Clinicians who work in settings other than oncology should have an understanding of breast cancer to help care for women who are at risk, undergoing a workup for an abnormal mammogram and/or a palpable breast mass, or being treated for breast cancer. Breast cancer incidence is increasing in almost all ethnicities in the United States, and estrogen-positive breast cancer incidence is increasing across all ethnicities.1 This cancer is the leading nondermatologic malignancy and the second most common cause of cancer death among women in the United States.1 Although overall death rates from breast cancer have continued to decrease since 1989, the death rate among non-Hispanic black women remains disproportionately high.1,2
Up to 80% of invasive breast cancers are infiltrating ductal carcinomas (IDC). Invasive lobular carcinoma is the second most common type. Of the noninvasive in situ carcinomas, more than 80% are ductal and about 10% are lobular.2
PATHOPHYSIOLOGY, RISK FACTORS, AND HISTOLOGY
The pathophysiology of breast cancer is multidimensional and still poorly understood, but certain risk factors are known. Advancing age and female sex are the most common risk factors. Genetic mutations, specifically BRCA 1 and 2, account for about 10% of breast cancers.2 Other known risk factors include a history of ductal carcinoma in situ, high body mass index (BMI), first birth at age greater than 30 years or nulliparity, early menarche (before age 13 years), family history of breast or ovarian cancer, late menopause, and postmenopausal hormone therapy use. Among women who use postmenopausal hormone therapy, white women and women with a normal BMI and dense breasts are at greatest risk.3 Women with a history of previous chest radiation also are at an increased risk.
The four breast cancer subtypes (Table 1) are associated with specific histologies and prognoses. Breast cancer also is classified by its anatomical origin, either lobular or ductal, and its hormone receptivity and human epidermal growth factor receptor 2 (HER-2) expression.
Hormone receptivity refers to the presence or absence of estrogen and progesterone receptor expression in the malignancy. Hormone receptor positive breast cancer, particularly when nonmetastatic, is amenable to hormone-blocking therapy. HER-2 positive malignancies are generally responsive to HER-2 directed monoclonal antibodies. Hormone receptor positive, HER-2 negative is the most common expression status of breast cancer.
Triple-negative breast cancer refers to malignancies that do not express hormone receptivity or HER-2. About 12% of women with breast cancer will have triple-negative disease.4 Triple-negative disease is more common among non-Hispanic black women, independent of age, but tends to be diagnosed at earlier ages than other subtypes.4 Women with triple-negative disease are also more likely to be diagnosed at a later stage (stage III or IV). In addition, triple-negative basal subtype breast cancers tend to be of higher grade and thus more aggressive malignancies than hormone receptor positive HER-2 negative disease.
The proliferation biomarker Ki-67 was recently used to help stratify risk of recurrence in breast cancer. It is no longer recommended, but other immunohistologic biomarkers are being discovered and may help to further stratify recurrence risk.
BREAST CANCER SUBTYPES
Ductal carcinoma in situ (DCIS) is a heterogeneous category of noninvasive, noninfiltrating malignancies that are localized inside the mammary ducts. (Sometimes IDC also will have mammographic or histologic evidence of DCIS.2) DCIS is further subclassified depending upon its morphology, location, and cytological characteristics. Lobular carcinoma in situ is less common than DCIS but tends to occur bilaterally. Both DCIS and LCIS are usually hormone receptor positive and HER-2 negative.
IDC is the most common type of breast cancer. About 70% of women with IDC will be hormone receptor positive and HER-2 negative.4
Infiltrating lobular carcinomas (ILCs) are more common among postmenopausal women and have an increased risk of bilateral incidence. They are almost always estrogen and progesterone receptor positive.2
Medullary breast cancer is more common in younger women who carry a BRCA 1 mutation.5 Inflammatory breast cancer is less common but more aggressive, and carries a worse prognosis than other breast cancers. Mammary Paget disease is an adenocarcinoma affecting the nipple and areola. Tubular, papillary, and mucinous breast cancers and Phylloides tumors are less common cancers.5
CLINICAL ASSESSMENT AND DIFFERENTIAL
A palpable breast mass is evident in about 30% of women with breast cancer.2,6 Visible signs associated with breast cancer include dimpling, an orange-peel appearance (peau d'orange), erythema, edema, blistering, excoriations, sanguineous nipple discharge, and nipple retraction. Skin changes such as peau d'orange and blistering are strongly associated with inflammatory breast cancer and Paget disease of the breast. Sanguineous nipple discharge is associated with papillary breast neoplasia. Ulcerations can be seen in advanced disease. Remember to rule out malignancy in patients being treated for mastitis or a breast abscess that is not improving clinically.
The differential diagnosis of a palpable breast mass in a woman includes benign conditions such as fibroadenoma, breast cyst, intraductal papilloma, and fibrocystic changes. Once a mass has been palpated, the next steps are to refer the patient for a diagnostic mammogram and ultrasound.
Mammography and ultrasonography are used as initial imaging modalities. MRI may be used in specific circumstances, such as in patients with dense breasts, those with a history of breast cancer, those who are being evaluated for contralateral disease, and those at high risk for breast cancer.7 MRI also can be used in the presurgical planning of biopsy-proven breast cancer or in the evaluation of patients with dense breasts, contralateral disease, or a history of breast surgery or radiation. MRI can more accurately identify skin changes common in inflammatory breast cancer, such as skin invasion.
Common imaging findings in invasive, infiltrating breast cancer include an irregularly shaped mass, spiculation, pleomorphic microcalcifications, anatomical distortion, axillary lymphadenopathy, and posterior acoustic shadowing. The American College of Radiology uses the Breast Imaging and Reporting Data System (BI-RADS) to categorize radiographic findings.8
Disease is confirmed by tissue biopsy; samples can be obtained through percutaneous ultrasound-guided core needle biopsy, excisional biopsy, stereotactic biopsy, or MRI-guided biopsy. The preferred method for most patients is ultrasound-guided large-bore core needle biopsy with or without a vacuum-assisted device.
Tissue biopsy results will contain information about:
- Tumor grade, which is based on cell differentiation. Low-grade tumors (grade 1) are well differentiated, and high-grade (grade 4) tumors are undifferentiated.
- Immunohistology, based on the tumor's hormone receptivity and HER-2 expression.
- Oncotype DX Breast Recurrence Score, which provides an estimate of the potential utility of neoadjuvant chemotherapy and risk of recurrence in patients with early-stage breast cancer.
Breast cancer is staged using the TNM (tumor, nodes, metastasis) classification system. Most women with a biopsy-proven malignancy should undergo genetic testing for BRCA 1 and 2 mutations (Table 2).9
Cowden syndrome and Li-Fraumeni syndrome also are associated with an increased risk of breast cancer. Patients with a family history of cancer of the breast, ovary, pancreas, prostate, colon, thyroid, or endometrium should undergo more extensive genetic testing.10
Treatment of breast cancer, including surgery, depends on the size of the lesion, hormone receptivity and histologic markers, presence or absence of metastatic or contralateral disease, patient age, and patient preference.
Surgical options include lumpectomy, mastectomy, and bilateral mastectomy. Breast-conserving surgery (lumpectomy) is the preferred intervention for most patients with unilateral disease, but many patients still opt for mastectomy.
Sentinel lymph node biopsy is preferred over wide lymph node dissections if the patient has no radiographic or clinical evidence of axillary lymph node involvement. In patients with evidence of lymph node involvement, expert consensus remains mixed as to whether axillary node dissection has clinical benefit.11
Chemotherapeutic options depend on multiple variables, including hormone reception status, HER-2 status, presence or absence of metastatic disease, and Oncotype DX recurrence score. Locally advanced disease and triple-negative breast cancer usually are treated with presurgical neoadjuvant chemotherapy. Chemotherapeutic agents include doxorubicin, cyclophosphamide, and paclitaxel. Doxorubicin can cause significant nausea, vomiting, diarrhea, and fatigue. Some women will experience a discoloration of their nails. A reddish discoloration of urine, tears, and sweat also can occur. Heart failure has been documented in women receiving doxorubicin, so carefully assess patients' cardiac function. Cyclophosphamide can cause neutropenia, alopecia, and significant nausea and vomiting. Paclitaxel can cause neutropenia, alopecia, arthralgias, myalgias, peripheral neuropathy, and mucositis. A discussion of chemotherapeutic options for recurrent or metastatic breast cancer is beyond the scope of this article.
Adjuvant chemotherapy is administered after surgery. Modalities include endocrine blockers, anthracycline- and taxane-based chemotherapy, and monoclonal antibodies, depending upon the histology, HER-2 status, and hormone receptor status of the malignancy.10
Aromatase inhibitors and selective estrogen receptor modulators (SERMs) can be used for nonmetastatic estrogen and progesterone receptor positive breast cancer.12 HER-2 positive breast cancer can be responsive to HER-2 blockers such as pertuzumab and trastuzumab. Neoadjuvant and adjuvant anthracycline-based chemotherapy, in addition to HER-2 blocking monoclonal antibodies, has shown clinical superiority.10 Monitor left ventricular ejection fraction before and during treatment in patients who are treated with trastuzumab. Primary resistance to trastuzumab is present in more than 30% of patients, and secondary resistance occurs in more than 70% of patients.13
SERMs are used in premenopausal patients. Current recommendations for hormone-positive breast cancer are to use a SERM for 5 years followed by an aromatase inhibitor for 5 years. High-risk patients (those under age 35 years with positive nodes, high-grade, or large tumors) who are hormone receptor positive and HER-2 negative may benefit from using the aromatase inhibitor exemestane plus chemical ovarian suppression with a gonadotropic-releasing hormone agonist, oophorectomy, or ovarian radiation.14 Tamoxifen is the most commonly used SERM. Tamoxifen use has some association with endometrial hyperplasia and carcinoma, so patients are advised to report any new abnormal uterine bleeding to their gynecologist. Avoid coprescribing paroxetine, fluoxetine, bupropion, and duloxetine, because these medications are strong inhibitors of CYP2D6 and may lower tamoxifen's effectiveness. Escitalopram, citalopram, sertraline, and desvenlafaxine are moderate inhibitors of CYP2D6. Venlafaxine seems to have a negligible effect on CYP2D6.15
Aromatase inhibitors are used in women with natural and surgically induced menopause. The National Comprehensive Cancer Network provides guidance in diagnosing menopause in patients with breast cancer. Consider a woman postmenopausal if she is:
- age 60 years or older
- has had an oophorectomy
- under age 60 years and has been amenorrheic for at least 12 months without any exogenous medications that could alter ovarian function
- under age 60 years and taking a SERM, but has serum estradiol and/or follicle-stimulating hormone levels that are consistent with menopause.10
Women who take aromatase inhibitors experience accelerated bone loss, so regular monitoring of bone density is recommended. Consider prescribing bisphosphonates in postmenopausal women with hormone receptor positive breast cancer to help prevent further bone loss from aromatase inhibitor therapy. Aromatase inhibitors can cause significant joint pain. Patient education and support are necessary to help ensure adherence. Treatment of aromatase-induced arthralgia includes NSAIDs and acetaminophen. Patients may find relief from physical therapy, acupuncture, exercise, and other complementary therapies.
Triple-negative basal subtype breast cancer is managed with a combination of doxorubicin, cyclophosphamide, and paclitaxel. Clinical trials with immunotherapies and other targeted therapies are underway. Because triple-negative breast cancer does not have endocrine receptivity, endocrine therapy is not indicated.
Radiation therapy is almost always used, either before surgery or more commonly after it. Whole-breast and targeted nodal radiation have been considered the gold standard treatment. Women typically receive radiation therapy five times a week for 4 to 7 weeks. A “boost” of lower radiation may be considered in women at high risk of recurrence. Accelerated partial breast irradiation may be considered in women over age 50 years who are node-negative, hormone receptor positive, and BRCA-negative.10 Women who undergo breast-conserving surgery receive postsurgical radiation of the breast and axilla. In women with positive lymph nodes and tumors greater than 5 cm, radiation may be used on the axilla, supraclavicular areas, and sternum.10
Presurgical radiation therapy often is used for tumors that have been staged at T2 or higher, using specific criteria to guide radiation decisions. Recent data suggest that women age 65 years and older with hormone receptor positive, node-negative disease with a primary tumor less than 3 cm may have the option of foregoing radiation.16
Patients undergoing radiation are advised to avoid the use of deodorants, antiperspirants, and underwire bras. In addition, patients should avoid the use of topical creams, lotions, and ointments before their treatments because thicker applications could affect the radiation dose received.17 They should not use heavily perfumed lotions and creams on the breast, and use only specific topical products (such as aloe vera and hydrocortisone) on skin burns that occur during radiation therapy. Other adverse reactions common to patients undergoing radiation include fatigue, pain, and breast discoloration. Women with large breasts are also at risk of developing a candidal dermatitis under the breast. Prompt treatment with an appropriate antifungal is essential.
BREAST CANCER SCREENING
The US Preventive Services Taskforce (USPSTF) recommends screening mammography in women ages 50 to 74 years.18 Women ages 40 to 49 years should have a screening regimen based on the best-available evidence, including the patient's risk factors, through shared decision-making.18 Annual mammography is not recommended for average-risk women in any age group, and the benefit of screening in women over age 75 years has not been established.18 However, the American College of Obstetricians and Gynecologists (ACOG) advocates for individualized shared decision-making about screening with each patient, taking into consideration the patient's risk factors and values.19 Monthly breast self-examinations are not explicitly recommended by any professional organization and clinical breast examination recommendations vary by professional organization. ACOG and the National Comprehensive Cancer Network recommend clinical breast examinations every 1 to 3 years, but the American Cancer Society and the USPSTF do not recommend clinical breast examinations.19
Breast cancer is a multifactorial, heterogeneous disease that requires clinical acumen and a multidisciplinary approach to diagnose and manage. Clinicians working in nononcology settings are likely to encounter patients who are in the early stages of diagnosis and later stages of treatment, thus an understanding of the current state of the evidence will help guide the care of these patients.
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8. American College of Radiology. ACR BI-RADS Atlas, 5th ed. quick reference. www.acr.org/-/media/ACR/Files/RADS/BI-RADS/BIRADS-Reference-Card.pdf
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9. National Cancer Institute. BRCA mutations: cancer risk and genetic testing. www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet#q6
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10. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: breast cancer. www.nccn.org/professionals/physician_gls/pdf/breast.pdf
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11. O'Sullivan CC, Loprinzi CL, Haddad TC. Updates in the evaluation and management of breast cancer. Mayo Clin Proc
12. National Cancer Institute. Breast Cancer Treatment (PDQ) – Health Professional Version. www.cancer.gov/types/breast/hp/breast-treatment-pdq
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13. Santa-Maria CA, Nye L, Mutonga MB, et al. Management of metastatic HER2-positive breast cancer: where are we and where do we go from here. Oncology (Williston Park)
14. Francis PA, Pagani O, Fleming GF, et al. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med
15. Juurlink D. Revisiting the drug interaction between tamoxifen and SSRI antidepressants. BMJ
16. Kunkler IH, Williams LJ, Jack WJ, et al. PRIME II investigators. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol
17. Baumann BC, Verginadis II, Zeng C, et al. Assessing the validity of clinician advice that patients avoid use of topical agents before daily radiotherapy treatments. JAMA Oncol
18. US Preventive Services Taskforce. Final recommendation statement: breast cancer screening. www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/breast-cancer-screening1
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19. American College of Obstetricians and Gynecologists. Breast cancer risk assessment and screening in average-risk women. www.acog.org/-/media/Practice-Bulletins/Committee-on-Practice-Bulletins—Gynecology/Public/pb179.pdf?dmc=1&ts=20180204T1824108792
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