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: Breast cancer patients being treated with the drug trastuzumab (Herceptin) receive the same benefits whether they take it intravenously (by IV) or as an injection.
“Subcutaneous trastuzumab demonstrated comparable safety and efficacy to IV trastuzumab in patients with HER-2–positive early breast cancer, according to results of an international randomized, open-label phase 3 study.
“Christian Jackisch, MD, PhD, of the Breast Cancer and Gynecology Cancer Center at Sana Klinikum Offenbach GmbH in Germany, and colleagues compared the pharmacokinetics, efficacy and safety of subcutaneous vs. IV trastuzumab (Herceptin, Genentech). The study included 596 women with HER-2–positive, operable, locally advanced or inflammatory breast cancer in the neoadjuvant/adjuvant setting.
“All women underwent treatment with eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab. Trastuzumab was administered either via 3-weekly fixed doses of 600 mg or via the standard weight-based method.
“Patients continued treatment with trastuzumab for 1 year after surgery.”
The gist: A clinical trial that tested a new drug called TDM-1 (Kadcyla) found disappointing results for patients with metastatic, HER2-positive breast cancer. The trial found that treatment with T-DM1 plus the drug pertuzumab is no better than treatment with trastuzumab plus chemotherapy. For more on TDM-1, see this recent news about its potential benefits for patients whose cancer has spread to the central nervous system (CNS).
“Results of the anticipated phase III MARIANNE trial found that HER2-positive metastatic breast cancer patients treated with trastuzumab emtansine (T-DM1) plus pertuzumab had similar progression-free survival (PFS) compared with those treated with trastuzumab plus a taxane-based chemotherapy.
“Though the trial met its noninferiority endpoint, showing a similar PFS in the first-line setting between the two combination therapies along with T-DM1 alone, it failed to demonstrate that T-DM1 performs better than trastuzumab plus chemotherapy.
“The study has been anticipated by clinicians as two of the treatment arms do not include a taxane, which often causes patients to lose their hair, among other toxicities. The full results of the study will be presented at a future medical meeting…
“ ‘In my opinion, given the substantial survival associated with [docetaxel plus trastuzumab and pertuzumab of over 56 months], it remains the current first-line standard regimen especially for those patients who have never been exposed to trastuzumab,’ said Hurvitz.”
The gist: Combining the breast cancer drugs Kadcyla and Perjeta does not seem to improve outcomes for advanced, HER2-positive patients, compared to Kadcyla alone or Herceptin plus chemotherapy. That was the conclusion of a recent clinical trial that tested the combo in people who had not yet been treated for their advanced cancer. Herceptin plus chemotherapy is a cheaper option than Kadcyla plus Perjeta.
“Patients who got a combination of Kadcyla and Perjeta lived without their disease worsening for a similar amount of time as those who got Kadcyla alone, or those receiving the older medicine Herceptin plus chemotherapy, the Basel, Switzerland-based company said in a statement today. The study, dubbed Marianne, looked at 1,095 patients with a genetic mutation known as HER2 whose cancer has spread and who haven’t already tried other treatments.
“A successful combination of Kadcyla and Perjeta may have helped Roche replace sales of Herceptin that the company would lose should that medicine face competition from cheaper copies in coming years. Herceptin was Roche’s third-biggest drug in the first nine months of this year, with revenue of 4.7 billion Swiss francs ($4.8 billion).”
“Novartis’ drug Afinitor failed to significantly improve disease-free survival in women with a certain type of advanced breast cancer, a late-stage study presented at the San Antonio Breast Cancer Symposium on Friday showed.
“Results of the Phase III study involving 719 patients found women taking Afinitor in combination with Roche’s breast cancer drug Herceptin and chemotherapy agent paclitaxel lived on average for 15 months without their disease worsening.
“This compared with 14.5 months for those on placebo, the Swiss drugmaker said.
“The study was evaluating the drug as a treatment for women with advanced HER2-positive breast cancer, which is responsible for approximately 20 percent of breast cancer diagnoses.
“Afinitor is already approved in the European Union as a treatment for HER2-negative advanced breast cancer. (Reporting by Caroline Copley)”
The gist: Stage II and III breast cancer patients whose tumors are HER2-positive may benefit from longer treatment with the anti-HER2 drugs trastuzumab (aka Herceptin) and lapatinib (Tykerb). In a clinical trial, 28% of patients who received the drugs for 24 weeks had no more signs of an invasive tumor after their treatment. Only 12% of patients who received the drugs for 12 weeks had the same result. However, the difference in response was significant only in patients whose tumors were hormone receptor (HR)-positive and HER2-positive.
The gist: In a clinical trial, people with HER2-positive, advanced breast cancer did no better when given the three-drug combo trastuzumab + paclitaxel + everolimus as a first treatment than when given just trastuzumab + paclitaxel. A previous trial showed that everolimus + trastuzumab + vinorelbine could help patients overcome resistance to trastuzumab, but only if they had already been treated for their cancer. Researchers wondered whether adding everolimus would help prevent trastuzumab resistance.
“The addition of everolimus to weekly trastuzumab (Herceptin) plus paclitaxel did not improve outcomes in the phase III BOLERO-1/TRIO-019, but did provide a “signal” in the hormone receptor–negative subset. The study was reported at the 2014 San Antonio Breast Cancer Symposium by Sara A. Hurvitz, MD, of the University of California, Los Angeles (Abstract S6-01).
“ ‘Trastuzumab has dramatically improved outcomes for patients, however, it’s not a win for everyone. Resistance to treatment remains a clinically unmet challenge,’ she said at a press briefing. One means of counteracting resistance could be to add a drug that would inhibit the mTOR pathway in early metastatic disease, according to Dr. Hurvitz.
“In the previously reported BOLERO-3 trial, everolimus added to trastuzumab and vinorelbine did significantly improve progression-free survival for patients with trastuzumab-resistant previously treated cancer.
“ ‘We were interested in evaluating whether inhibiting mTOR early in metastatic disease will help delay the development of resistance to HER2-targeted therapy,’ she said.”
The gist: A new clinical trial will enroll patients to see whether combining the drug pembrolizumab (aka Keytruda) with trastuzumab (aka Herceptin) might help them overcome resistance to trastuzumab. Pembrolizumab is an immunotherapy, meaning it boosts a patient’s immune system to fight cancer.
“The International Breast Cancer Study Group (IBCSG), Breast International Group (BIG), and Merck, known as MSD outside the United States and Canada, today announced the opening of the PANACEA study, a global collaborative study exploring a new way to treat HER2+ breast cancer that has become resistant to the current standard of care. The PANACEA study will investigate the use of pembrolizumab (KEYTRUDA®) in combination with trastuzumab to evaluate whether the addition of an anti-PD-1 therapy can reverse trastuzumab resistance in patients with HER2+ breast cancer whose cancer has spread while on trastuzumab therapy.
“Worldwide, breast cancer is the most common cancer among women.1 About one in five patients with breast cancer have too much of a growth-promoting protein known as HER2/neu (or just HER2) on the surface of cancer cells. Breast cancers with too much of this protein tend to grow and spread more aggressively.
“ ‘PANACEA is the first phase 2 immunotherapy trial not only in HER2+ breast cancer, but in the entire breast cancer field,’ said Sherene Loi, MD, PhD, study chair, division of cancer medicine, Peter MacCallum Cancer Centre, Australia. ‘If successful, this may herald a new treatment approach in certain types of breast cancer.’ ”
The gist: Many women with HER2-positive breast cancer take the drug trastuzumab (aka Herceptin) along with chemotherapy after tumor-removal surgery to keep the cancer from returning. However, new research shows that women who have high levels of certain immune system cells in their tumors might not benefit from Herceptin. For these patients, chemotherapy might be just as effective at preventing the return of cancer as the chemo/Herceptin combo.
“HER2-positive breast cancers with a high level of immune cell infiltration might not benefit from the addition of trastuzumab (Herceptin) to chemotherapy, a trial analysis suggested.
“The 10% of patients with stromal tumor-infiltrating lymphocyte-predominant breast cancer in the Alliance N9831 trial showed similar recurrence-free survival (RFS) whether they received chemotherapy alone or with trastuzumab (10-year rate 90.9% versus 80.0%,P=0.21), Edith A. Perez, MD, of the Mayo Clinic in Jacksonville, Fla., and colleagues found.
“The rest showed, as expected, significantly better recurrence-free survival with addition of trastuzumab (10-year rate 79.6% versus 64.3%, hazard ratio 0.49, P=0.0003), they reported here at the San Antonio Breast Cancer Symposium.”