Breast Cancer in Women

Background

• Breast cancer is a malignancy of the breast tissue and is the most common malignancy diagnosed in women worldwide.
• Early or operable breast cancer is considered potentially curable and includes stage I-IIB and some stage IIIA cancers, specifically T3, N1 tumors.
• Noninflammatory locally advanced inoperable breast cancer is considered potentially curable and includes stage IIIA-C breast tumors with the exception of some stage IIIA, specifically T3, N1 tumors.
• Inflammatory breast cancer is a rare, aggressive subtype of locally advanced breast cancer characterized by a substantial area of breast skin that is red in color, warm, and thickened or swollen (referred to as peau d'orange).
• Advanced (metastatic) breast cancer encompasses disease that has spread beyond the breast and regional lymph nodes and is either de novo stage IV (metastatic at the time of initial diagnosis) or a metastatic recurrence. Common sites of metastases include bone, liver, lung, and brain.
• Risk factors for breast cancer include genetic causes, increased age, reproductive history and hormone exposure, lifestyle factors, medical history, and radiation exposure.
• Women with breast cancer may present with breast abnormalities detected during screening, without any other signs or symptoms. Common signs and symptoms of breast cancer include palpable breast mass, axillary mass, nipple discharge, skin changes on breast or nipple, asymmetric thickening or nodularity, breast pain, or signs and/or symptoms due to metastatic disease.
• The 5-year survival after diagnosis of breast cancer is 99% for women with localized disease, 85% for women with regional spread, and 27% for women with distant metastases in the United States; in addition, women with estrogen receptor positive cancers treated with endocrine therapy have a 13%-41% risk of recurrence 5-20 years after diagnosis. Factors affecting prognosis include tumor and disease characteristics, age, response to therapy, race and ethnicity, and body mass.

Evaluation

• Diagnosis is based on examination of the breast and axillary lymph nodes with clinical exam and imaging, and confirmed by the pathological assessment of biopsy.
• Perform imaging including either or both diagnostic mammogram and ultrasound (Strong recommendation); magnetic resonance imaging (MRI) of breast may also be used in specific circumstances. Recommendations for specific imaging tests vary based on presentation.
• Pathological assessment of breast is generally performed using core needle biopsy, preferably with ultrasound or stereotactic guidance (Strong recommendation); also perform ultrasound-guided fine needle aspiration or core needle biopsy of suspicious lymph nodes (Strong recommendation).
• Consider testing to assess for distant metastatic disease in patients with inoperable breast cancer and in symptomatic or high-risk patients with operable breast cancer including blood tests, chest computed tomography (CT), abdominal ultrasound or abdominal with or without pelvic CT with contrast or magnetic resonance imaging, bone scan, or fluorodeoxyglucose positron emission tomography (PET)/CT (Weak recommendation).

Management

Management of early and locally advanced noninflammatory breast cancer

• Management of breast cancer is based on the disease stage and characteristics, comorbidities, and patient preferences; treatment may include neoadjuvant and/or adjuvant systemic therapy, surgery, and radiation therapy.
• For patients with early or operable breast cancer:
  • Neoadjuvant systemic therapy, using endocrine therapy or chemotherapy (either alone or in combination with human epidermal growth factor receptor 2 [HER2]-targeted therapy), may be indicated for:
    • patients who desire breast-conserving surgery but mastectomy would be required due to tumor size (Strong recommendation)
    • patients with clinically positive lymph nodes that are likely to become negative with neoadjuvant systemic therapy (Weak recommendation)
    • patients who may benefit from additional or different adjuvant (post-operative) therapy based on assessment of response to neoadjuvant therapy
  • Locoregional therapy includes surgery to the breast and axilla as well as radiation therapy; offer either
    • breast-conserving therapy by lumpectomy with surgical axillary staging (Strong recommendation), followed by radiation therapy according to lymph node status:
      • surgical axillary staging may be omitted in select older women with clinically negative lymph nodes
      • radiation may be omitted in select older women with estrogen positive breast cancer who receive adjuvant endocrine therapy
    • total mastectomy with surgical axillary staging (Strong recommendation) with or without breast reconstruction (Weak recommendation) and with or without postmastectomy radiation therapy according to lymph node status, tumor size and surgical margins
  • Adjuvant systemic therapy is determined based on tumor size, nodal status, tumor histology, hormone receptor (HR) status, HER2 status, and multigene assays.
• For patients with inoperable locally advanced noninflammatory breast cancer:
  • Neoadjuvant systemic therapy is recommended for all patients with inoperable locally advanced breast cancer (Strong recommendation).
  • For most patients with response to neoadjuvant systemic therapy, locoregional therapy follows and includes surgery to the breast and axilla and radiation therapy. Options include:
    • breast-conserving therapy by lumpectomy plus level I/II axillary dissection plus whole breast radiation therapy with or without boost radiation to tumor bed, plus radiation to infraclavicular region, supraclavicular area, internal mammary nodes, and any part of axillary bed at risk (Strong recommendation)
    • total mastectomy plus level I/II axillary dissection plus radiation therapy to chest wall, infraclavicular region, supraclavicular area, internal mammary nodes and any part of axillary bed at risk, with or without breast reconstruction (Strong recommendation)
  • Adjuvant systemic therapy should include:
    • adjuvant chemotherapy if not already completed in the neoadjuvant setting (Strong recommendation); patients with triple-negative tumor and residual invasive cancer after neoadjuvant therapy with taxane, alkylator, and anthracycline based chemotherapy, may receive adjuvant capecitabine (Weak recommendation)
    • adjuvant endocrine therapy should be offered to patients with HR positive (estrogen receptor and/or progesterone receptor positive) breast cancer (Strong recommendation)
    • adjuvant HER2 targeted therapy with trastuzumab up to 1 year should be offered to patients with HER2 positive breast cancer (Strong recommendation), with or without pertuzumab (Weak recommendation).

Management of inflammatory breast cancer

• The management of inflammatory breast cancer consists of trimodality therapy starting with neoadjuvant systemic therapy followed by mastectomy with axillary dissection and postmastectomy radiation therapy.
• Neoadjuvant (preoperative) systemic therapy
  • An anthracycline plus taxane is the preferred combination for neoadjuvant chemotherapy (Strong recommendation).
  • If the cancer is HER2 positive, add HER2 targeted therapy to the neoadjuvant chemotherapy (Strong recommendation).
• Following neoadjuvant therapy, assess the treatment response with a physical examination and repeat imaging of abnormal findings at the time of initial tumor staging (Strong recommendation).
• For patients with cancer response to neoadjuvant therapy:
  • Perform total mastectomy with level I/II axillary lymph node dissection (Strong recommendation).
    • Delayed breast reconstruction is an option for women who desire breast reconstruction (Weak recommendation).
    • Immediate breast reconstruction is contraindicated (Strong recommendation).
  • Provide postmastectomy radiation therapy (Strong recommendation).
  • Adjuvant (postoperative) systemic therapy:
    • Complete planned chemotherapy regimen if not completed preoperatively and give endocrine therapy following completion of chemotherapy if the cancer is HR positive (Strong recommendation).
    • Complete up to 1 year of HER2 targeted therapy if the cancer is HER2 positive (Strong recommendation); it should be given concurrently with radiation therapy and with endocrine therapy if indicated (Strong recommendation).
• For patients with cancer unresponsive to neoadjuvant chemotherapy:
  • Consider treating with additional neoadjuvant chemotherapy and/or preoperative radiation therapy to achieve response, or enrollment in a clinical trial (Weak recommendation).
  • For patients with cancer unresponsive to additional neoadjuvant chemotherapy or preoperative radiation therapy, consider individualized treatment, or enrollment in a clinical trial (Weak recommendation).
  • Mastectomy is generally not recommended if there is no response (Strong recommendation).

Management of locoregional recurrence of breast cancer

• Before treatment, assessment for evidence of metastatic disease is necessary to differentiate isolated locoregional recurrences from those associated with synchronous distant metastatic disease (Strong recommendation).
• For women with local only recurrence:
  • In women initially treated with breast-conserving surgery and radiation therapy, offer total mastectomy plus axillary lymph node staging if level I/II axillary dissection was not done previously (Strong recommendation).
  • In women initially treated with mastectomy, offer surgical resection if possible (Strong recommendation).
  • In women without previous radiation therapy, offer locoregional radiation therapy (Strong recommendation); if the initial treatment included radiation therapy, consider reirradiation to all or part of chest wall in select cases (Weak recommendation)
  • Offer systemic therapy if HR negative disease (Strong recommendation) and consider systemic therapy if HR positive disease (Weak recommendation) , especially if initially unresectable or in women who are not candidates for surgical resection.
  • In women who are not candidates for surgical resection, options include systemic therapy followed by surgical resection (Weak recommendation), definitive radiation therapy, or systemic therapy alone.
• For the management of regional or local and regional recurrence:
  • When possible, treat locoregional recurrence with curative intent (Strong recommendation). Treat areas of local recurrence based on recommendations under management of local only recurrence and areas of regional recurrence based on location of recurrence.
  • In women with axillary recurrence:
    • Perform surgical resection if possible, plus radiation therapy if possible (Strong recommendation).
    • If initially unresectable or in women who are not candidates for surgical resection, consider systemic therapy to best response followed by surgical resection, if possible (Weak recommendation).
  • In women with supraclavicular or internal mammary node recurrence, if no previous radiation therapy, offer locoregional radiation therapy (Strong recommendation); if initial treatment included radiation therapy, consider reirradiation to all or part of chest wall in select cases (Weak recommendation).
  • Offer systemic therapy if HR negative disease (Strong recommendation) and consider systemic therapy if HR positive disease (Weak recommendation)

Management of metastatic breast cancer

• Consider for all patients with metastatic breast cancer enrollment in a clinical trial (Weak recommendation).
• Palliative and supportive care should be offered to all patients throughout the course of metastatic disease (Strong recommendation).
• Treatment typically involves systemic therapy with endocrine therapy, chemotherapy, and/or targeted/biologic therapy based on HR status, HER2 status, BRCA1/2 mutation status, programmed cell death ligand 1 (PD-L1) status, status of other biomarkers, comorbidities, and severity of disease.
  • For HR positive, HER2 negative breast cancer:
    • Offer endocrine therapy with or without a cyclin dependent kinase (CDK) 4/6 inhibitor for first-line therapy unless there is a visceral crisis (Strong recommendation). Offer ovarian ablation or suppression in addition to endocrine therapy for premenopausal women (Strong recommendation). May consider a selective estrogen receptor modulator without ovarian suppression or ablation in select women who have not been on endocrine therapy for a year (Weak recommendation). If there is a visceral crisis, consider chemotherapy or targeted therapy for first line therapy (Weak recommendation).
    • Continue therapy until disease progression or intolerable toxicity (Strong recommendation), then, weighing benefits and harms, consider a different line of endocrine therapy, targeted therapy, and/or chemotherapy while continuing supportive care (Weak recommendation). Most patients are candidates for multiple sequential lines of systemic therapy.
    • May consider single agent poly adenosine diphosphate ribose polymerase (PARP) inhibitors for patients with a germline BRCA1/2 mutation after progression on endocrine therapy plus CDK4/6 inhibitor (Weak recommendation).
  • For HR positive, HER2 positive breast cancer:
    • Offer chemotherapy plus HER2 targeted therapy (Strong recommendation). May consider endocrine therapy plus HER2 targeted therapy for maintenance therapy following completion of chemotherapy and continued until progression or unacceptable toxicity (Weak recommendation). In select patients, may consider endocrine therapy, with ovarian suppression or ablation for premenopausal women, with or without HER2 targeted therapy as first-line therapy (Weak recommendation). For select premenopausal women, may consider a selective estrogen receptor modulator (SERM) plus HER2 targeted therapy without ovarian oblation or suppression (Weak recommendation).
    • Continue therapy until progression or intolerable toxicity (Strong recommendation), then, weighing benefits and harms, offer a different line of chemotherapy plus HER2 targeted therapy, other HER2 targeted therapy, or endocrine therapy with or without HER2 targeted therapy (Strong recommendation). Most patients are candidates for multiple sequential lines of systemic therapy.
  • For HR negative, HER2 positive breast cancer:
    • Offer chemotherapy plus HER2 targeted therapy (Strong recommendation).
    • Therapy should be continued until progression or intolerable toxicity (Strong recommendation), then, weighing benefits and harms, offer a different line of chemotherapy plus HER2 targeted therapy, other HER2 targeted therapy, or other targeted therapy (Strong recommendation). Most patients are candidates for multiple sequential lines of systemic therapy.
    • May consider single agent poly adenosine diphosphate ribose polymerase (PARP) inhibitors for patients with a germline BRCA1/2 mutation, although they are not FDA-approved for HER2 positive breast cancer (Weak recommendation).
  • For HR negative, HER2 negative (triple negative) breast cancer:
    • Offer chemotherapy and/or targeted therapy (Strong recommendation) until progression or intolerable toxicity (Strong recommendation), then, weighing benefits and harms, offer a different line of chemotherapy and/or targeted therapy (Strong recommendation). Most patients are candidates for multiple sequential lines of systemic therapy.
• For bone metastases, a multidisciplinary treatment approach may include systemic therapy, surgery, radiation and supportive care. Offer bone-modifying agents such as bisphosphonates or denosumab, with calcium and vitamin D supplement, for all patients with bone metastases (Strong recommendation).
• For brain metastases, a multimodal treatment approach is based on performance status, prognosis, number, size, and location of brain metastases. Consider steroids for patients who are symptomatic due to brain metastases or spinal cord compression (Weak recommendation). Do not offer routine prophylactic antiseizure medications (Strong recommendation), although they may be considered perioperatively (Weak recommendation).
• Surveillance includes periodic assessment of symptoms, physical exam findings, laboratory tests, imaging studies, and blood biomarkers where appropriate (Strong recommendation). The optimal frequency of testing is unknown, but generally consider every 2-4 months for endocrine therapy and every 2-3 cycles for chemotherapy (Weak recommendation) For patients with brain metastases, consider following with brain MRI every 2-3 months for 1-2 years, and then every 4-6 months thereafter (Weak recommendation).

Management of breast cancer during pregnancy

• For pregnant women with confirmed breast cancer diagnosis, considerations and selection of optimal local and systemic therapy are similar to those in nonpregnancy associated breast cancer; however, the timing and selection of chemotherapy, endocrine therapy, and radiation therapy is different for pregnant and nonpregnant women.
• Maternal fetal medicine consultation should include a review of treatment options and the possibility of pregnancy termination.
  • In the first trimester, discuss nontherapeutic pregnancy termination ( Weak recommendation). For women who choose to continue pregnancy:
    • consider mastectomy plus axillary staging as surgical treatment (Weak recommendation)
    • if late in first trimester, may consider neoadjuvant chemotherapy to begin in the second trimester; otherwise, offer adjuvant chemotherapy in second trimester (Weak recommendation)
  • In second trimester or early third trimester, options include:
    • mastectomy or breast-conserving surgery plus axillary staging, followed by adjuvant chemotherapy (Weak recommendation)
    • neoadjuvant chemotherapy followed by mastectomy or breast-conserving surgery plus axillary staging (Weak recommendation)
  • In late third trimester, consider mastectomy or breast conserving surgery plus axillary staging, followed by adjuvant chemotherapy if indicated (Weak recommendation).
• Chemotherapy should not be given after week 35 of pregnancy or within 3 weeks of planned delivery to avoid potential hematologic complications during delivery.
• HER2 targeted therapy is contraindicated in pregnancy.
• Adjuvant endocrine therapy and radiation therapy should not be used during any trimester of pregnancy, but may be offered in postpartum period if indicated by disease status (Strong recommendation).