Screening


Screening

  1. Scope of the Problem
    • There are ~ 230,000 new cases of breast cancer per year, with ~ 41,000 deaths
    • Breast cancer is the 2nd leading cause of cancer-related deaths in women
    • Women have a 1 in 8 lifetime risk of developing breast cancer
    • 5-year survival rates have steadily improved, from 63% in the 1960s to >90%, likely because of widely available mammographic screening and improvements in treatment

  2. Average Risk Women
    • Goal is to detect breast cancer that is not yet clinically evident
    • Benefits of early detection must be weighed against the cost of screening and the number of false-positive studies that require additional workup
    • Early detection reduces breast cancer mortality, but controversy exists over what ages to start and stop screening

  3. Screening Modalities
    1. Mammography
      • Primary imaging study for screening
      • 2 views are obtained: mediolateral oblique (MLO), and craniocaudal (CC)
      • Digital mammography allows the images to be manipulated for contrast and brightness, which is more accurate in younger women with mammographically dense breasts
      • BI-RADS categories classify mammographic findings by level of suspicion, and provide guidelines for patient management

      BIRADS Classififcation
    2. Clinical Breast Examination (CBE)
      • Important component of screening because 10% to 20% of breast cancers are not seen on screening mammogram but may be clinically palpable
      • Beginning at age 20, women should have a CBE every 2 to 3 years, and then annually after age 40

    3. Breast Self-Examination (BSE)
      • Limited value in detecting early cancer
      • Considered optional by ACS guidelines
      • Important to consider that most palpable lesions are detected by the patient

  4. High-Risk Patients
    1. Definition of High-Risk
      • Multiple risk stratification models exist: Gail, Claus, BRCAPRO

      1. Age and Gender
        • Two most important risk factors
        • Incidence of breast cancer increases with age
        • >99% of cases develop in women

      2. Personal History of Breast Cancer
        • History of breast cancer increases the chance of a second primary cancer in the contralateral breast
        • Magnitude of the risk depends on the age of diagnosis, estrogen receptor status, and use of adjuvant chemotherapy and hormonal therapy
        • In younger patients, the risk varies from 0.5% to 1% per year
        • in older patients, the risk is 0.2% per year

      3. Histologic Risk Factors
        • Diagnosed by breast biopsy
        • LCIS confers a risk ratio (RR) of 7:1, which is ~ 1% per year
        • Benign breast disease can be associated with increased risk: severe hyperplasia (RR = 1.3 to 1.9), atypical ductal or lobular hyperplasia (RR = 4)
        • ADH or ALH and a strong family history increases the relative risk to 9:1

      4. Family History
        • First-degree relatives of patients with breast cancer have a relative risk of 2:1 - 3:1
        • Risk is much higher if the affected first-degree relatives had premenopausal onset and bilateral breast cancers

      5. Genetic Risk Factors
        • BRCA1 and BRCA2 are tumor suppressor genes inherited in autosomal dominant fashion
        • Responsible for 5% - 10% of all breast cancers, but 25% of cases in women less than 30 years old
        • Confer a 50% to 80% lifelong risk of breast cancer, and a 20% to 45% lifelong risk of ovarian cancer
        • BRCA1 tumors are more likely to be high grade and estrogen receptor-negative
        • Mortality rates of BRCA1 and BRCA2-associated tumors are similar to sporadic tumors

      6. Reproductive Risk Factors
        • Related to increased lifetime exposure to estrogen
        • Menarche before 12, childbirth after 30, nulliparity, or menopause after 55 cause a relatively mild increased risk of breast cancer (RR up to 2)

      7. Hormone Use
        • Most common indications are OCP use and HRT
        • Slightly increased risk of breast cancer in OCP users
        • HRT with estrogen and progesterone is associated with a 20% increased risk of breast cancer; estrogen-only formulations do not appear to be associated with increased risk

    2. High-Risk Screening
      • Screening mammography should begin at age 30
      • Very high-risk women (BRCA patients or patients with a lifetime risk of > 20% - 25%) benefit from breast MRI screening, or screening ultrasound if MRI is not available

      1. MRI
        • Most breast cancers enhance after administration of contrast, making MRI very sensitive for detecting cancers
        • However, a very low specificity is a major drawback

      2. Tomosynthesis (3-D Mammography)
        • Main challenge in screening is the large number of false-positives in women with dense breasts, which may hide breast cancers
        • Multiple images of the breast are recorded at different angles and then reconstructed
        • Masses are more visible in these reconstructed slices than in conventional two-view mammography

    3. Chemoprevention for Breast Cancer
      1. Tamoxifen
        • Adjuvant tamoxifen reduces the risk of a second breast cancer in the unaffected breast by 47%
        • Substantially reduces the risk of estrogen-positive cancers developing in women with LCIS, ADH, or ALH
        • Tamoxifen taken for 5 years has its own significant risks: uterine cancer, pulmonary embolism, and deep vein thrombosis

      2. Raloxifene
        • Selective ER modulator
        • 54% reduction in incidence of breast cancer at 3 years of follow up in STAR trial
        • Significantly less uterine cancers, pulmonary embolisms, and DVTs than tamoxifen

    4. Prophylactic Mastectomy
      • Reduces breast cancer risk by 90%
      • Most applicable to BRCA mutation carriers, who should also consider risk-reducing salpingo-oophorectomy
      • Statistical analysis shows that BRCA mutation carriers have about a 10% chance of dying of breast cancer if they do not undergo risk-reducing surgery
      • In women newly diagnosed with breast cancer, the role of contralateral prophylactic mastectomy is controversial

  5. Biopsy Techniques
    1. Fine-Needle Aspiration (FNA)
      • Useful office technique for aspirating cysts, or determining whether a mass is solid or cystic
      • For solid masses, cytologic examination can determine benign versus malignant, but cannot distinguish between invasive cancer or DCIS

    2. Core Needle Biopsy
      • Method of choice for potentially malignant lesions
      • Performed under mammographic (stereotactic), ultrasound, or MRI guidance
      • Multiple cores should be obtained
      • Specimen radiography is done to ensure that the targeted lesion has been sampled
      • Clip is placed to mark the site in case wire-localized surgical excision is required
      • Besides histology, specimen should be sent for estrogen and progesterone receptors, and Her-2-neu

    3. Wire-Localized Excisional biopsy
      • Used when percutaneous core needle biopsy is technically risky because the lesion is too posterior, too close to the nipple, or too close to an implant
      • Also necessary when there is discordance between the imaging abnormality and the pathologic findings

Atypical Hyperplasia

  1. Atypical Ductal Hyperplasia (ADH)
    • Microscopically resembles low-grade DCIS, but is of limited extent (<2 mm)

    1. Diagnosis
      • Usually made after a core needle biopsy of suspicious mammographic microcalcifications

    2. Management
      1. After Core Needle Biopsy
        • Follow up excisional biopsy is required to exclude an associated malignancy
        • 10% - 20% of cases are upgraded to DCIS or invasive cancer after surgical biopsy

      2. After Surgical Biopsy
        • If ADH is present at the margin, re-excision is not required
        • Re-excision is required if there is DCIS at the margin or if the lesion was not completely excised

  2. Atypical Lobular Hyperplasia (ALH)
    1. Diagnosis
      • Incidental finding on breast biopsies
      • Microscopically resembles LCIS, but is lesser in extent

    2. Management
      1. After Core Needle Biopsy
        • Risk of upgrade to DCIS or invasive cancer is < 3%
        • Surgical re-excision is not required

      2. After Surgical Biopsy
        • No additional surgery is required, even if there is ALH at the margins

  3. Future Breast Cancer Risk and Prevention
    • Relative risk of developing a future breast cancer is ~ 4 for both ADH and ALH
    • Cancer risk affects both breasts almost equally
    • Patients with ADH or ALH require active surveillance and should be offered chemoprevention

Carcinoma in Situ

  1. Ductal Carcinoma in Situ (DCIS)
    1. Pathology
      • Defined as proliferation of cancer cells within the ducts without invasion of the basement membrane
      • Broadly classified into comedo and noncomedo subtypes
      • Comedo subtype is characterized by large pleomorphic nuclei, numerous mitoses, and necrotic cellular debris in the center of the ducts
      • Noncomedo subtype is characterized by monomorphic nuclei, few mitoses, and the absence of necrosis
      • Nuclear grade is classified as low, intermediate, or high grade
      • High grade DCIS exhibits more aggressive biologic behavior and has a greater frequency of occult microinvasion and local recurrence
      • DCIS in most cases is unicentric, although it may be extensive
      • Overall survival is > 98% at 10 years

    2. Diagnosis
      • Incidence rates have increased at least six-fold from the 1970s, likely due to widespread screening mammography
      • Typically presents as clustered pleomorphic microcalcifications on mammogram
      • In rare cases, it may present as a palpable mass or a mass seen on mammogram
      • Diagnosis is usually made by stereotactic core biopsy
      • May be difficult to distinguish atypical ductal hyperplasia from DCIS
      • If a diagnosis of atypical ductal hyperplasia is made after a stereotactic biopsy, then an excisional biopsy should be done to rule out coexisting DCIS or invasive cancer
      • Entire specimen must be thoroughly examined in order not to miss small areas of microinvasion

      DCIS Microcalcifications
      DCIS clustered pleomorphic microcalcifications

    3. Progression to Invasive Cancer
      • Untreated, some cases of DCIS will progress to invasive cancer (30% after 6 - 10 years)
      • Comedo subtype may be more likely to progress

    4. Treatment
      • Goals are to prevent progression to invasive cancer and to minimize local recurrence

      1. Excision Alone
        • Associated with the highest local recurrence rates
        • 50% of recurrences are invasive cancer
        • Recurrence rates are dependent upon grade and the presence of comedo necrosis, with low-grade, noncomedo carcinomas having a lower rate of recurrence
        • If wide negative margins can be obtained (> 10 mm), then excision alone may be adequate treatment for small (< 15 mm), low-grade, noncomedo DCIS

      2. Excision and Radiation
        • Considered the standard treatment
        • Lowest local recurrence rates are obtained with at least a 2 - 3 mm margin
        • Most local recurrences will require salvage mastectomy, but the survival rate is high

      3. Mastectomy
        • mastectomy should be strongly considered if the following conditions exist:
          • Large mass (> 4 cm)
          • Inability to obtain negative margins after excision or reexcision
          • Multicentric disease
          • Centrally located disease
          • Adjuvant radiation is contraindicated
        • Patients should be counseled about immediate breast reconstruction
        • Recurrence after mastectomy will require local excision, and chest wall radiation if possible

      4. Sentinel Lymph Node Biopsy
        • All patients undergoing a mastectomy for DCIS should also have a SLN biopsy, since this procedure will not be possible after a mastectomy
        • For patients undergoing breast-conserving surgery, SLN biopsy can be considered when the risk of finding invasive disease is high:
          • Large lesions
          • High-grade disease
          • Microinvasive disease
          • Suspicious axillary nodes on ultrasound or physical exam

      5. Radiation Therapy
        • Decreases local recurrence rates
        • No survival advantage
        • Should be offered to all patients undergoing breast conservation therapy

      6. Hormonal Therapy
        • Adjuvant tamoxifen or anastrozole reduces ipsilateral breast cancer recurrences in women with ER-positive DCIS treated with BCS
        • Hormonal therapy also reduces the risk of new cancers in both the ipsilateral and contralateral breast
        • Women who have had bilateral mastectomies for DCIS do not benefit from hormonal therapy

  2. Lobular Carcinoma in Situ (LCIS)
    1. Biologic Significance
      • Historically, LCIS has been viewed as a risk factor for developing invasive cancer, rather than as a precursor lesion like DCIS
      • Also, the risk was considered equal for both breasts, and subsequent malignancies were more likely to be ductal than lobular
      • New epidemiologic data suggests that LCIS may serve as a precursor lesion to lobular carcinoma as well as a risk indicator for invasive ductal cancer

    2. Diagnosis
      • No distinctive clinical or mammographic findings
      • Usually is an incidental finding in a breast biopsy done for other reasons (found in ~ 3% of all breast biopsy specimens)
      • More frequent in premenopausal women

    3. Classification
      • 2 variants: classic LCIS and pleomorphic LCIS
      • Pleomorphic LCIS may be difficult to distinguish from DCIS or pleomorphic lobular carcinoma

    4. Treatment
      • Excisional biopsy is often recommended after a core biopsy result of LCIS, although the cancer upgrade rate is <3%
      • For classic LCIS diagnosed by excisional biopsy, re-excision to negative margins is not required
      • For pleomorphic LCIS, management is the same as for DCIS (re-excision to negative margins)
      • LCIS in association with an invasive cancer is not a contraindication to breast conservation

      1. Careful Observation
        • Most commonly chosen treatment
        • Lifelong surveillance is required since the invasive cancer risk is 1% per year
        • Not risk free, since some patients (7%) will die from an invasive cancer
        • No role for breast irradiation
        • No role for a contralateral biopsy
        • Tamoxifen in premenopausal women, or tamoxifen or raloxifene in postmenopausal women, should be considered for risk-reduction
        • Patients will need an annual mammogram, and should have a clinical breast exam every 6 - 12 months
        • Insufficient data to support annual MRI screening

      2. Bilateral Mastectomy
        • Chosen for women with a genetic predisposition for breast cancer, strong family history, or for any women who is uncomfortable with the risk of observation
        • No role for ipsilateral mastectomy
        • No role for bilateral subcutaneous mastectomy
        • Immediate reconstruction is appropriate







References

  1. Sabiston, 20th ed., pgs 837 - 854
  2. Cameron, 13th ed., pgs 697 - 702
  3. UpToDate. Atypia and Lobular Carcinoma in Situ: High-Risk Lesions of the Breast. Sabel MD, Michael. Nov 29, 2017. Pgs 1 - 22
  4. UpToDate. Breast Ductal Carcinoma in Situ: Epidemiology, Clinical Manifestations, and Diagnosis. Collins MD, Laura. July 02, 2019. Pgs 1 - 13
  5. UpToDate. Ductal Carcinoma in Situ: Treatment and Prognosis. Collins MD, Laura. April 12, 2019. Pgs 1 - 32