Key molecular regulator of uterine fibroids

Uterine leiomyomas, also called uterine fibroids, are benign tumors that originate from the smooth muscle of the uterus. Fibroids are the most common non-cancerous tumor of the female genital tract, affecting 80% of all women during their lifetime. More than half of women develop fibroids during their reproductive years, often complicating pregnancy. Fibroids are a major source of heavy uterine bleeding, pain, and reduced fertility, resulting in reduced quality of life and significant stress for many women. 

Treatments for fibroids consist of surgery, including hysterectomy or myomectomy, hormonal modulators, such as gonadotropin-releasing hormone agonists, and uterine arterial embolization (UAE), which blocks the blood supply to the tumor. The only true cure is surgical resection, with hormonal approaches and UAE estimated to shrink tumors by 30-40%. Bleeding and pain can also be significantly reduced by these treatments. However, results vary, and many women do not derive benefit from available procedures. Progress in designing new treatments has been slow, largely because we have a poor understanding of the biology of fibroids.

A new study recently identified a molecule that is expressed at abnormally high levels in fibroids. The molecule, H19, belongs to a class of molecules called long noncoding RNAs. H19 was found at increased levels in fibroid tissues from 30 women, including 20 premenopausal, compared with normal uterine myometrium tissues from the same women. High expression of H19 caused fibroid cells to double in number faster, whereas getting rid of H19 actually slowed down growth. Importantly, H19 also drove expression of molecular profiles that have previously been linked to fibroid development and growth. Thus, H19 may function upstream as a key regulator of fibroids. Estrogen and progesterone are thought to influence fibroid growth. This new study showed that combined exposure to estrogen and progesterone increased H19 expression and other fibroid-promoting genes. When H19 was eliminated, the effects of estrogen and progesterone were abolished. 

Although these results are preliminary, they are exciting for several reasons. We know so little about fibroids, and options for women who suffer from this debilitating chronic medical condition are limited. Fibroids receive little attention from the research community. The few studies that have been published in recent years are mostly preclinical in animal models and do not generally include patient samples. This new study used matched human fibroid and normal myometrium tissue from the same patients. This study also explored molecular mechanisms and biology, demonstrating cause and effect and not purely correlative findings.

Further studies are urgently needed to confirm the role of H19 and to identify other major mechanisms promoting fibroids. Identification of key regulators of fibroid development and growth moves us one step closer to understanding this disease and improving therapeutic options for women.

Reference: Cao T et al. Oncogene 2019 May 15

Combining endocrine therapies for metastatic breast cancer

Breast cancer remains the most commonly diagnosed cancer among women worldwide and is a leading cause of cancer-related death (1). In 2018, more than two million new cases were diagnosed, and more than 600,000 deaths were attributed to breast cancer. Breast cancers that have metastasized, or spread to other organs, often benefit from treatment with a cocktail of drugs. Strategic selection of drugs is based on molecular analysis of a tumor biopsy.

Approximately 70% of breast cancers express the estrogen receptor (ER) and are amenable to therapies that block estrogen or ER activity (2). These therapies are often classified within a larger category of drugs called endocrine or hormone therapies. There are many types of endocrine therapies, each with different mechanisms of inhibiting hormone action. Aromatase inhibitors (AIs), such as anastrozole, block estrogen synthesis, whereas selective ER down-regulators, such as fulvestrant, bind and reduce levels of the ER. Because of their different mechanisms of action, drugs from different endocrine therapy classes may be combined to exert increased inhibitory effects on ER-positive breast cancer. This type of combination approach was used in the S0226 phase 3 trial (NCT00075764). In this trial, postmenopausal women with previously untreated metastatic breast cancer were treated with the combination of anastrozole plus fulvestrant and compared with patients who received anastrozole alone. The combination treatment was previously reported to increase progression-free survival compared with the single agent (15 vs 13.5 months) (3).

Updated outcomes of the S0226 trial were recently reported at a median follow-up of seven years (4). About 45% of patients in the single-drug arm had crossed over to the combination treatment by the time of follow-up evaluation. Among 694 patients included in the updated report, progression-free survival remained significantly higher for the group treated with the combination. In addition, median overall survival was significantly higher for those receiving the combination treatment vs anastrozole alone (49.8 vs 42.0 months). Importantly, the differences in overall survival appeared to be dependent on whether patients had previously been treated with another endocrine agent, the selective ER modulator tamoxifen. Among those who did not have a history of tamoxifen treatment, median overall survival was significantly different with the combination vs anastrozole alone (52.2 vs 40.3 months). However, if patients had previously received tamoxifen, median overall survival did not significantly differ between the combination and anastrozole-alone groups (48.2 vs 43.5 months). The authors of the updated report noted the importance of considering differences in patient populations when interpreting and comparing results across studies. Previous trials that failed to show significant differences between single-agent AIs and cocktails of AIs with fulvestrant included patients previously treated with endocrine agents. Response rates and survival outcomes may be lower in some patients in this subgroup due to underlying endocrine resistance resulting from prior exposure to other endocrine agents. In addition, any time more than one drug is used, there are increased concerns about safety and side effects. However, high-grade (≥3) side effects were similar between the two treatment groups, suggesting that safety and toxicity were not compromised by the combination treatment.

Overall, the updated results from this phase 3 trial support the efficacy of combining the AI, anastrozole, with fulvestrant as a first-line option for patients with postmenopausal ER-positive metastatic breast cancer. This treatment combination has the potential to improve survival outcomes in patients who have not previously been treated with endocrine therapy.

References: (1) Bray et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. (2) Waks and Winer. Breast Cancer Treatment: A Review. JAMA. 2019 Jan 22;321(3):288-300. (3) Mehta et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012 Aug 2;367(5):435-44. (4) Mehta et al. Overall Survival with Fulvestrant plus Anastrozole in Metastatic Breast Cancer. N Engl J Med. 2019 Mar 28;380(13):1226-1234.