Hormone Replacement Therapy Can Benefit Some Patients with Gynecologic Cancers

Despite significant concerns for some patients with cancer, such as those who are BRCA-positive, treatment with hormone therapies can have significant benefits, according to an expert panel at the Society of Gynecologic Oncology 2022 Annual Meeting on Women’s Cancer.

During the session titled “Bring Back That Loving Feeling…But Not Your Cancer: HRT in Gynecologic Cancer,” panelists noted that hormone replacement therapy (HRT) can improve quality of life without necessarily increasing the risk of recurrence. Panelist Melissa Gerardi Fairbairn, PA-C, Yale New Haven Hospital-Smilow Cancer Center, discussed the various uses of HRT.

Fairbairn said that estrogen is implicated in a myriad of disease states and its predominant mechanism of action is through estrogen receptors. In cognitive health, estrogen can have anti-inflammatory effects on the brain and mediate efficiency of prefrontal cortex-dependent working-memory tasks. Studies have also shown that women who received estrogen therapy had increased blood flow in the brain.

Low estrogen levels are also significantly correlated with mood lowering, and studies have shown that postmenopausal depression improved after patients’ estrogen levels were restored. Interestingly, Fairbairn said that a study in mice found that when estrogen levels were raised, rituals associated with obsessive-compulsive disorder (OCD) dramatically decreased, suggesting potential therapeutic implications for patients with OCD.

Researchers have also found significant implications with estrogen in cardiovascular and bone health. The SWAN study noted that HRT can have cardiovascular benefits, but typically when it was initiated early in menopause. Estrogen replacement therapy is not recommended for the treatment of osteoporosis, but a new position statement does support HRT for the prevention of bone loss. Its use is also supported in women with premature menopause or those who undergo surgically induced menopause.

Fairbairn emphasized that the abrupt cessation of HRT can have very damaging effects, particularly on mood and mental health. For pre-menopausal women, these impacts can be even more significant.

“HRT is always evolving,” Fairbairn said in her presentation. “It’s important for providers to stay abreast of all of the data and trials that are coming down the pike, just to refresh yourself on the indications of using HRT safely.”

Next, presenter Abdulrahman Sinno, MD, discussed HRT and cancer recurrence risk. He noted that the data on these issues continues to evolve, but said it is important to consider patients’ quality of life.

“I think the pendulum continues to swing in either direction every decade,” Sinno said in the presentation. “The important point is when you put someone in induced menopause, if they have an incurable cancer, what are we doing with their quality of life?”

Sinno said endometrial cancer is most often diagnosed in postmenopausal women, but notably, 25% of patients with endometrial cancer are premenopausal at their time of diagnosis. Importantly, type 1 endometrial cancer is estrogen responsive.

Many clinicians are reluctant to prescribe HRT due to the theoretical risk of recurrence, Sinno said, but the data does not necessarily support this hesitation. In a trial investigating this issue, researchers found no difference in survival between patients who did and did not receive estrogen therapy. Notably, however, this study was discontinued early due to the release of the Women’s Health Initiative data showing that the risks in this case exceeded the benefits. Still, Sinno said estrogen therapy appears to be safe for low-risk cancers.

Importantly, this does not necessarily translate to high-risk cancers. Treatment with estrogen therapy is “absolutely contraindicated” in patients with uterine leiomyosarcoma and endometrial stromal sarcoma, Sinno said.

There is also a growing body of evidence showing that preserving patients’ ovaries does not increase the risk of recurrence. One study found no difference between either cancer-specific survival or overall survival (OS) in patients with endometrial cancer who did or did not have their ovaries removed.

Unlike endometrial cancer, ovarian cancer often presents in advanced stages and estrogen receptors are present in many of these. Therefore, patients are often not recommended to receive estrogen replacement therapy. Despite this, one high-quality study with 19-year follow-up found improvements in OS and progression-free survival for patients administered estrogen therapy.

The safety of estrogen therapy in patients with borderline ovarian tumors is an evolving issue, Sinno said; however, he noted this decision can often depend on patients’ quality of life.

“If a patient is completely miserable from her induced menopause and nothing seems to be helping, I think this is a patient where you have a discussion about risks versus benefits,” Sinno said.

Finally, Sinno discussed the significant concerns around treating patients who are BRCA1-positive with estrogen therapy. In patients with no personal history of breast cancer but who are confirmed to have the BRCA1 gene, research has found no significant increase in the risk of breast cancers.

“This is level 1 evidence that estrogen replacement therapy is safe in this population,” Sinno said.

However, research has found a significantly increased risk of recurrence of breast cancers among patients who did have a personal history of cancer. This included almost every category of patients, including those who were hormone receptor positive. Although patients who were hormone receptor negative did not have a statistically significant increase, Sinno noted that there was still an increased risk of recurrence.

In the final presentation, Johanna D’Addario, MHS, PA-C, discussed the use of HRT for the treatment of menopause symptoms. Hormonal causes of menopause are permanent and can result in abrupt changes that are distressing to many patients. Anatomic or physiologic causes may not be permanent but can also be distressing.

Physical symptoms of menopause can include weakness, fatigue, nausea, pain, neuropathy, hair loss, and sleep disturbances. Psychological symptoms can include the fact that sexual organs are now associated with trauma and pain; a changing relationship with partners; a sense of disfigurement; and an emotional impact if the cancer affects fertility and sexual health.

“I cannot emphasize enough the importance of psychological symptoms for our patients,” D’Addario said. “There are really a lot of reasons that women need support, not only with medications but also emotional support for their hormonal and sexual symptoms.”

General guidelines for menopausal hormone therapy include conferring with a specialist for providers who may not be familiar with prescribing these therapies. Pharmacists can be essential team members in this role.

Comorbidities should also be taken into consideration, particularly a history of venous thromboembolism, liver or cardiovascular disease, and a history of smoking. Laboratory evaluation is not typically necessary prior to initiation of therapy but monitoring blood pressure is important at every office visit.

D’Addario said she often begins patients on a relatively low dose, depending on their age. Patients’ symptoms should be reviewed in 2 to 3 months and doses can be titrated up or down for symptom and adverse effect management.

Non-hormonal options can also be helpful, including oxybutynin for urinary symptoms, ospemifene for vaginal dryness, and sildenafil for women who have difficulty achieving orgasm. Working with a pelvic floor physical therapist can also be extremely beneficial for patients, D’Addario said.

Finally, she again emphasized the importance of psychological support for patients.

“Whether it’s provided by you the provider, whether you refer to someone in your health system or outside…but there’s so much that can be provided to patients in regard to support with mood, survivorship, relationship challenges, and communication with a partner,” D’Addario concluded.

REFERENCE

Fairbairn M, Sinno A, D’Addario J. Bring Back That Loving Feeling…But Not Your Cancer: HRT in Gynecologic Cancer. Presented at: Society of Gynecologic Oncology 2022 Annual Meeting on Women’s Cancer. March 18, 2022.