CNS metastases as an initial site of progression,’ wrote study authors led by Sai-Hong Ignatius Ou, MD, PhD, of the Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine in Orange, California. Alectinib is approximately five times as potent an ALK inhibitor as crizotinib, and can inhibit most of the acquired ALK resistance mutations to crizotinib.”
“The study is also a proof of principle that tests for cancer DNA in the bloodstream can be used to detect drug resistance mutations – allowing patients who will not benefit from one drug to be given an alternative treatment instead.
“Researchers at The Institute of Cancer Research, London, the Royal Marsden NHS Foundation Trust, and the University of Trento, Italy, analysed 274 blood samples from 97 patients using state-of-the-art DNA sequencing techniques.
“They found that mutations in a gene called the androgen receptor (AR) predicted resistance to the prostate cancer drug abiraterone, and that patients with these mutations had poorer survival.”
“In a phase III IMPRESS trial reported in The Lancet Oncology, Soria et al found no progression-free survival benefit of adding gefitinib (Iressa) to platinum-based doublet chemotherapy in patients with advanced EGFR-mutant non–small cell lung cancer (NSCLC) who had acquired resistance to first-line gefitinib.
“In the double-blind trial, 265 chemotherapy-naive patients from 11 countries who had stage IIIB to IV EGFR-mutant disease and disease control with first-line gefitinib and recent disease progression took part. They were randomly assigned between March 2012 and December 2013 to receive cisplatin 75 mg/m2 plus pemetrexed (Alimta) 500 mg/m2 on the first day of a maximum of six chemotherapy cycles plus either daily gefitinib 250 mg (n = 133) or placebo (n = 132) continued until disease progression or discontinuation for other reasons…
“The investigators concluded: ‘Continuation of gefitinib after radiological disease progression on first-line gefitinib did not prolong progression-free survival in patients who received platinum-based doublet chemotherapy as subsequent line of treatment. Platinum-based doublet chemotherapy remains the standard of care in this setting.’ ”
“The ALK and RET inhibitor alectinib yielded good response rates and was very well tolerated in a phase II trial of patients with advanced, ALK-positive non–small-cell lung cancer (NSCLC; abstract 8008). Results were presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 29 to June 2, in Chicago.
“Crizotinib is currently the standard-of-care for advanced, treatment-naive ALK-positive NSCLC. ‘However, the median progression-free survival (PFS) for these patients on crizotinib is under 12 months,’ said Sai-Hong Ignatius Ou, MD, PhD, of the UC Irvine Medical Center in California. ‘This is in part due to development of ALK mutations that are resistant to crizotinib.’
“Alectinib is a next-generation inhibitor that is highly selective for ALK and RET; as an ALK inhibitor, Ou said, it is approximately five times as potent as crizotinib. It can inhibit the majority of clinically relevant acquired ALK mutations.”