US Pharm. 2024;49(9):HS1-HS10.

ABSTRACT: Breast cancer is the second most common form of cancer in the United States. Early detection of breast cancer through regular screening substantially reduces mortality. Guidance on breast cancer screening in average-risk women varies among different organizations’ guidelines. The U.S. Preventive Services Task Force recently updated its recommendations regarding breast cancer screening in average-risk women. Many drugs are available to treat or slow the progression of breast cancer, and several drugs, primarily targeted therapies, have recently been FDA approved for treatment. When breast cancer is diagnosed, an individualized treatment plan is formulated based on breast cancer type, patient preference, and clinical judgment.

In the United States, breast cancer is the second most common cancer type.1 The World Health Organization notes that 670,000 deaths worldwide were caused by breast cancer in 2022, and 2.3 million women were diagnosed with breast cancer.2 Black women are 40% more likely than white women to die from breast cancer.3 About 0.5% to 1% of breast cancers occur in men.2

Risk Factors and Pathogenesis

Risk factors for developing breast cancer include female sex; increasing age; mutations in breast cancer genes 1 and 2 (BRCA1, BRCA2); history of early menarche (age <12 years), late menopause (age >55 years), older age at first pregnancy, or low parity; dense breasts (detection of tumors on a mammogram may be difficult); history of breast, ovarian, or endometrial cancer; previous treatment involving chest radiation; diethylstilbestrol exposure; estrogen use (oral contraception, hormone replacement therapy); and lifestyle (excessive alcohol consumption, overweight/obesity, physical inactivity, high fat intake).4-6 There are two hypotheses regarding breast cancer development and progression: the cancer stem cell theory and the stochastic theory.5 The cancer stem cell theory posits that all tumor subtypes derive from the same stem cells and that acquired genetic and epigenetic mutations in stem cells will lead to different tumor phenotypes; the stochastic theory proposes that a single cell type causes each tumor subtype.5

Screening

Early detection is important to reduce breast cancer morbidity and mortality. Breast self-examination, clinical breast examination, and mammography have been used to screen for breast cancer. Mammography, which uses low-energy x-ray to provide high-resolution images of the breast, has been shown to result in a 22% reduction in breast cancer mortality.5,7-9 Guidance on breast cancer screening in average-risk women varies among different organizations’ guidelines. The U.S. Preventive Services Task Force (USPSTF) recently updated its guidance, recommending that breast cancer screening in average-risk women start at age 40 years instead of 50 years and that mammograms be performed every other year in women aged 40 to 74 years; the USPSTF adds that current evidence on mammography in women aged >75 years is insufficient.3 The American College of Obstetricians and Gynecologists recommends that mammograms be offered to women starting at age 40 years, followed by annual or biennial screening (based on shared decision-making) to continue as long as the patient is in good health and expected to live >10 years.9 The American Cancer Society recommends offering women the option to begin screening with mammography at ages 40 to 45 years, with annual mammography recommended for those aged 45 to 54 years; women aged >55 years can either switch to biennial mammography or opt to continue annual mammography.9 The National Comprehensive Cancer Network (NCCN) recommends starting mammography at age 40 years and screening annually thereafter.9 The use of annual and biennial screening mammography in certain patient populations continues to be debated among the various organizations.

If a mammogram is abnormal, additional testing is needed for diagnosis. Treatment is individualized and depends on the type of cancer, cancer stage, tumor biomarkers, and personal preferences, with options including surgery, radiation therapy, and medications. The potential harms of screening mammography include 1) false-positive results leading to overdiagnosis and 2) overtreatment and radiation exposure.s

Chemoprevention

Chemoprevention is the use of medication to lower the risk of developing cancer or deter its recurrence after treatment. Breast cancer screening may not result in a diagnosis but could indicate the patient’s risk factors for developing breast cancer. Certain drugs used to treat breast cancer or slow its progression may also be used for risk reduction, whereas other agents are used specifically for risk reduction. The risk-reducing agents tamoxifen, raloxifene, and anastrozole are recommended for use in patients aged >35 years.10

Tamoxifen, a selective estrogen receptor (ER) modulator, is indicated for treating metastatic breast cancer but is also used to reduce the risk of breast cancer. It may be administered in premenopausal women in certain settings, as well as in postmenopausal women. To be utilized for risk reduction, according to the NCCN Breast Cancer Risk Reduction Panel, patients should be aged >35 years, have a life expectancy of >10 years, have a >1.7% 5-year risk for breast cancer (as determined by the modified Gail model), or have had lobular carcinoma in situ (LCIS). In the National Surgical Adjuvant Breast and Bowel Project’s Breast Cancer Prevention Trial (BCPT), tamoxifen demonstrated efficacy for breast cancer prevention.10 The BCPT found a 49% decrease in short-term risk for breast cancer in healthy subjects aged >35 years who were at increased risk for the disease; however, all age groups of premenopausal and postmenopausal participants had risk-reduction benefits.10

The selective ER modulator raloxifene, which is used for osteoporosis treatment and prevention, is also indicated to reduce the risk of invasive breast cancer in postmenopausal women with osteoporosis or at high risk for invasive breast cancer. The NCCN Breast Cancer Risk Reduction Panel states that its use should be limited to healthy postmenopausal women aged >35 years who have a >1.7% 5-year risk for breast cancer (as per the modified Gail model) or a history of LCIS. In the Continuing Outcomes Relevant to Evista trial, raloxifene use resulted in a 59% reduction in invasive breast cancer compared with placebo and reduced the incidence of invasive ER-positive breast cancer by 66%.10

The aromatase inhibitor anastrozole is indicated for adjuvant treatment of postmenopausal women with hormone receptor (HR)–positive early breast cancer; first-line treatment of postmenopausal women with HR-positive or HR-unknown locally advanced or metastatic breast cancer; and treatment of advanced breast cancer in postmenopausal women with disease progression after tamoxifen therapy. It is also used for risk reduction, sometimes combined with tamoxifen. In the Arimidex, Tamoxifen, Alone or in Combination trial, anastrozole administered alone significantly reduced contralateral breast cancer in patients with HR-positive first cancers.

Exemestane, also an aromatase inhibitor, is indicated for adjuvant treatment of postmenopausal women with ER-positive early breast cancer who received 2 to 3 years of tamoxifen and for treatment of advanced breast cancer in postmenopausal women whose disease progressed after tamoxifen therapy. In the Mammary Prevention 3 trial, exemestane reduced the reslative incidence of invasive breast cancers by 65% compared with placebo. The NCCN Breast Cancer Risk Reduction Panel states that exemestane for risk reduction should be limited to postmenopausal women aged >35 years with a Gail model 5-year risk score >1.66% or a history of LCIS.10

Treatment

Many drugs are used to treat or slow the progression of breast cancer. The accompanying tables provide information on selected breast cancer treatment options, including each agent’s class, indication, route of administration, and common adverse effects. TABLE 1 describes targeted therapies, TABLE 2 lists immunotherapies, and TABLE 3 summarizes hormone therapies. Several drugs, primarily in the targeted-therapy category, have recently been FDA approved for breast cancer treatment. Targeted therapies have slightly different indications for breast cancer, which enhances specificity of medication selection.




In April 2024, the FDA granted the targeted therapy fam-trastuzumab deruxtecan-nxki accelerated approval for use in adults with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)–positive solid tumors who received prior systemic treatment and have no satisfactory alternatives.11 In one clinical trial, the trastuzumab-treated group had a median progression-free survival (PFS) of 9.9 months versus 5.1 months for the physician’s-choice-of-therapy (i.e., nontrastuzumab) group and an overall survival of 23.4 months versus 16.8 months, respectively.12 Capivasertib was approved in November 2023 for use with fulvestrant for breast cancer. In the multicenter clinical trial, median PFS was 7.3 months in the capivasertib-fulvestrant group and 3.1 months in the placebo-fulvestrant group.13 In March 2023, abemaciclib received approval for use in HR-positive, HER2-negative, node-positive, early breast cancer. Invasive disease-free survival at 48 months was 85.5% for abemaciclib plus standard endocrine therapy and 78.6% for standard endocrine therapy alone.14 Sacituzumab was approved in February 2023 to treat HR-positive, HER2-negative breast cancer. The primary efficacy outcome measure was PFS, which was a median of 5.5 months in the treatment group and 4 months in the control group.15 Dostarlimab, an immunotherapy used in combination with chemotherapy to treat certain advanced-stage endometrial cancers, is also approved to treat mismatch repair–deficient advanced-stage solid tumors.16 In one of the RUBY clinical trials, dostarlimab showed a statistically significant 40% reduction in risk of disease progression or death.17

Conclusion

Various factors increase the risk of developing breast cancer. Screening and risk-reduction therapy are crucial for achieving a decrease in breast cancers. Guidance on breast cancer screening in average-risk women varies among guidelines. Chemopreventive agents may include tamoxifen, raloxifene, and anastrozole. There are many options for breast cancer treatment, and an individualized treatment plan is formulated based on breast cancer type, patient preference, and clinical judgment.

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