Breast Cancer Overview

Breast Cancer Overview

• Breast cancer originates from breast tissue and is considered a malignancy.
• Early, primary, or localized breast cancer refers to disease confined to a localized breast lesion and is considered curable.
• Advanced or metastatic breast cancer (MBC) is disease detected clinically or radiologically in sites distant from the breast, and is usually incurable.

Epidemiology

• Gender and age are the most strongly associated variables with breast cancer occurrence.
• Additional risk factors include endocrine factors (early menarche, nulliparity, late age at first birth, hormone replacement therapy).
• Genetic factors like personal and family history, and mutations of tumor suppressor genes (BRCA1 and BRCA2) are also risk factors.
• Environmental and lifestyle factors such as radiation exposure, tobacco use, and alcohol use contribute to risk.
• Breast cancer cells spread undetected by contiguity, lymph channels, and through the blood early, which can result in metastatic disease after local therapy.
• Common metastatic sites include lymph nodes, skin, bone, liver, lungs, and brain.

Prevention

• Risk reduction strategies include prophylactic mastectomy, oophorectomy, and pharmacologic agents.
• Selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) are available for pharmacologic risk reduction.
• Tamoxifen and raloxifene SERMs, taken for 5 years, reduce the risk of invasive and noninvasive breast cancer by about 50% in high-risk women.
  • Tamoxifen increases the incidence of endometrial cancer and both agents increase thromboembolic events.
• Exemestane and anastrozole AIs, showed a similar reduction in the risk of contralateral primary breast cancers in high risk, postmenopausal individuals.
• Clinical guidelines recommend SERMs or AIs for risk reduction in postmenopausal women at high risk.

Clinical Presentation

• A painless, palpable lump is often the initial sign of breast cancer.
• The typical malignant mass is solitary, unilateral, solid, hard, irregular, and nonmobile.
• Nipple changes are less common.
• Advanced cases may present with prominent skin edema, redness, warmth, and induration.
• Symptoms of MBC depend on metastatic site, including bone pain, difficulty breathing, abdominal pain or enlargement, jaundice, and mental status changes.
• Breast cancer is increasingly detected during routine screening mammography in asymptomatic women.

Diagnosis

• Initial workup includes a careful history, physical examination of the breast, three-dimensional mammography, and possibly other breast imaging techniques like ultrasound and MRI.
• Breast biopsy is indicated for a mammographic abnormality suggesting malignancy or for a palpable mass on physical examination.

Staging

• Stage is based on primary tumor extent and size (T1–4), presence and extent of lymph node involvement (N1–3), and presence or absence of distant metastases (M0–1).
• The staging system determines prognosis and assists with treatment decisions.
  • Stage 0: Carcinoma in situ
  • Stage I: Small primary invasive tumor without lymph node involvement
  • Stage II: Involvement of regional lymph nodes
  • Stage III: Large tumor with extensive nodal involvement
  • Stage IV: Metastases in organs distant from the primary tumor
• Staging is separated into clinical (before surgery, based on physical examination and imaging) and pathologic staging (after surgery, adds data from surgical exploration and resection).

Pathological Evaluation

• The development of malignancy is a multistep process involving preinvasive (or non-invasive) and invasive phases.
• The goal of treatment for noninvasive carcinomas is to prevent the development of invasive disease.
• Pathologic evaluation establishes the histologic diagnosis and confirms the presence or absence of prognostic factors.
• Most breast carcinomas are adenocarcinomas and are classified as ductal or lobular.

Prognostic Factors

• Age at diagnosis and ethnicity can affect prognosis.
• Tumor size and presence and number of involved axillary lymph nodes are independent factors that influence the risk for breast cancer recurrence and subsequent metastatic disease.
• Alcohol use, dietary factors, weight, and exercise are potentially modifiable prognostic factors.
• Hormone receptors (estrogen [ER] and progesterone [PR]) are not strong prognostic markers but are used to predict response to endocrine therapy.
• HER2 overexpression occurs in about 15%–20% of breast cancers and is associated with increased tumor aggressiveness, increased rates of recurrence, and increased rates of mortality.
• Genetic profiling tools provide additional prognostic information to aid in treatment decisions for subgroups of patients with otherwise favorable prognostic features.

Treatment Goals

• The intent of adjuvant systemic therapy for Stage I–III is to eradicate micro metastatic disease with cure as the desired outcome.
• Neoadjuvant systemic therapy may be administered for Stage III to decrease tumor size prior to surgery and/or to allow for breast conserving surgery if desired by the patient.
• Palliation is the desired therapeutic outcome in the treatment of MBC.
• Treatment can cause substantial toxicity, which differs depending on the individual agent, administration method, and combination regimen.

Curative Breast Cancer (Stage III) Treatment

• Local-Regional Therapy:
  • Surgery alone can cure most patients with in situ cancers, 70%–80% of stage I cancers, and approximately one-half of those with stage II cancers.
  • Breast conserving therapy (BCT) maintains acceptable cosmetic results and rates of local and distant recurrence and mortality seen with mastectomy.
  • BCT includes removal of part of the breast, surgical evaluation of axillary lymph nodes, and radiation therapy (RT) to prevent local recurrence.
  • RT is administered to the entire breast to eradicate residual disease after BCT.
  • Reddening and erythema of the breast tissue with subsequent shrinkage of total breast mass are less common complications associated with short-term RT.
  • Multiple sites of cancer within the breast and the inability to attain negative pathologic margins are indications for mastectomy.
  • Axillary lymph nodes should be sampled for staging and prognostic information.
• Systemic Therapy:
  • Chemotherapy, endocrine therapy, targeted therapy, or some combination of these agents improves disease free and/or overall survival (OS) for high-risk patients in specific prognostic subgroups (eg, nodal involvement, menopausal status, hormone receptor status, or HER2 status).

Cytotoxic Chemotherapy

• Systemic adjuvant therapy is the administration of systemic therapy following definitive local therapy when there is no evidence of metastatic disease but a high likelihood of disease recurrence.
  • The goal of such therapy is cure.
  • It is recommended in most women with lymph node metastases or with primary breast cancers larger than 1 cm in diameter (both node negative and node positive).
• Neoadjuvant (preoperative) systemic therapy is the standard of care for patients with locally advanced breast cancer.
• Common cytotoxic drugs used alone and in combination as adjuvant therapy for breast cancer include doxorubicin, epirubicin, cyclophosphamide, methotrexate, fluorouracil, carboplatin, paclitaxel, and docetaxel.
• Combination regimens are more effective than single agent chemotherapy.
• Anthracyclines (doxorubicin or epirubicin) and taxanes (paclitaxel or docetaxel) are the cornerstones of modern chemotherapy for adjuvant treatment of breast cancer.
• Initiate chemotherapy within 12 weeks of surgical removal of the primary tumor optimal duration of adjuvant treatment is unknown but appears to be 12–24 weeks, depending on the regimen used.
• Dose intensity refers to the amount of drug administered per unit of time.
  • Dose density is one way of achieving dose intensity by decreasing time between treatment cycles.
  • Avoid dose reductions in standard regimens unless necessitated by severe toxicity.

Biologic or Targeted Therapy

• Targeted therapies are directed at molecular targets through novel mechanisms; many are also biologic therapies because they are monoclonal antibodies (mAbs).
• Trastuzumab is an mAb targeted against the HER2 receptor protein used with or after adjuvant chemotherapy in patients with early stage, HER2 positive breast cancer.
  • It reduced the risk of recurrence up to 50% in clinical trials.
  • The risk of symptomatic heart failure with adjuvant trastuzumab regimens that contain an anthracycline ranges from 0.5% to 4%.
• Neratinib an oral tyrosine kinase inhibitor of EGFR, HER2, and HER4, is indicated for extended adjuvant therapy after completion of trastuzumab.
• Ado-trastuzumab emtansine (TDM1) is used in the adjuvant setting following neoadjuvant therapy when residual disease is found at the time of surgery.

Endocrine Therapy

• Tamoxifen, toremifene, oophorectomy, ovarian irradiation, luteinizing hormone–releasing hormone (LHRH) agonists, and AIs are endocrine therapies used in the treatment of primary or early-stage breast cancer.
  • Menopausal status determines the agent of choice.
  • Tamoxifen is generally considered the adjuvant endocrine therapy of choice for premenopausal women.
• Tamoxifen beginning soon after completing chemotherapy and continuing for 5–10 years, reduces the risk of recurrence and mortality.
  • It is usually well tolerated; hot flashes and vaginal discharge may occur.
  • Tamoxifen reduces the risk of hip radius and spine fractures.
  • It increases the risks of stroke, pulmonary embolism, deep vein thrombosis, and endometrial cancer, particularly in women aged 50 years or older.
• The combination of ovarian suppression with LHRH agonists (goserelin, triptorelin, and leuprolide) and an AI is recommended in premenopausal women.
• Guidelines recommend incorporation of AIs (anastrozole, letrozole, and exemestane) into adjuvant endocrine therapy for postmenopausal, hormone sensitive breast cancer.

Metastatic Breast Cancer (Stage IV)

• Treatment of MBC with cytotoxic, endocrine, or targeted therapy often results in regression of disease, improvements in quality of life, and improved OS with the addition of some biologic or targeted therapies.
• The choice of therapy for MBC is based on the extent of disease involvement and the presence or absence of certain tumor or patient characteristics.
• Bone modifying agents (pamidronate, zoledronic acid, or denosumab) should be considered to treat breast cancer patients with metastases to the bone to decrease rates of skeletal related events.

Biologic or Targeted Therapy (MBC)

• Cyclin-dependent kinases (CDK) inhibitors, abemaciclib, palbociclib, and ribociclib selectively inhibit CDK4 and 6, and are approved for MBC.
• The mammalian target of rapamycin (mTOR) inhibitor everolimus improved PFS when used in combination with either exemestane, fulvestrant, or tamoxifen.
• The phosphatidylinositol 3kinase (PI3k) inhibitor apelisib is approved in combination with fulvestrant for postmenopausal women and men, with hormone receptor–positive, HER2 negative, PIK3CA mutated, advanced, or metastatic breast cancer.
• The poly (ADPRIBOSE) polymerase (PARP) inhibitors olaparib and talazoparib improve PFS in appropriate patients.
• HER2 targeted agents available are trastuzumab, pertuzumab, adotrastuzumab emtansine, famtrastuzumab, deruxtecan, margetuximab, lapatinib, neratinib, and tucatinib.
• Firstline therapy with a pertuzumab-trastuzumab-taxane combination is the preferred option for HER2 over expressing MBC in patients who have not received pertuzumab in the neoadjuvant or adjuvant setting.
• Adotrastuzumab emtansine is the recommended second line HER2 targeted therapy after a patient progresses on or can no longer tolerate first line therapy.

Endocrine Therapy (MBC)

• Endocrine therapy in combination with a targeted agent should be considered as first line therapy for patients with hormone positive MBC, when feasible.
• The choice of endocrine therapy is based on the menopausal status of the patient, prior therapies and previous response, duration of response, or disease-free interval.
• No one endocrine therapy has clearly superior survival benefit.
  • The choice of agent is based primarily on mechanism of action, toxicity, and patient preference.
  • AIs, tamoxifen or toremifene, and fulvestrant are the preferred initial agents in MBC except when the patient’s cancer recurs during or within one year of adjuvant therapy.
• Fulvestrant, an intramuscular agent, is approved for second line therapy of postmenopausal patients with hormone receptor–positive tumors either alone or in combination with targeted therapy.
• Medical ovarian suppression with an LHRH analog (goserelin, leuprolide, or triptorelin) is a reversible alternative to oophorectomy in premenopausal women.

Chemotherapy (MBC)

• Chemotherapy is used as initial therapy for women with hormone receptor negative tumors, with triple negative tumors, and after failure of endocrine/targeted therapy regimens.
• In the absence of predictive biomarkers, chemotherapy is chosen based on overall efficacy, the risk of toxicity, performance status and presence of comorbidities in the patient, aggressiveness of disease, and patient preferences.
• Response rates are high with combination chemotherapy, but sequential use of single agents is an effective strategy and may be preferred due to decreased rates of adverse events.
• Treatment with sequential single agents is recommended over combination regimens unless the patient has rapidly progressive disease, life-threatening visceral disease, or the need for rapid symptom control.
• Anthracyclines and taxanes produce response rates as high as 50% when used as first line therapy for MBC.
  • Single agent capecitabine, vinorelbine, and gemcitabine have response rates of 20%–25% when used after an anthracycline and a taxane.

Immunotherapy

• Pembrolizumab (mAb against programmed cell death protein 1 [PD1]) is approved in combination with album inbound paclitaxel, paclitaxel, or the combination of carboplatin + gemcitabine.
• Atezolizumab (mAb against programmed death ligand [PDL1]) is approved in combination with albumin bound paclitaxel.

Radiation Therapy

• Commonly used to treat painful bone metastases or other localized sites of refractory disease, including brain, spinal cord, eye, or orbit lesions.
  • Pain relief is seen in approximately 90% of patients who receive RT for painful bone metastases.

Evaluation of Therapeutic Outcomes

• The goal of surgery, radiation, neoadjuvant/adjuvant therapy for early stage breast cancer is cure which cannot be fully evaluated for years after initial diagnosis and treatment.
• Patients are recommended to have a history and physical every 3–6 months for the first 3 years after completion of primary therapy, every 6 months for the following 2 years, and then yearly there after.
• Palliation is the therapeutic endpoint in the treatment of MBC.
  • Optimizing benefits and minimizing toxicity are general therapeutic goals; careful consideration of quality of life is important in this setting.
• Treatment end point response is measured by changes in laboratory tests, diagnostic imaging, or physical signs or symptoms.