Tamoxifen Therapy and Uterine Cancer Risk: The Data and Clinical Implications

SUMMARY:

Tamoxifen, a well known SERM, is used to treat breast cancer (hormone receptor positive) because of well-documented benefits including improved disease-free survival (5-year was 38% higher than placebo) and overall survival, regardless of menopausal status. It also is used as a chemoprophylactic agent for women at high risk for breast cancer. ACOG reaffirmed their guidance on tamoxifen monitoring (2019), which includes a statement that tamoxifen use may be extended to 10 years.

Tamoxifen for Breast Cancer Treatment

Uterine Cancer Risk (NSABBP)

  • Within first 5 years of follow up
    • Average annual hazard rate of endometrial cancer: 1.2/1000 patient-years
    • Cumulative hazard rate: 6.3/1000
  • Endometrial cancers following tamoxifen therapy are not of a different type, nor do they carry worse prognosis
  • Authors conclude “net benefit greatly outweighs risk”

Tamoxifen for Breast Cancer Risk Reduction

Uterine Cancer Risk (IBIS-I trial) – 96 month follow-up

  • Endometrial cancer incidence rate
    • Tamoxifen group: 0.59/1000 woman-years
    • Placebo group: 0.38/1000 woman-years
  • Majority FIGO state 1, diagnosed in women >50 years

KEY POINTS:

  • Screening with Transvaginal (TV) Ultrasound
    • Tamoxifen results in subepithelial stromal hypertrophy and therefore makes TV ultrasound screening more difficult and less reliable
    • Routine TV ultrasound and endometrial biopsy for surveillance have “not shown to be effective”
      • May lead to additional unnecessary procedures and is not recommended
    • However, these modalities, including sonohysterography, can be used for follow-up depending on the clinical scenario, especially bleeding
    • Counsel and encourage patients to report any bleeding, spotting, leukorrhea or unusual vaginal discharge
  • Work-up prior to beginning tamoxifen
    • Due to increased risk for polyps, screening and managing uterine polyps prior to tamoxifen initiation can reduce the incidence of atypical hyperplasia
    • The use of progestins to reduce risk for endometrial hyperplasia is not recommended
    • ACOG states that prior to beginning tamoxifen

…there may be a role for pretreatment screening of postmenopausal women with transvaginal ultrasonography, and sonohysterography when needed, or office hysteroscopy

  • Monitoring
    • Postmenopausal
      • Monitor closely “for symptoms of endometrial hyperplasia or cancer”
    • Premenopausal
      • Data does not demonstrate increased risk
      • Routine gyn care
  • If atypical hyperplasia is identified prior to beginning tamoxifen, the patient should be counseled and hysterectomy “should be considered”
    • If endometrial carcinoma occurs and is subsequently managed with hysterectomy, “tamoxifen use may be reinstituted” following consultation with the patient’s breast cancer oncology team

Learn More – Primary Sources:

ACOG Committee Opinion 601: Tamoxifen and Uterine Cancer

Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14

Long-Term Results of Tamoxifen Prophylaxis for Breast Cancer—96-Month Follow-up of the Randomized IBIS-I Trial

Endometrial Cancer: Beyond The Basics

SUMMARY:

Endometrial cancer is the most common gynecologic malignancy in the US and accounts for 7% of all cancers in women. Most cases are diagnosed early and can be treated with surgery alone.  with surgery alone. However, there are certain cell types and clinical features (such as extrauterine spread) that are associated with a high rate of relapse following surgical and medical therapy. There are two types of endometrial cancer that vary in epidemiology, genetics, treatment, and prognosis.

Types of Endometrial Cancer

Type 1 (more common): Endometrioid

  • Precursor is atypical endometrial hyperplasia (or endometrial intraepithelial neoplasia)
  • Most cases are low grade
  • Generally results from unopposed, prolonged estrogen stimulation
  • Risk Factors
    • Unopposed estrogen |Age| Obesity | Metabolic syndrome | Nulliparity | Infertility | Late menopause | Tamoxifen use | Type 2 diabetes | Hypertension | Lynch syndrome

Note: Tamoxifen risk may be related to age and is significant in women ≥50 years of age (NSABP prevention trial in high risk women)

Type 2: Papillary serous | Clear cell| Carcinosarcoma (Mixed Mullerian Tumor [MMT])

  • Type 2 more common in older, nonwhite, multiparous women and current smokers
  • Papillary serous on 10% of uterine malignancies, but accounts for 40% of deaths
    • Precursor thought to be endometrial intraepithelial carcinoma
    • High grade, risk of extrauterine disease at time of diagnosis
  • Clear cell
    • Also poorer prognosis
    • Increased risk in smokers
  • MMT is a rare but aggressive tumor

Uterine Cancer Symptoms

  • Abnormal uterine bleeding (AUB) or postmenopausal bleeding
  • Advanced disease
    • Abdominal pain
    • Distention
    • Bloating
    • Early satiety
    • Change in bowel/bladder function

KEY POINTS:

Evaluation of Premenopausal Patient

  • Routine screening of asymptomatic patients using transvaginal ultrasound or endometrial sampling is not recommended
  • Evaluate if patient symptomatic with AUB
    • Thorough medical history, exam, imaging and consideration of age-based risk
  • Diagnosis is by endometrial sampling with dilation and curettage or endometrial biopsy
    • Endometrial biopsy should be performed in all women >45 or
    • Any age with risk factors for endometrial hyperplasia or malignancy (exclude pregnancy first) including failed medical management, and persistent abnormal AUB
  • Ultrasound measurement of endometrial thickness has no diagnostic value
  • ACOG recommends that “The decision to histologically evaluate the endometrium should be based on symptomatology and clinical presentation”

Postmenopausal Patient

  • Prompt evaluation recommended for the following
    • Vaginal bleeding | Presenting symptom is 91% of women with endometrial cancer
    • Endometrial cells on pap smear cytology
  • Initial assessment can be either endometrial biopsy or transvaginal ultrasound
    • Biopsy is not required if endometrial thickness is ≤4 mm
    • Biopsy is required if endometrial thickness cannot be evaluated or is >4 mm
  • Persistent or recurrent bleeding requires biopsy regardless of endometrial thickness

Note: If biopsy has been performed and is benign, yet bleeding persists, dilation and curettage plus hysteroscopy is needed

Evaluation of Asymptomatic Patients with Incidental Findings

  • In an asymptomatic patient, incidental finding of endometrial thickness of >4 mm is not an accurate predictor of an endometrial cancer diagnosis
  • Endometrial thickness of >11 mm in asymptomatic patient has a similar risk of endometrial cancer as a symptomatic patient with >4 mm endometrial thickness
  • Polyps can be managed expectantly or surgically, depending on patient symptoms/risk factors
    • Low prevalence of malignancy in polyps (<5%)

Cervical Cytology Findings Requiring Evaluation (ASCCP)

Postmenopausal Women

  • Evaluate if endometrial cells present on cytology

Asymptomatic Premenopausal Women

  • Endometrial cells
    • Do not evaluate
  • All categories of atypical glandular cells or adenocarcinoma in situ
    • Endometrial sampling in conjunction with colposcopy and endocervical sampling in nonpregnant patients ≥35 years
    • <35 years old if risk factors for endometrial neoplasia are present
  • Atypical endometrial cells
    • Endometrial and endocervical sampling alone is preferred
    • Colposcopy is acceptable as part of the initial evaluation

Endometrial Sampling

  • Office-based endometrial sampling is minimally invasive and cost-effective for evaluation of endometrial cancer
    • Pipelle catheter Detection rates for endometrial cancer
      • Postmenopausal: 99.6%
      • Premenopausal: 91%
      • Posttest probability of endometrial cancer with a negative biopsy <1%
  • If AUB is persistent
    • Further evaluation is required
    • SGO recommends hysteroscopic-guided biopsy

Referral to Gyn Oncology

  • Metastases may be found in approximately 20% of presumed early-stage endometrial cancer at surgery
  • ACOG recommends referral to gyn oncology subspecialist for patients with diagnosis of endometrial cancer

Patient outcomes are improved when high-volume surgeons in high-volume institutions render care, and this outcomes model typically is reproduced by standard gynecologic oncology practice

Learn More – Primary Sources:

ACOG/ SGO Practice Bulletin 149: Endometrial Cancer

NCI: Endometrial Cancer – Health Professional Version

Executive Summary of the Uterine Cancer Evidence Review Conference

Locate a GYN Oncology Specialist:

Gyn Oncology Locator – SGO