Radiation Therapy for Early-Stage Breast Cancer

Etiology

In the United States, about one in eight women will develop breast cancer in her lifetime. The lifetime risk of developing breast cancer is about 12%. Unfortunately, the etiology of most breast cancer cases is unknown; however, many risk factors have been identified. The most important risk factors for breast cancer are female gender and older age. Other significant risk factors include age at menarche, age at menopause, age at first pregnancy, family history, use of exogenous estrogen, alcohol consumption, prior history of chest irradiation, benign proliferative breast disease, mammographic breast density, and genetic mutations. Approximately 10% of breast cancer cases are associated with germline mutations such as BRCA1 and BRCA2. Mutations in BRCA1 and BRCA2 are the most common. Other genetic mutations have been identified to carry mild to moderate risk for breast cancer. BRCA1 mutation carriers have a 55% to 65% lifetime risk of breast cancer while BRCA2 mutation carriers have about a 45% risk. In men, BRCA2 mutations carry a lifetime breast cancer risk of about 7%. BRCA mutations also carry an increased risk for ovarian cancer. BRCA2 mutations carry 10-15% lifetime risk of ovarian cancer. Prophylactic mastectomy significantly reduces the risk of breast cancer. Prophylactic bilateral salpingo-oophorectomy decreases the risk of ovarian and fallopian tube cancers by 80% and breast cancers by 50%.  Majority of breast cancers are diagnosed in women who do not have a family history of breast cancer.  Most breast cancers occur as a result of somatic mutations due to the aging process and environmental factors as opposed to inherited germline mutations.[4][5]

Epidemiology

In 2017, it is estimated that there will about 252,000 new cases of invasive breast cancer diagnosed in the United States along with 63,000 of noninvasive breast cancer (in-situ) cases. About 40,000 women are expected to die, although mortality rates have been declining. In the United States, breast cancer is the second most common cause of cancer-related deaths after lung cancer. Mortality rates are however higher in African Americans compared to whites.  The risk of developing and dying from breast cancer is lower in Asians, Hispanics, and Native Americans.[6][7]

Pathophysiology

Ductal carcinoma in situ (DCIS) comprises 15% to 20% of breast cancer cases. Ductal carcinoma in situ represents cancer cells that have not broken through the basement membrane. One-third of ductal carcinoma in situ can develop invasive disease. Invasive ductal carcinoma is the most common type of breast cancer. Lobular carcinoma carries similar prognosis as ductal carcinoma. Medullary, mucinous, and tubular carcinomas have a better prognosis.

History and Physical

History should include risk factors and gynecologic history. A physical exam is important with attention to breast and regional nodes (tumor, skin or chest wall involvement, nipple changes, axillary and supraclavicular exam). Patients can present with a palpable breast mass, nipple inversion, discharge, or bleeding, or axillary node involvement.

Evaluation

Breast imaging typically begins with mammogram and ultrasound. Breast magnetic resonance imaging (MRI) can be considered for dense breasts, mammographically occult tumors, or if there is the concern for the multifocal or multicentric disease. Additional studies can include computed tomography (CT) of the chest and abdomen, bone scan, magnetic resonance imaging (MRI) of the brain, and positron emission tomography-computed tomography (PET-CT) when indicated. Diagnosis can be obtained through breast biopsy as well as a biopsy of suspicious axillary nodes. Both histologic assessments including a status of estrogen receptor (ER), progesterone receptor (PR), HER2/neu (HER2), and Ki-67 and cancer staging are crucial to helping guide treatment recommendations. Also, Oncotype DX which is a 21 gene RT-PCR assay can be ordered for hormone positive, HER2 negative, node-negative breast tumors to help determine the need for chemotherapy. Lab work includes a complete blood count (CBC), blood chemistries, and liver function tests. Genetic counseling is offered to patients who are at high risk for hereditary breast cancer and fertility counseling if the patient is premenopausal. Distress screening and management addressing psychological, social, and physical needs of the patient are also integral in care of breast cancer patients.[8][9]

Treatment / Management

Typically, early-stage breast cancer (stage I and II) is treated with breast conservation therapy (BCT). Surgery includes lumpectomy and axillary staging with sentinel lymph node biopsy for invasive breast cancer. Axillary staging is not needed for ductal carcinoma in situ.  Contraindications to breast conservation therapy are multicentric disease, high tumor to breast ratio, diffuse microcalcifications, persistent positive margins despite re-excisions, previous breast radiation therapy, scleroderma, and pregnancy. In these cases, mastectomy is recommended.

Treatment for ductal carcinoma in situ (Stage 0) is individualized based on clinical and pathological features and patient preference. Typically, patients with ductal carcinoma in situ are treated with lumpectomy. Radiation therapy is recommended to reduce the risk of local breast recurrence. In some patients with a low-risk profile, radiation therapy can be omitted. Increasingly, Oncotype DX ductal carcinoma in situ score is utilized in the decision-making process for ductal carcinoma in situ to assess risk for recurrence and help guide treatment. In patients with invasive tumors, chemotherapy is recommended if there is a high risk of recurrence especially in the setting of a large tumor, node positive, triple-negative (ER, PR, HER2- negative), or HER2 positive disease.

Oncotype DX also plays a role in determining the need for chemotherapy in hormone positive, HER2-negative, node-negative breast tumors. Chemotherapy has traditionally been given in the adjuvant setting. Increasingly, neoadjuvant chemotherapy has been used in cases to allow tumor shrinkage in hopes of preserving the breast and in triple negative or HER2 positive breast tumors. Neoadjuvant therapy is now considered standard of care in high-risk populations such as young patients and those with more advanced or aggressive disease. Radiation therapy is recommended in the post-lumpectomy setting to reduce the risk of local recurrence. 

Whole breast radiotherapy targets the entire breast tissue. Conventional dose of 45 Gy to 50 Gy is delivered to the whole breast, followed by a boost to the lumpectomy bed for an additional 10 Gy to 16 Gy.  Conventional fractionation typically given over 6 weeks. Depending on the risk of recurrence, radiation therapy is also delivered to regional nodes to 45 GY to 50 Gy.  Nodal irradiation includes the supraclavicular, axillary, and internal mammary regions if clinically indicated. Hypofractionation is considered for low-risk node-negative patients who are 50 years or older, not getting chemotherapy, and have a separation of 25 cm or less.

Recommended hypofractionation schedule is 42.56 Gy in 16 fractions plus lumpectomy bed boost (approximately 2 weeks less than conventional fractionation). Partial breast irradiation targets the lumpectomy bed only and is considered in low-risk patients who are 50 years or older with unicentric/unifocal tumors 3 cm or less, negative margins, and negative nodes. Partial breast irradiation is delivered in 10 fractions, twice daily, over 1 week.  Adjuvant therapy also includes endocrine therapy in patients with hormone-positive tumors.[10][11][12](B3)

Differential Diagnosis

• Duct ectasia 

• Ductal carcinoma 

• Extramedullary acute myeloid leukaemia

• Hyalinized fibroadenoma

• Inflammatory carcinoma

• Mastitis 

• Radial scar