Breast Cancer: Overview, Risk Factors, and Prevention

Breast Cancer Overview

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

Epidemiology & Risk Factors

• Gender and age are the variables most strongly associated to breast cancer occurrence.
• Endocrine factors like early menarche, nulliparity, late first birth, and hormone replacement therapy.
• Genetic factors like personal and family history, mutations of tumor suppressor genes BRCA1 and BRCA2.
• Environmental and lifestyle factors like radiation exposure, tobacco and alcohol use can increase risk.
• Breast cancer cells often spread undetected, leading to metastasis, commonly to lymph nodes, skin, bone, liver, lungs, and brain.

Prevention

• Risk reduction can be achieved through prophylactic mastectomy, oophorectomy, and pharmacologic agents.
• Selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) are available for pharmacologic risk reduction.
• 5-year use of SERMs like tamoxifen and raloxifene reduces 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.
• AIs like exemestane and anastrozole demonstrated a similar reduction in 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 the initial sign of breast cancer in most women.
• The typical malignant mass is solitary, unilateral, solid, hard, irregular, and nonmobile.
• Nipple changes are less common.
• Advanced cases present with skin edema, redness, warmth, and induration.
• MBC symptoms depend on metastases site, like bone pain, breathing difficulty, abdominal issues, 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 breast examination, three-dimensional mammography, and other breast imaging like ultrasound and MRI.
• Breast biopsy is indicated for mammographic abnormality suggesting malignancy or for a palpable mass on physical examination.

Staging

• Stage or anatomical extent of disease, is based on primary tumor extent and size (T1–4), 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 is carcinoma in situ, Stage I is a small invasive tumor without lymph node involvement, and Stage II involves regional lymph nodes.
• Stage III is usually a large tumor with extensive nodal involvement, while Stage IV involves metastases in distant organs.
• Clinical stage is assigned before surgery and is based on physical examination and imaging with pathologic examination of tissues.
• Pathologic staging occurs after surgery and adds data from surgical exploration and resection.

Pathological Evaluation

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

Prognostic Factors

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

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 before surgery and/or to allow for breast conserving surgery if desired.
• Palliation is the desired therapeutic outcome in MBC treatment.
• Treatment can cause substantial toxicity, which differs depending on the individual agent, administration method, and combination regimen.

Curative Breast Cancer (Stage I-III)

• Surgery alone can cure most patients with in situ cancers, 70%–80% of stage I cancers, and about half of 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 removing 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 with reddening and erythema of the breast tissue with subsequent shrinkage of total breast mass are less common complications associated with short-term RT.
• Multiple cancer sites 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.
• Chemotherapy, endocrine therapy, targeted therapy, or a combination of these, these agents improves disease free and/or overall survival (OS) for high-risk patients in specific prognostic subgroups.

Systemic Therapy

• Systemic adjuvant therapy is the administration of systemic therapy after 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.
• Neoadjuvant (preoperative) systemic therapy is standard for patients with locally advanced breast cancer.
• Common cytotoxic drugs used alone and in combination as adjuvant therapy include doxorubicin, epirubicin, cyclophosphamide, methotrexate, fluorouracil, carboplatin, paclitaxel, and docetaxel.
• 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 adjuvant treatment duration 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, achieved by increasing dose, decreasing time between doses, or both.
• Dose density is one way of achieving dose intensity by decreasing time between treatment cycles and 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 in combination with or sequentially after adjuvant chemotherapy in patients with early stage, HER2 positive breast cancer. The risk of recurrence was reduced 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%, can be lowered when given sequentially after chemotherapy and with non-anthracycline based regimens.
• 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 with menopausal status determining the agent of choice.
• Tamoxifen is generally considered the adjuvant endocrine therapy of choice for premenopausal women.
• Tamoxifen reduces recurrence and mortality when beginning soon after completing chemotherapy and continuing for 5–10 years.
• Tamoxifen reduces the risk of hip radius and spine fractures and 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 (eg, 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 disease regression, quality of life improvements, 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 (eg, pamidronate, zoledronic acid, or denosumab) should be added to treat breast cancer patients with bone metastases to decrease rates of skeletal related events.

Biologic or Targeted Therapy

• Cyclin-dependent kinases (CDK) form complexes that control cell cycling; 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 with exemestane, fulvestrant, or tamoxifen.
• The phosphatidylinositol 3kinase (PI3k) inhibitor apelisib is approved with fulvestrant for postmenopausal women and men, with hormone receptor–positive, HER2 negative, PIK3CA mutated, advanced, or metastatic breast cancer following progression on or after an endocrine based regimen.
• The poly (ADPRIBOSE) polymerase (PARP) inhibitors olaparib and talazoparib improve PFS in appropriate patients.
• HER2 targeted agents available in the United States are trastuzumab, pertuzumab, adotrastuzumab emtansine, famtrastuzumab deruxtecan, margetuximab, lapatinib, neratinib, and tucatinib.
• First-line 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 HER2targeted therapy after a patient progresses on or can no longer tolerate first line therapy.

Endocrine Therapy

• Endocrine therapy with a targeted agent should be considered as first line therapy for patients with hormone positive MBC, when feasible with choice of endocrine therapy is based on the menopausal status of the patient, prior therapies and previous response, duration of response, or diseasefree 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

• Chemotherapy is used as initial therapy for women with hormone receptor negative tumors, 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 (eg, indolent vs visceral crisis), and patient preferences related to chemotherapy schedules, dosing route (eg, oral vs intravenous), and frequency (eg, weekly vs every 3 weeks).
• Combination chemotherapy has high response rates, but sequential use of single agents is an effective strategy and may be preferred due to decreased rates of adverse events.
• 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 albumin bound 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

• Radiation therapy is 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 thereafter. Metastatic Breast Cancer
• Palliation is the therapeutic endpoint in the treatment of MBC.
• Treatment end point response is measured by changes in laboratory tests, diagnostic imaging, or physical signs or symptoms