The 39th annual San Antonio Breast Cancer Symposium, the world’s premier meeting devoted to recent advances in breast cancer, was held from December 6-10, 2016 in San Antonio, Texas. The program this year featured presentations and posters on a wide range of topics including tumor cell and molecular biology, risk, detection, prognostic and predictive factors, treatment, psychosocial issues, quality of life, and access to care. Three plenary talks focused on the management of metastatic, hormone receptor-positive breast cancer, the utility of cell free tumor DNA in breast oncology, and the global cost of cancer care. Below is a summary of findings from select abstracts presented during the general sessions. A full listing of conference resources, including oral presentations, slides, and posters is available at www.sabcs.org.
Extended Therapy with Aromatase Inhibitors
Post-menopausal women with hormone receptor-positive early breast cancer are often recommended five years of endocrine therapy with an aromatase inhibitor (AI, i.e. Arimidex (anastrozole), Aromasin (exemestane), Femara (letrozole)) to reduce the risk of recurrence. However, the risk of recurrence for hormone receptor-positive breast cancer persists even beyond five years of therapy. Since previous studies have shown a benefit to extended endocrine therapy with tamoxifen, researchers wondered whether there is a similar benefit to extending the duration of therapy with an AI. The NSABP B-42 trial enrolled 3,966 post-menopausal women who completed five years of endocrine therapy with an AI (or 2 years of tamoxifen followed by 3 years of an AI). The women were randomly assigned to either five additional years of therapy with an AI or five years of a placebo. The women were followed to see if their breast cancer recurred and how long they lived. After a follow up period of nearly seven years, they found no statistically significant differences in the rate of disease free survival or overall survival between the two groups. In this trial, disease free survival was defined as freedom from local, regional, and distant recurrences, new primary breast or other cancers, and death from any other cause. Extended therapy with an AI did, however, decrease the rate of distant metastases by 28% and improved the breast cancer free interval. Breast cancer free interval was defined as no local, regional or distant recurrences and no new primary breast cancers. Two similar studies presented at San Antonio this year, the IDEAL trial and the DATA trial, had similar outcomes, suggesting that there is limited benefit to extended therapy with an AI and highlighting the need for new therapies that are effective at preventing late recurrences.
A Treatment for Aromatase Inhibitor-Associated Muscle and Joint Pain
Joint and muscle pain is a common side effect experienced by women who take a daily aromatase inhibitor (AI) like Arimidex (anastrazole), Femara (letrozole), or Aromasin (exemestane). These side effects can be debilitating and can have a negative impact on the quality of life. The AIMSS (AI-associated Musculoskeletal Symptoms) study sought to determine whether the drug duloxetine, an FDA-approved serotonin norepinephrine reuptake inhibitor used to treat chronic pain and depression, could improve musculoskeletal pain in women on an AI. The study randomized 299 post-menopausal women with early-stage breast cancer, who had been on an AI for at least 3 weeks and at most 36 months, to daily duloxetine or placebo for 13 weeks. Women were assessed for pain and quality of life at regular intervals after initiating therapy. Women treated with duloxetine experienced a larger reduction in pain (46% compared to 36% at 12 weeks) and an increased quality of life compared to women treated with placebo.
Scalp Cooling to Prevent Chemotherapy-Induced Hair Loss
Hair loss is one of the most distressing side effects of chemotherapy. The SCALP (Scalp Cooling Alopecia Prevention) trial is the first randomized controlled trial to assess whether scalp cooling is a safe and effective method of preventing chemotherapy-induced hair loss. In this trial, women with early-stage breast cancer who planned to receive chemotherapy were randomized to scalp cooling with the Orbis Paxman Hair Loss Prevention System or to the no cooling control group. In the scalp cooling group women wore a snug fitting “cold cap,” attached to a refrigeration unit, for thirty minutes before, during, and 90 minutes after each chemotherapy infusion. An early analysis of the study showed that 50% of the 95 women who used the Paxman device preserved their hair, compared to 0% of the 47 women in the control group. The most common side effects experienced by women in the scalp cooling group were headaches, nausea and dizziness. The women in this study will be followed for at least five years to assess the impact of scalp cooling on recurrence, survival, and scalp metastases. Based on these outstanding results, the study researchers are seeking FDA approval for the Paxman device.
Impact of Radiation on Breast Reconstruction
The use of radiation therapy after mastectomy has recently increased. For women considering breast reconstruction after post-mastectomy radiation, there has been a lack of high quality information to support their decision-making. The findings of the MROC (Mastectomy Reconstruction Outcomes Consortium) study provide much needed information about the impact of post-mastectomy radiation on reconstruction outcomes. The study enrolled 2,014 women who had a single or bilateral mastectomy and implant or autologous (tissue flap) reconstruction. Of this group, 553 women had post-mastectomy radiation and 1,461 women did not have radiation. Researchers compared the rate of complications and patient satisfaction with reconstruction among the study participants. Two years after reconstruction the rate of complication (i.e. hematoma, wound infection) was higher in patients who had post-mastectomy radiation compared to those who did not (34.1% versus 22.5%). When the type of reconstruction was taken into account, they found that radiation increased the rate of complications two-fold in patients with implant reconstruction but had no impact on patients with autologous (flap) reconstruction. Similarly, when they compared patient satisfaction, they found that radiation negatively impacted patient satisfaction in women with implant reconstruction but had no effect on women with autologous reconstruction. The researchers concluded, “autologous reconstruction appears to yield superior patient-reported outcomes and lower risk of complications than implant-based approaches among patients receiving post-mastectomy radiation therapy.”
Targeting the PI3K Pathway in Endocrine Resistant Metastatic Breast Cancer
Women with metastatic, hormone-receptor positive breast cancer frequently develop resistance to drugs that block estrogen signaling. It is thought that one cause of this endocrine resistance is the activation of the cellular PI3K pathway. Therefore, researchers have hypothesized that blocking the PI3K pathway with a targeted drug might be an effective way of treating endocrine resistant breast cancer. The BELLE-3 trial was a phase III randomized trial that tested this hypothesis. The trial included women with hormone-receptor-positive, HER2-negative, metastatic breast cancer whose disease progressed while taking or shortly after taking an aromatase inhibitor in combination with the targeted drug Afinitor (everolimus). Women were randomized to treatment with Faslodex (fulvestrant), a drug that blocks estrogen signaling by causing destruction of the estrogen receptor, or treatment with Faslodex plus the PI3K inhibitor buparlisib. The study was successful in that addition of buparlisib increased progression free survival, or the length of time that cancer did not grow (3.9 months vs. 1.8 months). However, this improvement came with the cost of high toxicity. The most common side effects experienced by women on the combination therapy were an increase in liver enzymes and high blood sugar levels. Addition of buparlisib also increased levels of depression and anxiety and lead to several suicide attempts. The toxicity of buparlisib may prohibit its future use in breast cancer, but other more specific and potentially less toxic PI3K inhibitors are currently being studied in clinical trials.
Treatment of Estrogen Receptor-Positive, HER2-positive Metastatic Disease with Three Targeted Drugs
Resistance to endocrine therapy is also a concern in women with HER2-positive, hormone receptor-positive, metastatic disease. One possible way of overcoming endocrine resistance in this setting might be to more completely block the HER2 pathway using two targeted drugs instead of one. To test this, the phase II PERTAIN trial enrolled 258 post-menopausal women with HER2-positive, hormone receptor-positive, metastatic breast cancer who had not yet received treatment for their metastatic disease. All of the women in the trial were treated with an aromatase inhibitor (AI) to block the estrogen pathway, and they were randomly assigned to treatment with either one or two HER2-targeted drugs. Half of the women received Herceptin (trastuzumab), while the other half received Herceptin and Perjeta (pertuzumab). Additional treatment with a taxane chemotherapy drug was allowed and left to the discretion of the oncologist. The triple combination of Perjeta, Herceptin, and AI was more effective than Herceptin + AI. Women on the three drug combination lived, on average, for 18.9 months without disease progression, whereas those on the two drug combination lived 15.8 months without disease progression. Treatments were safe and well tolerated in both groups. These women will be followed over time to determine whether the triple combination also extends overall survival.
Breast Cancer Risks Associated with Genetic Mutations
Genetic testing for breast cancer risk has changed appreciably over the past few years. In the past, women with a personal or family history of breast cancer were tested for mutations in two well-established breast cancer predisposition genes-BRCA1 and BRCA2. Now, genetic testing for breast cancer risk commonly involves the use of multi-gene panels, some of which test for mutations in as many as fifty genes. It is unclear whether mutations in many of the genes included on these panels significantly increase breast cancer risk. Researchers from the Mayo Clinic collaborated with Ambry Genetics to better establish the relationship between mutations in potential cancer susceptibility genes and the risk of breast cancer. They studied the records of 60,000 breast cancer patients who had gene panel testing, and compared the frequency of mutations in twenty one genes in this population to a control population. They identified twelve genes as significantly associated with breast cancer risk. Among these, three are considered “high risk”-BRCA1, BRCA2, and PALB2, increasing the risk of breast cancer at least five-fold. Three new “moderate risk” genes, which increase risk at least two-fold, were identified-RAD51D, MSH6, and BARD1. Other moderate risk genes included CHEK2, ATM, NF1, TP53, PTEN, and CDH1. Importantly, several genes that are currently included on some breast cancer risk panels-BRIP1, MRE11A, NBN, RAD50 and RAD51C, were not associated with an increased risk of breast cancer in this study. The results of this study should help inform people with mutations in these genes about their actual breast cancer risk and help identify appropriate risk management strategies.
Outcomes in Young Women with BRCA Mutations
Women with mutations in BRCA1 or BRCA2 have an increased risk of developing breast cancer. It has been unclear, however, whether BRCA mutations affect the survival of women diagnosed with breast cancer. To address this question, researchers from the United Kingdom designed the POSH (Prospective Study of Outcomes in Sporadic and Hereditary Breast Cancer) study. This observational study enrolled women under the age of forty with early-stage, invasive breast cancer from 2000-2008. Blood was collected from these women at the time of treatment and was later used to determine whether the women carried an inherited BRCA mutation. Comprehensive data were collected regarding the participants’ diagnosis and treatment and the women were followed over time to assess their survival. After an average follow up period of 8.2 years, there was no difference in survival among BRCA mutation carriers and non-carriers. At five years, the average overall survival was 84% in both groups. Interestingly, when they studied the subgroup of women with triple-negative breast cancer, they found that BRCA mutation carriers had better survival outcomes than women without BRCA mutations. At five years the overall survival for BRCA-positive patients with triple negative disease was 83.5%, whereas for BRCA-negative patients it was 71.5%, a difference of 12%. While this finding is provocative and suggests BRCA mutations are favorable prognostic factors in this subgroup, the researchers pointed out that their sample size for this subgroup was small and the finding did not reach statistical significance.
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