Breast Cancer

Resident Conference March 26, 2008

Breast Cancer: Cellular, Biochemical and Molecular Markers

Increased insight into molecular and genetic mechanisms involved in breast carcinogenesis Pathways amenable to intervention classified into
Hormonal Nonhormonal Genetic Markers

Overlapping and complex interaction between molecular and genetic factors.

Traditional Markers of Proliferation

Proliferative activity proven prognostic significance in breast cancer evaluating the number of mitoses Bloom-Richardson score (BRS) common histologic grading system used
Histologic grade prognostic in primary operative invasive breast ca and predictor of overall survival for lymph node-negative and positive patients.
High grade tend to be larger, more mononuclear cellular reaction and necrosis, ER-, younger patients.

Traditional Markers of Proliferation

BRS and other grading scales subject to interobserver variability. Need for more objective measures. Ki67 objective measure of proliferative activity
Immunohistochemical stain representing objective substitute for mitotic counts Correlates significantly with BRS High Ki67 percentages have a worse overall and diseasefree survival in all groups except for untreated lymph node negative group.

Hormonal Targets
Estrogen receptor (ER) and Progesterone receptor (PR) well characterized hormonal targets
Estrogen effect mediated by ER subtypes and 70 to 80% of all invasive breast cancers and nearly all intraductal express ER (ER +)
Reflects generally better differentiated tumor with improved prognosis and predictive of response to endocrine therapy

Vitamin D receptor expression higher in invasive breast cancers than in normal breast tissue
Vit D plays significant role in cell growth and differentiation

Nonhormonal Targets
Her2/neu protein is a member of the tyrosine kinase receptor family
Involved in signal transduction, cell proliferation and differentiation. Amplified in as many as 1/3 of breast ca patients Overexpression associated with shortened diseasefree and overall survival. Most accurate technique available for identifying overexpression is fluorescence in situ hybridization (FISH).

Cell Cycle and Apoptosis

p53 tumor suppressor gene activated with DNA damage and hypoxia.
Negative correlation between p53+ and age, ER status, PR status Positive correlation with tumor grade

Clinical presence of p53 dysfunction or loss correlates with more aggressive tumors, early metastases, and decreased survival. Some studies suggest improved response to chemotherapy if p53 overexpression not seen. Patients who overexpress Her2/neu and p53 have even poorer prognosis.

Breast Cancer Surgical Therapy

Review of Noninvasive Disease

Noninvasive Disease
Incidence of positive lymph nodes in DCIS is 1-3%
Sentinel lymph node appropriate for:
Evidence of extensive disease/multifocal High grade with or without comedo type Evidence or suggestion of invasion Treatment with mastectomy

Adjuvant Therapy in DCIS

NSABP-B24 study suggests that tamoxifen after lumpectomy and radiation will further reduce rates of ipsilateral local recurrence and first-time events bilaterally
Recommendation for use generally based on estrogen receptor status

Invasive Breast Cancer

Most early stage invasive breast cancer should be treated with breast conservation, lumpectomy and radiation.
Local recurrence rates too high to warrant the absence of radiation therapy

Relative contraindications to breast conservation

Large breast cancers relative to small breast size Inability to receive radiation therapy Multicentric disease

Equivalent survival data comparing breast conservation and mastectomy.

Invasive Breast Cancer

Reconstruction following Mastectomy

Type of cancer should have little impact on the decision of plastic surgeon
Exception locally advanced cancer requiring postmastectomy radiation Reconstruction should be delayed until treatment completed

Multiple options:
Implants and tissue expanders Autologous tissue transfers
TRAM, free TRAM, Lat Flap, deep inferior epigastric perforator (DIEP)

Surgical Technique
Basic principles of lumpectomy
Curvilinear incision reflecting the circular skin tension lines Incisions placed directly over or as close to cancer as possible Excising tumor and obtaining adequate margins while preserving cosmetic integrity
Maintenance of orientation of original sample Additional samples from six margins (A/P/S/I/M/L)

Meticulous hemostasis No need to reapproximate breast tissue

Surgical Technique
Basic principles of Mastectomy
Skin sparing should be considered when possible Complete circumareolar incision with or without lateral extension. Care should be taken to preserve skin flaps Skin, subcutaneous tissue, and fascia exist superficial to glandular tissue Dissection includes superficial to the fascia anteriorly to pectoralis fascia posteriorly, medial to lateral edge of sternum, laterally to latissimus, superiorly to inferior edge of clavicle, inferiorly to superior edge of rectus.

Axillary Dissection
Should be performed for a positive sentinel lymph node or clinically suspicious axilla. Level 1 dissection justified in most cases Diminishing return of lymph nodes Increased morbidity when moving into level 2 & 3. Boundaries: anterior clavipec fascia; posterior subscapularis muscle; inferior- upper outer breast tissue; superior-below axillary vein; medially-lateral edge of pec major; laterally-anterior border of latissiumus muscle. Preserve long thoracic and thoracodorsal nerves Avoid skeletonizing axillary vein Increases risk of lymphedema

Management of Axilla in Invasive Breast Ca

Lymphatic Mapping and Lymphadenectomy

Lymphatic Mapping and Lymphadenectomy

Staging of the axilla provides the best prognostic information for patients with invasive breast cancer. Technique of lymph node preservation in an attempt to spare patient lymphedema and nerve damage. The principle is that the breast cancer will drain to a first node before draining to higher nodes.

Indications
Clinically recognized T1 or T2 lesion with clinically negative nodes T3 or locally advanced tumors or multicentric cancers may be amenable
Few data exist

Not offered to patients with multiple tumors or multicentric disease Inappropriate in patients with obvious metastatic disease. Lower concordance in patients with larger upper outer quadrant excisions or previous axillary surgery, preoperative radiation, or chemotherapy.

Technique of Localization
Available materials include blue dye (1% isosulfan blue, methylene blue and vital blue dye) and technetium 99m sulfur colloid tracer
Can be used alone or in combination

Tracer injected prior to OR Blue dye injected intraoperatively Following incision, localization with gamma probe and visual identification
Sentinel lymph node may be hot (radioactive), blue, or both

Adjuvant Systemic Therapy

Adjuvant Systemic Therapy

Systemic therapy recommended for all patients except those with most favorable tumor stages (node negative, primary tumor size less than 10 mm) Guidelines for exact type of systemic therapy are based on patient age, menopausal status, histologic status of axillary lymph nodes, size and histologic subtype of primary tumor, and level of estrogen receptor expressed by tumor.

Chemotherapy Agents
Anthracyclines
e.g. doxorubicin and epirubicin

Considered antitumor antibiotics Earlier experience demonstrated cardiotoxicity

Limiting maximal cumulative dose and using prolonged infusion schedule have reduced cardiac dysfunction to less than 1%

Superior long-term clinical trial outcomes for anthracyclinecontaining drug regimens when compared to combination of alkylating agent (cyclophosphamide) and two antimetabolites (methotrexate and 5-FU). Preferred chemotherapy regimen for at least four cycles.

Chemotherapy Agents
Taxanes
e.g. paclitaxel and docetaxel

Stabilize microtubule polymerization, blocking cells in the G2/M phase of cell cycle Does not result in cross-resistance with other agents. Effective in crossover protocols in patients who develop resistance to anthracyclines. Both taxanes have been shown to increase response rates, duration of response, and overall survival in patients with metastatic disease.

Chemotherapy Agents
Combination of taxane with anthracyclines produced overall response rates (complete and partial) of 46% to 94% in patients with advanced breast cancer. Early data suggests that addition of paclitaxel or docetaxel to standard regimens for early stage cancer is likely to reduce the risk of recurrence and may favorably change the natural history of disease.

Scheduling of Chemotherapy
Strives to balance the need for frequent treatments that allow minimal time for tumor regrowth with the need for patient recovery from the cytotoxic effects of the drug. Most protocols allow for 21 to 28 days recovery between treatments. Increasing the dose density of chemotherapy may improve outcomes while shortening the course of the treatment Dose intense chemotherapy did not result in improved outcomes compared with standard therapy

Hormonal Therapy
For patients with hormone receptor-positive tumors, anti-estrogen hormonal therapy is an important component of the treatment plan. Aim to modulate the ability of the estrogen receptor to bind estrogen (tamoxifen) or at decreasing the production of estrogen (ovarian ablation or aromatase inhibitors). Unlike multidrug combination chemo, combination of anti-estrogens do not appear to offer superior results when compared to single agents.

Hormonal Therapies

Hormonal Therapy
Tamoxifen
When used for 5 years, it is associated with a significant reduction in the risk of recurrence and risk of death in patients with hormone receptor-positive tumors, regardless of menopausal status.
Benefits appear restricted to patients with hormone receptor positive tumors

Sequential administration with chemo resulted in increased disease-free survival when compared to concurrent administration. Only agent recognized as effective for prevention of contralateral breast cancer and primary cancer in women at high risk.

Hormonal Therapy
Aromatase Inhibitors Inhibit synthesis of estrogen from androgens in postmenopausal women. Early findings suggest that anastrozole may increase diseasefree survival in hormone receptor positive patients compared with tamoxifen May also significantly reduce the risk of invasive contralateral breast cancer compared with tamoxifen. Lower incidence of endometrial cancer, vaginal bleeding and discharge, cerebrovascular events, VTE, and hot flashes compared to tamoxifen
However, significantly higher incidence of musculoskeletal disorders and bone fractures.

Hormonal Therapy
Ovarian Ablation Effective treatment option for some breast cancers in premenopausal women
Either irreversible (surgery or radiation) or reversible (medical castration with LH releasing hormone analogs

Comparison of ovarian ablation vs CMF as adjuvant therapy in premenopausal patients with lymph node positive breast cancer yielded comparable 6 year outcomes but with a much lower occurrence of toxic side effects such as nausea, alopecia and infection

Inflammatory Breast Cancer

Inflammatory Breast Cancer

Accounts for 1-6% of all cases of breast cancer Most aggressive and lethal form of primary breast cancer
Frequently presents with metastases.

Although the incidence has doubled, the 3 year survival improved from 32% to 42%

Clinical Presentation
Clinicopathologic entity that typically presents with erythematous, indurated, enlarged breast that is characterized by edema or peau dorange. Breast is typically warm, and erythema involves most of the skin of the breast. Palpable mass associated with the induration and erythema may be present. Must be distinguished from mastitis, which typically presents with a lighter erythema, less brawny induration, and a less erysipeloid border

Clinical Characteristics
Clinical Characteristics of Inflammatory Breast Cancer Erythematous, indurated, edematous breast Often no underlying mass Younger women Fairly quick onset (<3 mo) Failed 2-week trial of antibiotics for suspected "mastitis"

Complicating Scenarios
May present in association with pregnancy
Pregnancy - can arise within days to weeks and is often mistaken for mastitits. Can rapidly progress and requires aggressive staging and treatment with little potential harm to the fetus.

May present as failure from breast conservation

A year or more after breast conservation and radiation, IBC may cause diffuse erythema and induration of the ipsilateral breast in 8-12% of recurrent cases. May be difficult to distinguish from post-radiation changes Carries a far worse prognosis than other recurrences and is more often associated with distant metastases Limited treatment options because of chemoresistance and prior radiation therapy

Diagnosis
Core biopsy of the skin and underlying mass or breast parenchyma Skin punch biopsy including skin of the erysipeloid edge of erythema to demonstrate dermal lymphatic plugging by tumor emboli.
Diagnosis based primarily on clinical findings

Proper imaging include bilateral mammography, U/S, CT, and bone scans for staging purposes.

Diagnosis
MGM First to look for ipsilateral extent of disease and any involvement of contralateral breast. Certain suspicious findings on MGM include:
Skin thickening (more than 2.5 to 3.0 cm) Trabecular thickening Diffusely increased breast density due to edema Malignant microcalcifications

Therapy
Combined modality treatments have significantly improved survival rates over single modality treatments Important to control systemic occult metastases with early induction chemotherapy, followed by surgery and radiation to control locoregional disease. Aggressive systemic and locoregional control has translated to improved disease-free and overall survival
Response to systemic therapy must be followed with a local modality such as mastectomy or radiation to guarantee a survival advantage.

Algorithm for IBC

Surgical Issues
Mastectomy should be performed only after a favorable response to induction chemotherapy alone or followed by radiation.
Most would recommend a 2-3 week rest period after induction therapy to allow patient to normalize

Mastectomy is the operation of choice for pts with IBC Role of axillary dissection vs sentinel lymph node dissection remains largely unanswered.