Hormone therapy use and cancer survivorship

Worldwide, approximately 9 million new cases of cancer are diagnosed annually in women, with more than 15 million cancer survivors.¹ Breast cancer accounts for a quarter of cases, followed by lung (9%), colorectal (9%), cervical (6%), thyroid (6%), uterine (4%), stomach (4%), ovarian (3%), liver (3%), and non-Hodgkins’s lymphoma (2%). Because of earlier detection and improved targeted treatment, cancer survival rates have risen, highlighting the need to address survivorship sequelae including those associated with menopause.^2,3 The average age of natural menopause in high-income countries is 51 years (46-48 y for low- and middle-income countries), with the normal range between 45 and 55 years; however, menopause can occur even earlier in the context of cancer and its therapies, with median onset of 44 years.^3,4

HOW DOES CANCER AND ITS TREATMENT AFFECT MENOPAUSE?

Cancer treatments (eg, bilateral salpingo-oophorectomy, chemoradiotherapy, and endocrine therapies) often accelerate the onset of premature (before age 40) and early menopause (between the ages of 40 and 44 y).³ Premature and early menopause are associated with elevated risk of chronic disease later in life, particularly cardiovascular disease, neurocognitive decline, and decrease in bone density.⁵ In addition, menopause symptoms are a common reason for not starting or prematurely stopping adjuvant endocrine therapy, which can directly worsen cancer outcomes. Menopause symptoms, including vasomotor symptoms (VMS), sleep disturbances, mood swings, sexual dysfunction, and genitourinary syndrome of menopause (GSM), are often more severe in cancer survivors.^2,3,6

Hormone therapy (HT) is highly effective for managing VMS and GSM and preventing osteoporosis. At doses aimed to restore estrogen serum concentrations to premenopause levels, HT is recommended for those without contraindications to reduce cardiovascular, bone, and cognitive risks in those with premature or early menopause and should be continued until the natural age of menopause is reached.⁵ The evidence for preventive benefit beyond the natural age of menopause is less clear. Despite potential HT benefits, risk of recurrence or increased cancer-related morbidity and mortality in survivors of cancer often prohibit use, which is a conundrum, given elevated disease risk and symptom burden. Patient discussion of options and limits of evidence should be included.

IS LOW-DOSE VAGINAL ESTROGEN THERAPY SAFE TO USE IN PATIENTS WITH CANCER?

Hypoestrogenism due to menopause is associated with a constellation of genitourinary signs and symptoms, referred to as GSM.⁷ Hallmark symptoms include vaginal dryness and decreased lubrication, which may lead to dyspareunia and postcoital bleeding. In those with a history of cancer, GSM is often worse because of medication adverse effects, including chemo- and endocrine therapies, specifically aromatase inhibitors, and anatomic changes after pelvic surgery and radiation therapy.^2,3,8 A systematic review found that a sizeable proportion of those with gynecologic cancer (78%) and breast or colorectal cancer (65%) reported sexual dysfunction signaling the importance of treatment.⁹

Low-dose vaginal estrogen therapies (ET) are highly effective in managing GSM and considered to be of minimal risk, even in those with history of cancer, due to relative low systemic absorption if used as directed.⁷ The only contraindication to use is in those with a history of hormone-secreting granulosa cell ovarian tumors and uterine sarcomas.^2,3 A recent systematic review did not find an elevated risk of breast cancer recurrence or increase in breast cancer-specific mortality with use of low-dose vaginal ET.⁸ The caveat was in those with concomitant use of an aromatase inhibitor, in which two studies found an increase in breast cancer recurrence but not in overall or breast cancer-specific mortality.^3,8

When another option is needed, intravaginal prasterone, a dehydroepiandrosterone insert, and oral ospemifene, a selective estrogen-receptor modulator, may be considered for women with nonhormone-sensitive cancers.^10,11

WHEN IS SYSTEMIC HORMONE THERAPY APPROPRIATE FOR PATIENTS WITH CANCER AND SURVIVORS?

Menopause symptom burden can be high in survivors of cancer.^2,3 In patients with a history of cancer or at higher risk for developing cancer, the decision to start systemic HT is a delicate balance of benefits and risks that depends on cancer type, age, underlying medical comorbidities, and time since diagnosis of cancer and menopause.³ Systemic HT confers less cardiovascular risk when initiated before the age of 60 or within 10 years from the onset of menopause, and transdermal ET is preferred over oral options because of lower venous thromboembolic (VTE) and metabolic risk.⁵ In women with a uterus, systemic estrogen requires endometrial protection with a progestogen or bazedoxifene. After hysterectomy, estrogen-only therapy is preferred. For endometrial cancer, the optimal HT regimen after hysterectomy remains uncertain, but current practice often favors low-dose estrogen alone.

Most of the safety data around systemic HT use in survivors of cancer is gleaned from observational studies along with a few systematic reviews.³ Evidence of moderate-to-low quality supports the use of systemic HT in those with history of renal, colorectal, pancreatic, hepatocellular, thyroid, hematologic, melanoma, head and neck, and certain gynecologic cancers including cervical, low-grade or early stage endometrial cancer, genital squamous cell carcinoma, and ovarian germ cell and epithelial ovarian cancers (eg, high-grade serous, endometrioid, mucinous, clear cell, and borderline).³ BRCA 1 and 2 mutation carriers without a personal history of breast cancer or contraindications should be started on hormone replacement therapy dosing after oophorectomy until they reach the natural age of menopause.^3,12 There is mixed evidence suggesting lung and bladder cancer may be estrogen sensitive; therefore, use of nonhormone therapy options should be offered as first-line treatment. However, for persistent symptoms, based on shared-decision making and input from oncology, a trial of HT may be considered.³

HOW DOES SYSTEMIC HORMONE THERAPY AFFECT RISK OF VENOUS THROMBOEMBOLISM IN PATIENTS WITH CANCER?

Most evidence on cancer-associated thrombosis refers to VTE, with active cancer conferring an estimated 4- to 7-fold higher risk and accounting for 20% to 30% of new VTE cases. Risk is not uniform across malignancies; brain, pancreatic, gastric cancers, and adenocarcinomas carry the highest VTE risk, followed by lung, ovarian, renal, and bladder cancers, with hematologic malignancies such as multiple myeloma, acute leukemia, and lymphoma also implicated. Metastatic disease, recent diagnosis, chemotherapy, targeted therapy, hospitalization, surgery, central venous catheters, and tumor-mediated procoagulant mechanisms further increased risk. Although not widely studied in patients with cancer, transdermal estrogen has not been associated with increased VTE compared with nonuse in patients at high risk for VTE.¹²

WHO SHOULD NOT RECEIVE SYSTEMIC HORMONE THERAPY?

The use of systemic HT confers higher risk of recurrence and worse prognosis in estrogen-responsive cancers and therefore is not recommended without shared decision-making in patients with estrogen receptor-positive breast cancer, uterine sarcomas, low grade serous and granulosa cell ovarian cancers, non-human papillomavirus (HPV)-related vulvovaginal cancers (eg, differentiated vulvar intraepithelial neoplasia-associated vulvar squamous cell carcinoma), and in gastric and esophageal cancers.³

In general, systemic HT should be avoided in survivors of breast cancer; however, HT may be considered when nonhormone options have been ineffective or not well tolerated in women with triple-negative breast cancer or history of prophylactic mastectomy.^3,12 A meta-analysis including the landmark Hormone Replacement Therapy After Breast Cancer (HABITS) and Stockholm trials demonstrated increased risk of breast cancer recurrence in the treatment groups with highest associated risk in the combined estrogen-progestogen arm,¹² although these trials used regimens that differ from many contemporary formulations.

For patients in whom HT is not advisable, there are a number of nonhormone treatment options for managing bothersome VMS.¹³

KEY SUMMARY POINTS

• Cancer survival rates have risen because of earlier detection, and newer targeted treatment options highlight the need to address survivorship sequelae, including those associated with menopause.

• Cancer treatments such as bilateral salpingo-oophorectomy, chemoradiotherapy, and antiendocrine treatments contribute to induced premature and early menopause and can be associated with more severe menopause symptoms and increased risk of cardiovascular disease, accelerated bone loss, and dementia later in life.

• Use of hormone therapy in persons with cancers responsive to estrogen poses elevated risk of recurrence and increased cancer-related morbidity and mortality. Use of nonhormone treatment modalities should be considered first-line therapy; however, in persons who fail nonhormone therapies with significant impairment, use of hormone therapy may be considered with shared decision-making, including input from the oncologist.

• Low-dose vaginal estrogen therapy is highly effective for managing genitourinary syndrome of menopause and can be used in most survivors of cancer, except for those with a history of hormone-secreting, granulosa germ cell ovarian tumors.

• Consider offering systemic hormone therapy in symptomatic patients with history of renal, colorectal, pancreatic, hepatocellular, thyroid, hematologic, melanoma, head and neck, and certain gynecologic cancers including cervical, low-grade/early stage endometrial cancer, genital squamous cell carcinoma, and ovarian germ cell and epithelial ovarian cancers. It should not be prescribed to individuals with estrogen receptor positive breast cancer, uterine sarcomas, low grade serous and granulosa cell ovarian cancers, non-human papillomavirus-related vulvovaginal cancers, and in gastric and esophageal cancers.

CLINICAL RECOMMENDATIONS

• Integrate screening for menopause-related symptoms into cancer survivorship visits, with emphasis around treatment and prevention, especially in those undergoing premature or early menopause.

• Counsel on the associated benefits and risks of hormone therapy, including differences in low-dose vaginal estrogen therapy versus systemic hormone therapy. Transdermal estrogen with or without oral progesterone has not been associated with increased venous thromboembolism compared with nonuse in patients at high risk of venous thromboembolism but has not been widely studied in cancer populations.

• Take a proactive approach in managing menopause symptoms in persons with history of cancer using evidence-based guidelines for initiating treatment based on cancer type and estrogen responsiveness. Although hormone therapy may be a viable option for some patients, there are additional available therapies that provide symptom relief without risk of estrogen exposure.

• Involve the oncology team in the decision regarding symptom relief, especially if therapy is ongoing.

Coming next in the Step-by-Step series: Ashley Wentworth, MD, senior associate consultant, Department of Dermatology, Mayo Clinic, Jacksonville, Florida, reviews the menopause-related skin changes linked to the abrupt decline in estrogen levels, such as increased dryness (xerosis), pruritus, thinning, and atrophy of the skin; decreased dermal collagen content, reduced elasticity, impaired wound healing, and increased skin fragility.

This article is part of the ongoing series Menopause Step-by-Step, a monthly Menopause education feature.¹⁴ The Editors of this series are Dr. Cynthia Stuenkel, Dr. Cheryl Cox Kinney, and Dr. Isaac Schiff.