The Skills Checkup series provides a quick, case-style interactive quiz highlighting key guidelines- and evidence-based information to inform clinical practice.
Background
A 64-year-old woman presents for her well-woman examination. She has no children. She is obese and has type 2 diabetes that is well-controlled. She does not smoke. She reports that she generally feels well but has some back pain and occasional hip pain that have become increasingly bothersome.
On clinical workup, she has a laboratory analysis that evaluated complete blood count and complete metabolic profile. All of her laboratory values are normal, except for an alkaline phosphatase that was elevated, at 560 U/L (upper limit of normal in that laboratory, 140 U/L). Because of the elevated alkaline phosphatase level and bone pain, she is referred for mammography, which reveals an irregular-appearing mass in the left breast with suspicious axillary nodes.
Breast masses are a common clinical finding and may be palpable or nonpalpable, benign or malignant. The majority of palpable breast masses are benign, but some women who present with this finding will have a diagnosis of cancer. This patient has not only a mass but also "suspicious" axillary nodes, as well as an elevated alkaline phosphatase level — findings associated with metastatic breast cancer.
Fibroadenomas are more common in younger patients. These are benign tumors composed of stromal and epithelial elements. Multiple or complex fibroadenomas may indicate a slightly increased risk for breast cancer. The relative risk for breast cancer in patients with such fibroadenomas is approximately twice that of patients of similar age without fibroadenomas. Fibroadenomas may be excised, especially if they grow or change the shape of the breast. Sometimes, however, these tumors stop growing or even shrink on their own without treatment.
Phyllodes tumors of the breast are rare, accounting for less than 1% of all breast tumors. They are most common in women in their 40s. On a mammogram, this type of tumor may appear similar to a fibroadenoma. Phyllodes tumors tend to grow quickly, but they rarely metastasize outside the breast. Whether phyllodes tumors are benign, borderline, or malignant, the treatment is the same: surgery to remove the tumor.
A radial scar is a star-shaped breast mass that may be benign, precancerous, or contain a mixture of tissue, including hyperplasia, atypia, or cancer. However, radial scars tend to be a discrete tumor without metastasis. They are removed surgically.
Evaluation of a breast mass is guided by findings on history, physical examination, imaging, and biopsy. Although all of the tests might be appropriate at some point, the triad of clinical breast examination, imaging (eg, mammography and ultrasonography), and needle biopsy can lead to a definitive diagnosis in nearly all cases. Thus, the next test would be biopsy.
Hormone receptor (ie, estrogen receptor and progesterone receptor) status as well as HER2 status are usually confirmed via immunohistochemistry staining of a biopsy specimen if there is evidence of cancer. There are four main histologic subtypes of breast cancer: hormone receptor (HR)–positive/human epidermal growth factor receptor 2 (HER2)–negative, HR-negative/HER2-negative (triple negative), HR-positive/HER2-positive, and HR-negative/HER2-positive. Determination of hormone receptor status is crucial for selecting therapy.
According to the National Cancer Institute, HR-positive/HER2-negative is the most common breast cancer subtype, accounting for about 68% of breast cancers, based on 2014-2018 cases. This is nearly seven times higher than the rate of triple-negative breast cancer and the rate of HR-positive/HER2-positive, which each account for 10% of cases. HR-negative/HER2-positive accounts for about 4% of cases, and in the rest of cases, the receptor status is unknown.
Triple-negative breast cancer is considered to be more aggressive and tends to have a poorer prognosis than other types of breast cancer, mainly because there are fewer targeted medicines that treat triple-negative breast cancer. Studies have shown that triple-negative breast cancer is more likely to spread beyond the breast and more likely to recur after treatment.
HER2-positive breast cancer is more aggressive and more likely to spread than HER2-negative breast cancer. However, in recent years, in de novo metastatic disease, women with the HR-positive/HER2-positive subtype have better survival than those with the HR-positive/HER2-negative subtype (often considered the best prognostic feature). This remarkable change is probably attributable to major advances in HER2-targeted therapies.
Of the approximately 200,000 cases of incident breast cancer diagnosed in the United States each year, 1 in 3 will have a distant metastasis. Women with breast cancer are most prone to bone metastases, which is often the first detectable distant site. However, the first location of distant metastasis varies by subtype; in those with HR-positive/HER-negative breast cancer, it spreads to the bone in about 70% of cases. Other common sites are the lungs and the liver, but breast cancer can spread to almost any other part of the body, including the brain and skin.
Traditionally, high-risk patients were screened for occult metastases using bone scintigraphy, chest radiography, and abdominal ultrasound or bone scintigraphy and CT of the chest, abdomen, and pelvis. However, conventional imaging frequently detects bone disease and visceral metastases only in later stages, which are associated with poorer outcomes. Moreover, these methods often fail to demonstrate the heterogeneity of the tumor biology, leading to delays in the opportunity for therapeutic modifications. More modern methods of investigating metastases involve combinations of techniques, such as PET/CT.
Preferred first-line systemic endocrine-based therapy options, which are category 1 recommendations (based on phase 3 clinical trial evidence) per National Comprehensive Cancer Network (NCCN) clinical practice guidelines, include an aromatase inhibitor (ie, anastrozole, exemestane, or letrozole) in combination with a CDK4/6 inhibitor (ie, palbociclib, ribociclib, or abemaciclib); fulvestrant with or without a nonsteroidal aromatase inhibitor (ie, anastrozole or letrozole); or fulvestrant in combination with a CDK4/6 inhibitor.
Given that HR-positive/HER2-negative metastatic breast cancer will ultimately progress after first-line therapy, second-line systemic endocrine-based therapy options must be considered. Preferred second-line systemic endocrine-based therapy options, which are category 1 recommendations per the NCCN guidelines, include fulvestrant in combination with a CDK4/6 inhibitor (if a CDK4/6 inhibitor was not utilized in the first-line setting) or fulvestrant in combination with alpelisib (only in patients with PIK3CA mutations). Other preferred second-line systemic endocrine-based therapy options include everolimus in combination with exemestane, tamoxifen, or fulvestrant; fulvestrant monotherapy; nonsteroidal aromatase inhibitor monotherapy; or selective estrogen receptor modulator monotherapy.
A HER2 receptor antagonist, with or without chemotherapy, is used only for HER2-positive breast cancer. According to the NCCN guidelines, most women with HER2-positive breast cancer will receive one or more chemotherapy drugs plus trastuzumab, the anti-HER2 receptor antagonist. Many studies have shown that these treatments dramatically improve survival for women with HER2-positive breast cancer.
Currently, cytotoxic chemotherapy (eg, with a taxane) remains the mainstay of systemic treatment for triple-negative disease, although studies are investigating the use of other drug classes, including checkpoint inhibitors, agents that target the androgen receptor pathways, and antibody-drug conjugates.
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