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Tuesday, March 19, 2019

HONOLULU─Results from a recent clinical trial show that a new immunotherapy treatment, when added to standard chemotherapy, significantly prolongs survival in women with recurrent ovarian cancer (Abstract 35).

The randomized phase II trial compared overall survival of 64 women, half of whom received chemotherapy combined with immunotherapy, and half who received chemotherapy alone. The combination of chemotherapy and immunotherapy corresponded with 73 percent survival at 2 years, compared to 41 percent survival when chemotherapy was used alone.

The treatment is referred to as dendritic cell-based immunotherapy. It uses the patient's own immune system to combat cancer and offers long-lasting antitumor immunity. Immunotherapies are one of the newest and most promising treatments for ovarian cancer, which typically is diagnosed at a later stage and subsequently harder to treat.

David Cibula, MD, PhD, a physician with Gynecologic Oncology Centre, First Faculty of Medicine, Charles University and General University Hospital in Prague, presented the results at the Society of Gynecologic Oncology's 50th Annual Meeting on Women's Cancer.

The most important objective of cancer treatment, according to Cibula, is to prolong overall survival while maintaining a good quality of life during treatment. A major advantage of this immunotherapy, he noted, is "an excellent safety profile and tolerance by patients thanks to an almost absence of any toxicity."

This study is a result of many years of research in the field of active cellular immunotherapy conducted by scientists at the Second Faculty of Medicine at Charles University and the Motol University Hospital, both in Prague, and, later, by the study sponsor.

"There are currently not many other alternatives in clinical development with such promising results," said Cibula.

A larger phase III clinical trial is planned for 2019.

Monday, March 18, 2019

Research performed over the last several decades has led to an increased understanding of the genetics of cancer. The clinical application of this knowledge for pediatric cancer has lagged behind studies performed for adults.

In a perspectives article published in the journal Science, Jaclyn Biegel, PhD, FACMG, from Children's Hospital Los Angeles, and Alejandro Sweet-Cordero, MD, of the University of California, San Francisco, survey the landscape of this young field and present opportunities for using genomic information to advance a new era of care for children with cancer (2019; doi:10.1126/science.aaw3535).

Cancer arises from genetic changes, including DNA mutations, that are either present at birth, or are acquired over time. Many adult cancers are initiated by mutations acquired through exposure to substances like smoking and radiation or simply from aging. The tumors may contain hundreds of sequence alterations, and identifying which changes drive the growth of the tumors, and impact treatment response can be challenging.

In contrast, pediatric malignancies often develop from a very small number of mutations, only some of which overlap with the types of mutations seen in adult cancers. Furthermore, an estimated 20 percent of pediatric cancers arise in children who have a genetic predisposition to malignancy. For this reason, the clinical genetic assays developed to inform prognosis and treatment decisions for adult cancers have not been as useful in pediatrics.

OncoKids was one of the first next-generation sequencing panels to detect DNA and RNA changes that characterize pediatric cancers. The panel was developed at Children's Hospital Los Angeles under the guidance of author Biegel, Director of CHLA's Center for Personalized Medicine. The OncoKids panel provides a molecular diagnosis, informs prognosis, and highlights novel therapeutic targets across the broad spectrum of cancers in children, including leukemias, brain tumors, and other solid tumors.

"To truly achieve personalized medicine in pediatric oncology, we need to be able to determine if a child is genetically predisposed to develop cancer," said Biegel. In addition to tumor testing, germline testing that uses a sample of a patient's blood, is critical for identifying those children who have a genetic risk for developing cancer in the future. Besides benefiting the patient, this information has implications for the entire family, since an abnormality that is passed down from parent to child can also raise the risk of developing cancer in siblings.

Although tremendous progress has been made in pediatric cancer care, treatment resistant disease and relapse continue to negatively impact patient outcomes. Genetic profiling of pediatric cancers is typically done at the time of diagnosis or at the time of relapse to help determine treatment planning. According to Biegel, future studies that may be performed over the course of treatment and at remission have the potential to provide critical information about the mechanisms of tumor progression, treatment resistance and metastasis.

Tremendous opportunity exists for changing outcomes in children with cancer by using an integrated approach to evaluating children and their families that includes genomic medicine as a central component in their care.

Monday, March 18, 2019

The FDA has granted accelerated approval to atezolizumab in combination with paclitaxel protein-bound for adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering ≥ 1% of the tumor area), as determined by an FDA-approved test. The FDA also approved the VENTANA PD-L1 (SP142) assay as a companion diagnostic device for selecting TNBC patients for atezolizumab.

Approval was based on IMpassion130 (NCT02425891), a multicenter, international, double-blinded, placebo-controlled, randomized trial that included 902 patients with unresectable locally advanced or metastatic TNBC who had not received prior chemotherapy for metastatic disease. Patients were randomized (1:1) to receive either atezolizumab (840 mg) or placebo IV infusions on days 1 and 15 of every 28-day cycle, plus paclitaxel protein-bound (100 mg/m2) administered via IV infusion on days 1, 8, and 15 of every 28-day cycle.

Tumor specimens (archival or fresh) were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory and the results were used as a stratification factor for randomization and to define the PD-L1 positive population for pre-specified analyses.

In patients whose tumors express PD-L1, median progression-free survival (PFS) was 7.4 months (6.6, 9.2) for patients receiving atezolizumab with paclitaxel protein-bound and 4.8 months (3.8, 5.5) for those receiving placebo with paclitaxel protein-bound. The stratified hazard ratio for PFS was 0.60 (95% CI: 0.48, 0.77; p<0.0001) in favor of the atezolizumab plus paclitaxel protein-bound arm. Objective response rate in patients with confirmed responses was 53 percent compared to 33 percent for the atezolizumab and the placebo-containing arms, respectively. Overall survival data were immature with 43% deaths in the intent-to-treat population.

The most common adverse reactions (reported in ≥ 20% of patients) with atezolizumab with paclitaxel protein-bound were alopecia, peripheral neuropathies, fatigue, nausea, diarrhea, anemia, constipation, cough, headache, neutropenia, vomiting, and decreased appetite.

This indication is approved under accelerated approval based on PFS. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

The recommended atezolizumab dose for patients with TNBC whose tumors express PD-L1 is 840 mg administered as an IV infusion over 60 minutes, followed by 100 mg/m2 paclitaxel protein-bound. For each 28-day cycle, atezolizumab is administered on days 1 and 15, and paclitaxel protein-bound is administered on days 1, 8, and 15 until disease progression or unacceptable toxicity.

Monday, March 18, 2019

The lower risk of breast cancer from multiple pregnancies and from breastfeeding seen in average risk women extends to those at the highest risk of breast cancer, according to the largest prospective study of BRCA1 and BRCA2 mutation carriers to date conducted by researchers at Columbia University Mailman School of Public Health and the Institut National de la Santé et de la Recherche Médicale in Paris.

Women with BRCA1 mutations who had two, three, or four or more full-term pregnancies were at 21 percent, 30 percent, and 50 percent decreased risk of breast cancer compared to women with a single full-term pregnancy. Breastfeeding also reduced risk in BRCA1 mutation carriers. The results are published online in the Journal of the National Cancer Institute Cancer Spectrum (2018; DOI:10.1093/jncics/pky078).

In contrast, women with BRCA2 mutations did not have a decrease in risk from multiple pregnancies except if they had four or more pregnancies. Women with BRCA1 mutations who had only one full-term pregnancy were at an increased risk of breast cancer as were women with BRCA2 mutations who had fewer than four pregnancies.

"What we have learned is that timing really matters for many risk factors and the dual effect of pregnancy we see in non-mutation carriers with a long-term protection but short-term increase following a pregnancy may not extend to all women with BRCA1 and BRCA2 mutations as the short-term increase and long-term protection may relate much more to the timing of when these pregnancies occur," said lead author Mary Beth Terry, PhD, Professor of Epidemiology and Environmental Health Sciences at the Mailman School of Public Health at Columbia University and the Herbert Irving Comprehensive Cancer Center.

"Moreover, the hormonal upheaval that occurs during the first pregnancy may have a more or less important impact on the risk of breast cancer depending on whether the first pregnancy occurs during periods of life at higher risk of developing a breast cancer or at less high risk, periods shifted by about 10 years between BRCA2 and BRCA1 mutation carriers, with a later peak for BRCA2 mutation carriers," said senior author Nadine Andrieu, PhD, Director of research at the Institut National de la Santé et de la Recherche Médicale and at the Institut Curie, Paris.

The study followed 5,707 BRCA1 and 3,535 BRCA2 mutation carriers using a retrospective cohort analysis and 2,276 BRCA1 and 1,610 BRCA2 mutation carriers. The cohort known as IBCCS (International BRCA1/2 Carrier Cohort Study) includes data from 21 national or center-based prospective follow-up studies whose the national EMBRACE cohort from the U.K.; the national GENEPSO cohort from France and the national HEBON cohort from the Netherlands, the Kathleen Cuningham Foundation Constortium for Research into Familial Breast Cancer Followup Study, and the Breast Cancer Family Registry.

Monday, March 18, 2019

Scientists at the University of Illinois have found that free fatty acids in the blood appear to boost proliferation and growth of breast cancer cells. The finding could help explain obese women's elevated risk of developing breast cancer after menopause (Cancer Res 2019; doi:10.1158/0008-5472.CAN-18-2849).

"When taken up by estrogen-receptor positive breast cancer cells, these fatty acids activated pathways that increased tumor cell growth, survival, and proliferation," said Zeynep Madak-Erdogan, PhD, Food Science and Human Nutrition Professor who led the study.

"Our clinical data provide a more complete understanding of the mechanisms that connect obesity with breast cancer and provide an opportunity to assess the ability of pathway-preferential estrogens to decrease breast cancer risk in obese postmenopausal women," said Madak-Erdogan, also the Director of the Women's Health, Hormones and Nutrition Lab.

Scientists have long known that excess body weight increases women's risks of ER-positive breast cancer after menopause, but the specific metabolic pathways and genetic processes that trigger the disease have been less clear. Pathway-preferential estrogens are chemically modified to reduce their potential adverse effects on reproductive and breast tissues.

To explore associations of body mass index with breast cancer risk, the researchers obtained blood samples from the Susan G. Komen Tissue Bank and compared those of healthy women with the samples of women who were healthy at the Baltimore study's outset but later developed breast cancer, looking for the presence of various metabolites, biomarkers of inflammation, and cancer-related proteins.

Women who developed breast cancer—and women who were overweight or obese—had significantly higher blood concentrations of five free fatty acids and glycerol, which are released as byproducts when fat tissue breaks down triglycerides.

Madak-Erdogan's research group analyzed additional blood samples from 37 nonobese and 63 obese postmenopausal women, as well as samples from 21 postmenopausal women who previously were obese but lost weight. All of the women were participants in the Midlife Women's Health Study, a long-term study of women ages 45-64 in the Baltimore area.

They found that obese women's levels of free fatty acids were significantly higher; however, blood levels of all the fatty acids fell significantly in women who were obese at the outset of the Baltimore study but later lost a significant amount of weight.

To explore the impact that obesity has on ER-positive cancer cells, the researchers treated several lines of primary tumor and metastatic cancer cells with the blood of obese women. They found that the cancer cells became more viable and multiplied—effects that increased as the fatty acid levels in the women's blood samples increased.

Exposure to the fatty acids in the women's blood also appeared to make the disease more aggressive. One line of primary tumor cells became more motile and an enzyme pathway that regulates cell growth, proliferation, and survival in a metastatic cell line was activated, according to the study.

The greater the cells' level of exposure to the fatty acids, the more pronounced was the effect on this enzyme pathway, known as the mammalian target of rapamycin, or mTOR pathway.

In previous studies, Madak-Erdogan's team found that modifying the mTOR pathway's interaction with ER-positive cells through a pathway-preferential estrogen compound elicited favorable responses in certain genes, such as preventing fat accumulation in mouse livers, without adversely affecting reproductive tissues.

To examine how this estrogen would affect gene expression in the current study, they treated one group of breast cancer cells with oleic acid and another group of cells with a combination of oleic acid and the estrogen.

Among other effects, oleic acid increased the expression of genes involved in cell proliferation and downregulated about 500 genes, including those involved in fatty acid metabolism and adhesion with other cells.

However, these effects were greatly reduced in cells that were treated with the estrogen and oleic acid combination, the research team found.