Locally Advanced Breast Cancer


Locally Advanced Breast Cancer

  1. Definition
    • T3 lesions (> 5cm)
    • T4 lesions – tumors involving the skin, chest wall, or inflammatory breast cancer
    • N2 or N3 disease - bulky or fixed axillary adenopathy

  2. T3 Disease
    1. Neoadjuvant Chemotherapy
      • in general, T3 tumors are too large for a cosmetically acceptable lumpectomy
      • preoperative chemotherapy can result in a significant reduction in tumor size for 50% - 80% of patients, often allowing them to avoid a mastectomy
      • HER2-positive patients should also receive a HER2-targeted drug
      • multiple studies demonstrate increased rates of breast conservation with the use of neoadjuvant therapy
      • there is no survival advantage or detriment to neoadjuvant therapy, but clinical response does correlate with survival
      • since 10% - 15% of patients will have a complete response by clinical exam and imaging, a metallic clip should be placed at the primary tumor site before beginning treatment

    2. Surgical Treatment
      • clinical exam is usually sufficient to judge tumor response
      • whether a patient is a candidate for breast conservation is dependent on the extent of tumor involvement after completing neoadjuvant treatment
      • patients who have a complete clinical response still require surgery
      • patients whose disease progresses while getting neoadjuvant treatment should have surgery, rather than switching to another chemotherapy regimen

    3. Management of the Axilla
      • depends on whether the axilla was positive prior to treatment, and whether the patient had a SLN biopsy prior to treatment
      • whether to perform the SLN biopsy before neoadjuvant treatment or after completion is unknown
      • pretreatment SLN biopsy allows for accurate pretreatment staging
      • posttreatment SLN biopsy provides nodal status information after treatment, which is the strongest predictor of outcome
      • there is a higher failure rate of lymphatic mapping after neoadjuvant treatment

      1. Clinically Negative Axilla Pretreatment
        1. No Pretreatment SLN Biopsy
          • patient should have a posttreatment SLN biopsy

        2. Negative Pretreatment SLN Biopsy
          • no further treatment of the axilla is required

        3. Positive Pretreatment SLN Biopsy
          • patients will require axillary radiation or a completion axillary node dissection
          • if a patient has one or two positive SLNs and will undergo breast conservation treatment, then axillary radiation is reasonable
          • if a patient will require mastectomy and has no indication for postmastectomy radiation, then completion axillary node dissection is indicated

      2. Clinically Positive Axilla Pretreatment
        • patients with grossly positive nodes (N2, N3) should undergo ALND at the time of definitive breast surgery
        • management of biopsy-proven N1 disease will depend on the response to neoadjuvant treatment
        • f the node remains clinically positive then an ALND should be done at the time of definitive breast surgery
        • if the node becomes clinically negative, then a posttreatment SLN biopsy can be done

      3. Posttreatment SLN Biopsy
        • if negative, then axillary radiation is sufficient
        • if one or two positive SLNs, then axillary radiation is sufficient
        • for three or more positive SLNs, then ALND is required

  3. T4 Disease
    • includes tumors involving the chest wall, skin, ulceration, satellite skin nodules, bulky or fixed axillary nodes, internal mammary or supraclavicular nodal involvement, inflammatory breast cancer
      • T4 Breast Cancer with Skin Involvement
    • surgery alone provides poor local control
    • current management includes surgery, radiation, and systemic chemotherapy, with the sequence determined by the patient’s circumstances

    1. Inflammatory Breast Cancer (IBC)
      • most aggressive subtype of breast cancer
      • long-term survival rates are < 50%
      • accounts for 0.5% - 2% of breast cancer cases
      • results from diffuse tumor involvement of the dermal lymphatics

      1. Clinical Presentation
        • has a rapid onset, with progression over several weeks to months
        • presents with erythema, warmth, and swelling of at least one third of the breast
        • may be confused with mastitis
        • skin may have the classic peau d’orange appearance: edema and dimpling at sites of hair follicles
        • there may or may not be a discrete mass on exam
        • nipple changes such as retraction may be present
        • palpable or matted axillary nodes are usually present

        Inflammatory Breast Cancer
      2. Diagnosis
        • mammographic findings may include an obvious tumor mass, a large area of calcifications, skin thickening
        • pathologic hallmark is a full-thickness skin biopsy that demonstrates cancer invading the dermal lymphatics
        • however, IBC is a clinical diagnosis and can be made without pathologic confirmation of dermal lymphatic invasion
        • if a lesion is identified in the breast, or if there are suspicious axillary nodes, then an image-guided core biopsy should be done to confirm the diagnosis and to provide tissue for ER, PR, and HER2 receptors

        1. Diagnostic Criteria
          • all of the following must be met to make a diagnosis of IBC:
          • rapid onset of breast erythema, edema and/or peu d’orange, and/or warm breast, with or without an underlying palpable mass
          • duration < 6 months
          • erythema of > one-third of the breast
          • pathologic diagnosis of breast cancer

      3. Staging Work Up
        • at diagnosis, ~33% of patients will already have distant metastases
        • CT of the chest, abdomen, pelvis
        • bone scan
        • breast MRI and PET scan are not routinely obtained

      4. Treatment
        1. Neoadjuvant Chemotherapy
          • systemic chemotherapy is the cornerstone of treatment
          • Trastuzumab is added for HER2-positive tumors
          • clinical response to neoadjuvant chemotherapy can be a good indicator of prognosis

        2. Surgery
          • modified radical mastectomy is the procedure of choice in patients who have had a good response to chemotherapy
          • no role for breast conservation or skin-sparing mastectomies
          • SLN biopsy is unreliable in patients with IBC
          • reconstruction should be delayed until all treatments are finished
          • palliative mastectomy may have a role in some patients who do not respond to chemotherapy

        3. Radiation
          • used in a neoadjuvant role for patients who do not respond to chemotherapy
          • following MRM, patients receive radiation to the chest wall, axilla, supraclavicular nodes, and possibly the internal mammary nodes
          • purpose is improved locoregional control – there is probably no effect on overall survival

        4. Hormonal Therapy
          • most cases of IBC are ER- and PR-receptor negative
          • tamoxifen or an aromatase inhibitor is valuable in the small subset of patients who are receptor-positive

Unusual Breast Tumors

  1. Paget’s Disease
    • accounts for ~ 1% of breast cancer cases
    • ~90% of patients have an underlying invasive or in situ breast cancer
    • the invasive cancers tend to present at a more advanced stage and are often ER-negative; their 5-year survival is ~ 40%

    1. Presentation
      • characterized by nipple irritation and erythema
      • may progress to crusting and ulceration
      • may spread out onto the skin of the areola and breast
      • differential includes dermatitis, eczema, postradiation dermatitis
      • 50% of patients have a palpable breast mass
      • 20% of patients have a mammographic abnormality without a palpable mass
      • 25% of patients have an occult DCIS without a mass or mammographic abnormality
      • diagnosis is made by a full thickness biopsy of the nipple
      • any underlying mass or mammographic abnormality should be biopsied as well

      Paget Disease
    2. Pathology
      • Paget cells (intraepithelial adenocarcinoma cells) do not originate in the skin of the nipple
      • they spread into the lactiferous sinuses under the nipple and upward to invade the epidermis of the nipple
      • Paget cells do not invade the dermal basement membrane and are characterized as carcinoma in situ
      • Paget cells can resemble melanoma, and occasionally immunohistochemistry may be required to make the diagnosis

    3. Staging
      • Paget’s disease does not change the stage of the underlying breast cancer
      • if an invasive cancer or in situ cancer is not identified, then the stage is Tis (Paget)

    4. Treatment
      1. Management of the Breast with a Palpable Mass or Abnormal Mammogram
        • the nipple-areolar complex and the underlying breast cancer must both be excised
        • for the majority of patients, this will require a simple mastectomy with or without immediate reconstruction
        • in a few patients, breast conservation/XRT can be performed with an acceptable cosmetic result and negative margins

      2. Management of the Breast when there is no Palpable Mass or Abnormal Mammogram
        • most patients will have an occult DCIS or invasive cancer, making a simple mastectomy the standard treatment option
        • breast conservation with resection of the nipple-areolar complex and XRT is another acceptable option

      3. Management of the Axilla
        • indications for SLN biopsy or ALND are the same as for any breast cancer
        • for DCIS requiring mastectomy, a SLN biopsy should be done in case an invasive cancer is identified on final pathology
        • invasive cancers with a clinically-negative axilla require a SLN biopsy
        • invasive cancers with a clinically-positive axilla require a confirmatory biopsy, and then an ALND

      4. Adjuvant Therapy
        • systemic therapy will be guided by the standard indicators: tumor size, nodal status, receptor status

  2. Male Breast Cancer
    • accounts for 0.8% of breast cancer cases (2100 cases/year)
    • when matched for stage, survival is the same as for women

    1. Risk Factors
      • radiation exposure
      • estrogen and androgen imbalance: testicular disease, obesity, cirrhosis
      • genetic risk factors include Klinefelter’s syndrome (47, XXY), BRCA2 mutations, family history

    2. Presentation
      • most present with a breast mass
      • major differential diagnosis is gynecomastia
      • may also have axillary adenopathy or nipple retraction

    3. Diagnosis
      • mammogram
      • core needle biopsy

    4. Treatment
      • depends on stage and local extent of the tumor
      • breast conservation/radiation is possible if desired
      • SLN biopsy is an effective staging procedure in men
      • majority of patients are treated with mastectomy/SLN or modified radical mastectomy
      • adjuvant hormonal therapy with tamoxifen or aromatase inhibitors is indicated for ER-positive disease
      • systemic chemotherapy is used for patients at high risk of systemic disease

  3. Phyllodes Tumors
    • account for < 1% of all breast neoplasms
    • capable of a wide range of biologic behaviors, from benign to widely metastatic
    • classified as benign, borderline, or malignant

    1. Presentation
      • most present as a smooth, well-defined multinodular mass that is mobile, painless, and fast-growing
      • average tumor size is 4 – 7 cm
      • 20% present as a nonpalpable mass identified on screening mammogram
      • median age at presentation is 42 – 45 years

      Benign Phyllodes Tumor
    2. Diagnosis
      • core biopsy is preferred over FNA, and is usually diagnostic
      • features that distinguish phyllodes tumors from fibroadenomas include increased cellularity, mitosis, stromal overgrowth, and fragmentation
      • if core biopsy is indeterminate, than an excisional biopsy will be necessary

    3. Treatment
      1. Surgery
        • goal is a wide excision with 1 cm margins, especially for borderline or malignant tumors
        • breast conservation is a reasonable option if adequate margins and an acceptable cosmetic outcome can be obtained
        • sentinel node biopsy is not necessary since lymph node involvement is very rare

      2. Radiation
        • not indicated for benign tumors that have been widely excised
        • recommended for borderline or malignant lesions following excision to reduce local recurrence rates

      3. Adjuvant Chemotherapy
        • no role in benign and borderline tumors
        • controversial whether it benefits patients with high-risk (>10 cm) malignant tumors
        • hormonal therapy is not effective against phyllodes tumors







References

  1. Sabiston, 19th ed., pgs 863 – 867
  2. Cameron, 11th ed., pgs 595 – 599, 599 – 601, 618 – 621
  3. UpToDate. Overview of the Treatment of Newly Diagnosed, Non-metastatic Breast Cancer. Taghian MD, Alphonse. Aug 21, 2019. Pgs 1 - 30
  4. UpToDate. General Principles of Neoadjuvant Therapy for Breast Cancer. Sikov MD, William. May 16, 2019. Pgs 1 – 39
  5. UpToDate. Inflammatory Breast Cancer: Clinical Features and Treatment. Taghian MD, Alphonse. Sep 26, 2018. Pgs 1 – 23
  6. UpToDate. Paget Disease of the Breast. Sabel MD, Michael. Apr 03, 2018. Pgs 1 – 29
  7. UpToDate. Phyllodes Tumors of the Breast. Grau MD, Ana. May 09, 2019. Pgs 1 – 23