Novel Approach for Estrogen-Receptor-Positive Breast Cancer Reported

The gist: Drugs called gamma secretase inhibitors (GSI) are being explored as a potential way to overcome resistance to endocrine therapy drugs (like tamoxifen or letrozole) for women with estrogen-receptor-positive (ER+) breast cancer. A GSI drug called MK-0752 was recently given to patients in a clinical trial. The researchers found 18 tumor genes that could be used to predict how well GSI might work for a given patient. A larger study will explore the gene “signature” and measure just how effective GSI drugs are for breast cancer patients.

“Loyola researchers and collaborators have reported promising results from a novel therapeutic approach for women with estrogen-receptor-positive breast cancer.

“The new approach, a new drug class called gamma secretase inhibitors (GSI), specifically inhibits Notch and shuts down critical genes and cancer cells responsible for tumor growth.

“Kathy Albain, MD, FACP, who led the study, will present findings Dec. 11 during the 2014 San Antonio Breast Cancer Symposium.

“Existing cancer drugs are effective in killing mature breast cancer cells. But a handful of immature breast cancer stem cells are resistant to such drugs. They survive and are responsible for tumor growth and progression. Resistance to standard therapy is a major cause of death in women with estrogen-receptor-positive breast cancer. Approximately 75 percent of breast cancers are estrogen-receptor positive…

“Researchers are planning a larger, phase II study to evaluate the efficacy of the GSI class of drugs added to endocrine therapy versus endocrine therapy alone. This study also will determine how well the 18 gene “signature” will predict who responds to therapy.

” ‘This is an exciting new strategy to overcome resistance to a very common class of drugs (tamoxifen, letrozole), so it is our hope that in the future a vast number of patients with estrogen-receptor-positive breast cancer could benefit,’ Dr. Albain said.”


New Drug Combination for Advanced Breast Cancer Delays Disease Progression

The gist: A new treatment that combines the drugs bortezomib and fulvestrant has shown promise in treating post-menopausal women with metastatic hormone receptor-positive breast cancer whose disease worsened after being treated with drugs called aromatase inhibitors. The combo treatment was tested in 118 patients in a clinical trial. It doubled the number of patients still alive after 12 months, and it lowered the chance of patients’ cancer worsening. Further studies will continue to measure the effectiveness of the treatment.

“A new combination of cancer drugs delayed disease progression for patients with hormone-receptor-positive metastatic breast cancer, according to a multi-center phase II trial. The findings of the randomized study (S6-03) were presented at the 2014 San Antonio Breast Cancer Symposium, held Dec. 6-9, by Kerin Adelson, M.D., assistant professor of medical oncology at Yale Cancer Center and chief quality officer at Smilow Cancer Hospital at Yale-New Haven.

“The trial enrolled 118 post-menopausal women with metastatic hormone-receptor-positive breast cancer whose cancer continued to progress after being treated with an aromatase inhibitor. The study, based on work done by Doris Germain of Mt. Sinai Hospital, found that the combination of the drugs bortezomib and fulvestrant—versus fulvestrant alone—doubled the rate of survival at 12 months and reduced the chance of cancer progression overall.

“Bortezomib, used most commonly in treating multiple myeloma, is a proteasome inhibitor that prevents cancer cells from clearing toxic material. Fulvestrant causes clumping of the estrogen-receptor protein. When bortezomib blocks the ability of the cell to clear these protein clumps, they grow larger and become toxic to the cancer cells. This, in turn, amplifies the effectiveness of fulvestrant, a drug commonly used in this subset of patients.

“The drug combination doubled the number of patients whose cancer had not progressed after one year from 14% to 28%, according to Adelson.”


Subsidies Help Breast Cancer Patients Adhere to Hormone Therapy

“A federal prescription-subsidy program for low-income women on Medicare significantly improved their adherence to hormone therapy to prevent the recurrence of breast cancer after surgery.

” ‘Our findings suggest that out-of-pocket costs are a significant barrier’ to women complying with hormone therapy, said Dr. Alana Biggers, assistant professor of clinical medicine at the University of Illinois at Chicago College of Medicine, and lead investigator on the study. Programs that lower these costs can ‘improve adherence—and, hopefully, breast cancer outcomes—for low-income women,’ she said. Biggers presented the results of the study at an Oct. 14 press conference in advance of the American Society for Clinical Oncology Quality Care Symposium in Boston.

“Breast cancer is a leading cause of cancer-related deaths for women of all races, but survival rates differ by race and socioeconomic status, with African American women and women of low income having higher rates of death.”


Pfizer Announces FDA Acceptance of Palbociclib New Drug Application with Priority Review

The gist: In the U.S., a drug must be approved by the U.S. Food and Drug Administration (FDA) in order for it to be prescribed to patients with specific diseases. Particularly promising drugs might be granted Priority Review, meaning that the FDA agrees to work with the drug manufacturer to accelerate the approval process. The FDA recently granted priority review to a drug meant to treat certain breast cancer patients. The drug is called palbociclib. It is meant to be combined with another drug called letrozole as a treatment for “postmenopausal women with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer who have not received previous systemic treatment for their advanced disease.”  The FDA’s decision was based on promising results for the treatment in a clinical trial that tested it in volunteer patients. People who are interested in getting the treatment before it is approved can look into participating in Pfizer’s expanded access trial.

“Pfizer Inc. today announced the New Drug Application (NDA) for palbociclib has been accepted for filing and granted Priority Review by the United States Food and Drug Administration (FDA). This NDA requests FDA approval of palbociclib, in combination with letrozole, as a first-line treatment for postmenopausal women with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer who have not received previous systemic treatment for their advanced disease. The submission is based on the final results of PALOMA-1, a randomized, Phase 2 trial comparing palbociclib plus letrozole versus letrozole alone in this population of patients.

“The FDA’s Priority Review status accelerates the review time from 10 months to a goal of six months from the day of acceptance of filing and is given to drugs that may offer major advances in treatment or may provide a treatment where no adequate therapy exists. The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is April 13, 2015.

“Palbociclib received Breakthrough Therapy designation from the FDA in April 2013, for the first-line systemic treatment of women with advanced or metastatic ER+, HER2- breast cancer.

“ ‘If approved as a first-line therapy in combination with letrozole, palbociclib will be an important new option for the thousands of women in the U.S. who are living with metastatic breast cancer,’ said Garry Nicholson, president, Pfizer Oncology. ‘We look forward to continuing to work closely with the FDA through the review process.’

“Pfizer recently announced the initiation of a multi-center, open-label expanded access program (EAP) in the United States for palbociclib. Through the program, palbociclib is available to post-menopausal women with hormone receptor-positive (HR+), HER2- advanced breast cancer who are eligible for letrozole therapy and for whom enrolling in other palbociclib clinical trials is not an option. Healthcare professionals and patients can learn more about the palbociclib EAP by visiting www.clinicaltrials.gov (trial number: NCT02142868).”


Breast Conserving Therapy Shows Survival Benefit Compared to Mastectomy in Early-Stage Patients

Editor’s note: Women with early-stage breast cancer have surgery to remove their tumors. They can choose between a mastectomy to remove the entire breast or a lumpectomy to remove the diseased part of the breast (breast conserving therapy, or BCT). Until now, it was thought that a mastectomy and BCT had similar results in terms of long-term survival for a patient. But a new study shows that BCT offers better survival for women who are PR-positive or ER-positive. Further studies are needed to figure out why. The researchers speculate it may have to do with the radiation treatment usually given just after BCT to keep the cancer from returning. Unfortunately, there appear to be socioeconomic barriers to receiving BCT instead of a mastectomy.

“When factoring in what is now known about breast cancer biology and heterogeneity, breast conserving therapy (BCT) may offer a greater survival benefit over mastectomy to women with early stage, hormone-receptor positive disease, according to research from The University of Texas MD Anderson Cancer Center.

“The study findings defy the conventional belief that the two treatment interventions offer equal survival, and show the need to revisit some standards of breast cancer practice in the modern era.

“The research was presented at the 2014 Breast Cancer Symposium by Catherine Parker, MD, formerly a fellow at MD Anderson, now at the University of Alabama Birmingham.”


Gene Marker may Predict Breast Cancer Response to Tamoxifen

The gist: Oncologists can sometimes check a patient’s tumor for specific genetic mutations that indicate how well different treatment options might work. Researchers recently discovered a genetic mutation found in some breast cancer tumors that could help oncologists predict how well the drug tamoxifen will work for a patient with ER-positive breast cancer. Further studies are needed to explore just how useful the discovery might be.

“Researchers have identified genes that may help predict whether a patient with estrogen receptor (ER)-positive breast cancer is likely to benefit from tamoxifen therapy, according to a study published in the July 15 issue of Cancer Research.

“Hendrika M. Oosterkamp, M.D., of The Netherlands Cancer Institute in Amsterdam, and colleagues conducted a large-scale loss-of-function genetic screen in ZR-75-1 luminal breast cancer cells to identify candidate genes for tamoxifen resistance.

“The researchers found that loss of function in the deubiquitinase USP9X prevented proliferation arrest by tamoxifen, but not by the ER downregulator fulvestrant. RNAi-mediated attenuation of USP9X stabilized ERα on chromatin in the presence of tamoxifen, and this caused a global activation of ERα-responsive genes driven by tamoxifen. A gene signature defined by differential expression after USP9X attenuation in the presence of tamoxifen was used to identify patients with ERα-positive breast cancer experiencing a poor outcome after adjuvant therapy with tamoxifen. Correlation of the gene signature with survival was not observed in patients with breast cancer who did not receive endocrine therapy.

” ‘Overall, our findings identify a gene signature as a candidate biomarker of response to tamoxifen in breast cancer,’ the authors write.”