“Among women with locally advanced or metastatic hormone receptor-positive breast cancer that was resistant to hormone therapy, those who had mutated PIK3CA detected in their blood benefited from a combination of the investigational PI3K inhibitor buparlisib and fulvestrant, according to data from the phase III BELLE-2 trial presented at the 2015 San Antonio Breast Cancer Symposium, held Dec. 8–12.
“ ‘BELLE-2 is a randomized, phase III clinical trial designed to assess the efficacy of the investigational PI3K inhibitor buparlisib in combination with fulvestrant in breast cancer patients whose tumors no longer respond to aromatase inhibitors,’ said José Baselga, MD, PhD, physician-in-chief and chief medical officer at Memorial Sloan Kettering Cancer Center in New York.”
“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.”
The gist: Women with HER2-positive breast cancer whose tumors also have a mutation called PIK3CA might not respond as well to HER2-targeted treatments. Scientists looked at tumor samples from patients who had taken the drugs trastuzumab (Herceptin) and/or lapatinib (Tykerb). They had also taken neoadjuvant (before surgery) chemotherapy. Patients whose tumors had PIK3CA mutations had a significantly lower rate of treatment success. These findings highlight the need for more research into PIK3CA-targeted therapy. They also echo findings from other researchers.
“Patients with HER-2–positive breast cancer who harbored activating mutations in PIK3CA were considerably less likely to achieve total pathologic complete response to neoadjuvant HER-2–targeted therapies than patients who did not have PIK3CA mutations, according to findings in the randomized, phase 3 NeoALTTO trial.
“PIK3CA activating mutations are present in all subtypes of breast cancer. However, they are enriched in HER-2–positive and ER-positive disease, according to study background.
“José Baselga, MD, PhD, physician-in-chief and chief medical officer at Memorial Sloan Kettering Cancer Center, and colleagues investigated whether an association existed between PIK3CA mutation status and patients’ response to HER-2–targeted therapy.”
The gist: Recent research suggests that women whose tumors have a mutation in the PIK3CA gene may be resistant to treatment with the drugs trastuzumab (Herceptin) and lapatinib. However, two new studies say that PIK3CA mutations can’t be used to predict how well Herceptin and lapatinib will work.
“While preclinical studies indicate that PIK3CA mutations result in resistance to the two HER2-targeted therapies trastuzumab and lapatinib, two recently published studies suggest that this mutation cannot be used as a predictive biomarker to guide therapy.
“The first study found that PIK3CA mutations are associated with a decreased benefit to neoadjuvant HER2-directed therapies. The second study showed that PIK3CA mutations did not affect outcomes for HER2-positive patients receiving adjuvant trastuzumab treatment.
“Preclinical studies using HER2-positive cell lines have previously shown that an additional mutation in PIK3CA, the alpha-catalytic subunit of PI3K, results in downstream constitutive signaling, making breast tumor cells that harbor both aberrations resistant to trastuzumab and lapatinib. PIK3CA is among the most commonly mutated oncogene in breast cancer and is present in about one-fourth of all HER2-positive breast cancers. Because of this prevalence and the effect of PI3K pathway activation on HER2 therapy, clinicians have posited that PIK3CA mutations may serve as predictive biomarkers, both preventing ineffectual therapy in some patients and guiding appropriate treatment choices.”
The gist: Some metastatic breast cancer patients can be treated with a combination of the drugs pertuzumab (Perjeta) and trastuzumab (Herceptin). New research shows that, when deciding whether to use the combo for a patient, the only tumor mutation an oncologist must consider is HER2. HER2 is one of many tumor mutations that could potentially be used to predict whether a certain treatment will work. The new research showed that, while only HER2 is necessary for the treatment decision, other biomarkers like HER3 and PIK3CA might help predict how well the treatment will work for a patient.
“In an analysis in the CLEOPATRA trial population reported in the Journal of Clinical Oncology, Baselga et al found that HER2 was the only biomarker suitable for use in selecting patients for first-line pertuzumab (Perjeta)/trastuzumab (Herceptin)-based treatment in patients with HER2-positive metastatic breast cancer…
“The study involved analysis of mandatory tumor and serum samples from 808 patients receiving first-line pertuzumab, trastuzumab, and docetaxel vs trastuzumab and docetaxel in CLEOPATRA. Samples were assessed (58%–99.8% assessable) for amphiregulin, betacellulin, EGF, transforming growth factor alpha, EGFR, HER2, HER3, insulin-like growth factor 1 receptor, PTEN, phosphorylated AKT, PIK3CA, CMYC, serum HER2 extracellular domain (sHER2), and FCγR. The CLEOPATRA trial showed significant increases in progression-free survival and overall survival with the addition of pertuzumab…
“The investigators concluded: ‘Through comprehensive prospective analyses, CLEOPATRA biomarker data demonstrate that HER2 is the only marker suited for patient selection for the trastuzumab plus pertuzumab-based regimen in HER2-positive metastatic breast cancer. HER2, HER3, and PIK3CA were relevant prognostic factors.’ “
The gist: Women with HER2-positive breast cancer whose tumors also have a mutation called PIK3CA might not respond as well to HER2-targeted treatments. Scientists looked at tumor samples from patients who had taken the drugs trastuzumab (Herceptin) and/or lapatinib (Tykerb). They had also taken neoadjuvant (before surgery) chemotherapy. Patients whose tumors had PIK3CA mutations had a significantly lower rate of treatment success. These findings highlight the need for more research into PIK3CA-targeted therapy.
“Newly diagnosed patients with HER2-positive breast cancer with tumors that harbor a PIK3CA mutation are not as likely to have a pathologic complete response (pCR) following HER2-targeted therapy plus neoadjuvant chemotherapy. This was the case regardless of whether patients were treated with single or combination HER2-targeted therapy. pCR rates were lowest for those patients with hormone receptor (HR)-positive, HER2-positive disease who harbored a PIK3CA mutation.
“This mutation may be a negative prognostic biomarker for HER2-positive patients. The study was published in the Journal of Clinical Oncology.
“According to the authors, this is the largest study to assess the link between PIK3CA mutations and pCR in HER2-positive disease.
“Only about one-third of women with HER2-positive breast cancer respond to anti-HER2 therapy—a treatment that has side effects and is costly. Still, all of these patients are ultimately treated with the same regimens because there are currently no assays that test whether a patient is likely to have an improved disease-free or overall survival from the therapy.”
“Experts from The Cancer Genome Atlas Research Network – a US-wide government-funded research project – analysed 295 samples of stomach cancers to find similarities that may be targeted when developing treatments.
“Research into the biology of stomach cancer and the development of new therapies has been difficult because of the different forms that the disease can take.
“Lead author Dr Adam Bass, from the Dana-Farber Cancer Institute, said that, despite stomach cancer being a diverse disease up until now researchers had tended to take a ‘one-size-fits-all’ approach to stomach cancer treatments.”
Someone had to do it; now it looks like Novartis may be the first. The pharma company’s new series of clinical trials, SIGNATURE (also known as, ‘bring the protocol to the patient,’ or ‘P2P’), is recruiting patients with different cancers to receive investigational targeted drugs selected to match the distinct genetic changes found in each patient’s tumor. Continue reading…
American Association for Cancer Research │Oct 20, 2013
An experimental drug could keep melanomas and breast cancer from resisting targeted therapies, according to findings reported at the 2013 International Conference on Molecular Targets and Cancer Therapeutics. Called LEE011, the new drug inhibits proteins called cyclin-dependent kinases (CDKs), which make cells divide. The targeted CDKs are abnormally active in many cancers, including melanomas with BRAF mutations and breast cancers with PIK3CA mutations. The researchers found that LEE011 keeps cultured tumor cells from dividing and that combining the drug with targeted treatments prevents resistance in melanomas and breast cancer in mice. Now, these combination treatments are being tested in several phase I clinical trials on a variety of cancers in adults, as well as in children.