New Research Raises Concerns About PI3K Mutation as A Drug Target in Breast Cancer

“A leading gene candidate that has been the target of breast cancer drug development may not be as promising as initially thought, according to research published in open access journal Genome Medicine.”Mutation in the gene PIK3CA is the second most prevalent gene mutation in breast cancer and is found in 20% of all breast cancers. This has led people to think these changes may be driving breast cancer. Yet these mutations are also known to be present in neoplastic lesions -pre-cancerous growths many of which are thought to be benign, that have not invaded the surrounding tissue.

“Researchers from Stanford University wanted to better understand these neoplastic growths and how they related to the carcinoma. They sequenced the genes from tissue taken from the breasts of six women who had undergone a mastectomy, leading to a total of 66 samples, which included 18 carcinomas and 34 neoplastic lesions.

“A specific mutation in the PIK3CA gene occurs in the same patient multiple times. This was found to be the case for four out of the six women. In two out of these four cases, this mutation occurs in the neoplastic lesions, which are not considered tumors, but does not occur in the invasive carcinoma.”


Lung Cancer Pioneer Thomas Lynch Discusses the State of the Art

“Thomas Lynch, MD, has been a leader in the development of numerous novel therapies for the treatment of lung cancer. His significant contributions to the field have earned him great recognition, including the 2013 Giants of Cancer CareTM award in Lung Cancer for his pioneering use of molecular testing for EGFR mutations.

“Lynch, who is director of the Yale Cancer Center and physician-in-chief at the Smilow Cancer Hospital at Yale-New Haven, recently sat down with OncLive and discussed key strategies and trends in the management of lung cancer. In a wide-ranging interview, Lynch provides expert insight across the spectrum of care, from screening to the challenges associated with resistance mutations.”


Crizotinib Is Highly Active in Lung Cancer with ROS1 Abnormality

“In a retrospective study in the European EUROS1 cohort reported in the Journal of Clinical Oncology, Mazières found that crizotinib (Xalkori) treatment was associated with an 80% response rate in patients with stage IV lung adenocarcinoma with ROS1 rearrangement.

“The study involved 31 patients who received crizotinib therapy through individual off-label use. Patients had a median age of 50.5 years, 64.5% were women, and 67.7% were never-smokers. Patients had received zero (n = 1), one (n = 9), two (n = 5), three (n = 3), or more than three (n = 13) lines of chemotherapy before crizotinib.

“Among 30 patients evaluated for response, 24 (80.0%) had objective response, including complete response in 5; 2 had stable disease (disease control rate of 86.7%); and 4 had disease progression. Median progression-free survival was 9.1 months, and 12-month progression-free survival was 44%. No unexpected adverse effects were observed…

“The investigators concluded: ‘Crizotinib was highly active at treating lung cancer in patients with a ROS1 rearrangement, suggesting that patients with lung adenocarcinomas should be tested for ROS1. Prospective clinical trials with crizotinib and other ROS1 inhibitors are ongoing or planned.’ ”


In NSCLC, Why Some Patients Respond to Immunotherapy

“Immunotherapy with drugs that act on the program death (PD) pathway offers a novel approach to the treatment of non–small cell lung cancer (NSCLC), and a new study provides insights into how these drugs may result in lasting and durable responses in these patients.

“The new study, published online on March 12 in Science, suggests that patients with a high mutational burden in their tumors may be most likely to benefit from treatment with a PD-1 inhibitor.

” ‘The study suggests that the genomic landscape of lung cancers shapes the response to anti-PD-1 therapy,’ corresponding author Timothy Chan, MD, PhD, cancer geneticist in the Human Oncology and Pathogenesis Program and vice chair of radiation oncology at the Memorial Sloan Kettering Cancer Center (MSKCC), in New York City, commented in an institution press release.”


NCCN Recommends Only One Genomic Test for Breast Cancer

“The National Comprehensive Cancer Network (NCCN) only endorses one genomic test for use in patients with early-stage breast cancer, according to a presenter here at the NCCN 20th Annual Conference.

“Oncotype DX, a 21-gene assay from Genomic Health, has won that honor, said presenter Amy Cyr, MD, from the Siteman Cancer Center at Washington University in St. Louis, Missouri.

“The test serves two functions. In addition to providing a prognosis, the test has ‘some prediction capabilities in terms of therapy; it actually predicts a response to chemotherapy, compared with no chemotherapy,’ she explained.”


New Test to Aid Melanoma Diagnosis: Ready for Clinical Use?

“Differentiating between malignant melanoma and benign skin moles can be difficult in about 15% of cases, where histopathologic analysis is not straightforward because of ambiguous findings.

“A new 23-gene signature test (myPath Melanoma, Myriad Genetics) could be helpful in these instances, researchers working with the company suggest.

“The test was developed with a training set and then validated in an independent cohort. The results were published online March 2 in the Journal of Cutaneous Pathology.

” ‘myPath Melanoma is a powerful new molecular diagnostic test that analyzes genetic information inside skin cells to help us understand the biology of a patient’s skin lesion and objectively differentiate benign moles from potentially lethal melanomas,’ researcher Loren Clarke, MD, medical director for dermatology at Myriad, said in a company press release.”


Doctors Study Tumors' Genetic Makeup to Guide Cancer Treatment

“When Jen Morey was diagnosed with colon cancer in June 2013, her oncologist began treating her with a chemotherapy usually prescribed for that type of cancer. But after a couple of months, the malignancy was still growing, and rapidly. The therapy was failing.

“So her doctor ordered a test to identify aspects of the tumor’s genetic makeup that might be fueling its growth.

“Morey’s oncologist was surprised when the tumor profile test, as the technology is called, showed that the cancerous cells in her colon had a genetic mutation found almost exclusively in breast cancer. So he started her on a drug used mostly for fighting breast cancer.”


Melanomas with NRAS Mutations Are More Responsive to Immunotherapies

“Researchers investigating whether tumor genotype correlates with benefit from immune therapy in melanoma has found that patients whose tumors had NRAS mutations had better response to immunotherapy and better outcomes than patients whose tumors had other genetic subtypes. The results suggest that immune therapies, especially immune checkpoint inhibitors, may be particularly effective treatment options for NRAS-mutant melanoma. Activating NRAS mutations are found in 15% to 20% of melanomas. The study by Johnson et al is published in Cancer Immunology Research.

“Between 2010 and 2012, the researchers reviewed the electronic medical records of 229 patients with melanoma treated at Vanderbilt-Ingram Cancer Center in Nashville, Memorial Sloan Kettering Cancer Center in New York, and Massachusetts General Hospital in Boston. Of these patients, 143 received ipilimumab (Yervoy), 58 received interleukin (IL)-2 (Proleukin), and 28 received anti–PD-1 (nivolumab [Opdivo] or pembrolizumab [Keytruda]) or anti–PD-L1 (MPDL3280A) therapy.

“All patients underwent genotyping for ‘hotspot’ mutations in BRAF and NRAS; most patients also underwent ‘hotspot’ testing of other genes, including CKIT, GNAQ, GNA11, and MEK1. Sixty patients (26%) had tumors with NRAS mutations, 53 (23%) had BRAF mutations, and 116 (51%) had wild-type forms of NRAS and BRAF.”


Blood Samples as Surrogates for Tumor Biopsies in Patients with Lung Cancer

“A study examined the feasibility of using circulating free DNA (cfDNA) from blood samples of patients with advanced non-small-cell lung cancer as a surrogate for tumor biopsies to determine tumor-causing epidermal growth factor receptor (EGFR) mutations and then correlate that with expected patient outcomes, according to a study published online by JAMA Oncology.

“The analysis was a secondary objective of the EURTAC trial, which demonstrated the efficacy of erlotinib compared with standard chemotherapy for the first-line treatment of European patients with advanced non-small-cell lung cancer (NSCLC) with oncogenic EGFR mutations (exon 19 deletion or L858R mutations in exon 21) in tumor tissue.

“Rafael Rosell, M.D., of the Hospital Germans Trias I Pujol, Badalona, Spain, and coauthors examined EGFR mutations in cfDNA isolated from 97 baseline blood samples.

“Results show that in 76 samples from 97 (78 percent) patients, EGFR mutations in cfDNA were detected. Median overall survival was shorter in patients with the L858R mutation in cfDNA than in those with the exon 19 deletion (13.7 vs. 30 months). For patients with the L858R mutation in tissue, median overall survival was 13.7 months for patients with the L858R mutation in cfDNA and 27.7 months for those in whom the mutation was not detected in cfDNA. For the 76 patients with EGFR mutations in cfDNA, only erlotinib treatment was an independent predictor of longer disease progression-free survival.”