Breast Cancer
New Drug Seen as Possible ‘Game Changer’
Last month, Pfizer Inc. received Food and Drug Administration accelerated approval of Ibrance® (palbociclib) in combination with letrozole for the treatment of postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer as first-line endocrine-based therapy for their metastatic disease.
Erika P. Hamilton, MD, associate director of the Breast and Gynecologic Cancer Program at Sarah Cannon Research Institute said the approval was based on results of the Phase 2 PALOMOA-1 trial and continued approval might be contingent upon clinical benefit verification from the Phase 3 PALOMA-2 trial, which is fully enrolled.
In the PALOMA-1 trial, Hamilton said, “The progression-free survival from 10.2 to 20.2 months was almost a doubling.”
Hamilton, a medical oncologist with Tennessee Oncology, explained palbociclib is a first-in-class cyclin-dependent kinase (CDK) 4/6 inhibitor and is taken in combination with letrozole, which is a non-steroidal aromatase inhibitor.
“It’s hitting the cancer cell in two completely different ways,” she said. Hamilton explained the palbociclib blocks a signal for the cancer cell to grow and divide while the letrozole decreases the levels of estrogen in the body that feed the cancer.
She said it is a benefit that both drugs are oral, which makes it easier for women to take at home. “I think that’s an attractive option for patients,” she noted, adding the letrozole is taken daily, and the palbociclib is taken three weeks on followed by one week off.
One caution, she noted, is that this has been approved as a first-line therapy in ER+/HER2- patients. “You want to use that option for as many patients as you can because if it’s not used in the first-line setting, you lose the opportunity to use palbociclib.”
Hamilton, who is involved in the PALOMA-2 trial, said it is completely enrolled and just waiting to report out. “I think if PALOMA-2 shows what PALOMA-1 did, this will be the new standard for first-line patients,” she said. “The biggest side effect is neutropenia, and in general, that’s asymptomatic in patients.”
The early indications have been positive enough that Hamilton said research is moving forward to look at use in other settings for ER+ breast cancer and to see if there are additional combination therapies to enhance outcomes. “There are trials right now looking at triplet therapy,” she said. “We have two studies at Sarah Cannon looking at adding a PI3 kinase inhibitor to make further strides.”
Gene Mutation Linked to Therapy Resistance
A group of Vanderbilt-led investigators has identified a new gene mutation that could explain why some breast cancer patients do not respond to anti-hormone therapy.
The study, published online late last year in the Journal of Clinical Investigation, was led by senior author Carlos Arteaga, MD, director of the Breast Cancer Program and the Center for Cancer Targeted Therapies at Vanderbilt-Ingram Cancer Center, with Luis Schwarz, MD, and Emily Fox, PhD, serving as co-first authors, along with colleagues at M.D. Anderson in Houston and Emory University in Atlanta.
A significant portion of women with estrogen receptor positive (ER+) metastatic breast cancer don’t respond to endocrine therapy because their tumors are initially resistant or acquire resistance after an initial response to anti-estrogens. Profiling ER+ breast tumors from four patients who did not respond to letrozole prior to mastectomy, the investigators performed deep sequencing on the tumors and identified a novel mutation (D189Y) in a gene of the Src family of kinases called LYN. The team also identified other LYN mutations in breast tumors that increased the activity of the LYN protein.
“Src family kinases like LYN are known to be associated with carcinogenesis, cancer cell invasion and metastatic progression,” said Luis Schwarz, MD, postdoctoral research fellow at VICC. “When present in ER+ breast cancer cells, these mutations induce an advantage in proliferation of cells as well as resistance to anti-estrogen therapies,” he continued. “To the best of our knowledge, no one had previously described how these LYN mutations work.”
The authors tested assays in three cell lines and in a mouse model to identify potential therapies for ER+ breast cancers harboring D189Y LYN. They tested two Src inhibitors and identified the drug dasatinib as the most effective. Since it is already approved for another form of cancer, dasatinib could be adapted for testing in breast cancer. However, the authors noted the agent is not an ideal drug because it is not a pure LYN inhibitor. The hope is their identification of the new LYN mutation will spur development of a LYN inhibitor for testing in patients with breast cancer.
Study Suggests Potential Postpartum Therapy
Nearly 25 percent of all breast cancers among premenopausal women occur within two to five years following a pregnancy. These postpartum tumors are more likely to spread or metastasize to other parts of the body, leading to an increased risk of death.
“Unfortunately, these are young women who have just had children. All breast cancer deaths are tragic but the loss of a young woman who is also a mother is so devastating for families and has a profoundly negative societal impact,” said Rebecca Cook, PhD, assistant professor of Cancer Biology.
A new study led by Cook and published last fall in the Journal of Clinical Investigation helps explain the cellular activity that leads to breast tumor metastasis among women who have recently given birth. Breast tissues undergo massive transformations during pregnancy in preparation for nursing the new infant. After milk production has ended, there is a cascade of cell death.
“This cell death removes about 90 percent of breast epithelial cells during a very short window of time, which triggers widespread remodeling and repair of breast tissue by the immune system,” explained Cook.
During this remodeling, immune cells called macrophages gobble up the dying cells before the dying cells can release intracellular contents, which can provoke immune attack. As another safeguard against immune attack, macrophages also secrete immune suppressive factors … use one molecule - Mer tyrosine kinase (MerTK) - to control both of those processes. Using a mouse model, Cook and her colleagues found that immune suppression in the postpartum breast triggered by MerTK mistakenly protects tumors, increasing their ability to spread.
The investigators treated mice harboring postpartum tumors with an investigational drug labeled BMS-777607, designed to inhibit the MerTK. Following treatment, investigators saw decreased cleanup of dying breast cells in the postpartum breast, decreased immune suppression and decreased metastasis. While more research is needed, Cook said the results suggest that using a MerTK inhibitor in conjunction with other therapies could be helpful.
RELATED LINKS:
