History of Breast Cancer Surgery and Landmark Clinical Trials

Deanna J. Attai, MD, FACSAssistant Clinical Professor of Surgery

David Geffen School of Medicine at UCLA

7 January 2015

No Disclosures

Breast Cancer Epidemiology

• Most common type of cancer among women

• 1 in 8 women will develop breast cancer over her lifetime; 1 in 100 men

• Second most common cause of cancer deaths among women

• ~200,000 new cases and ~40,000 deaths per year

• Risk increases with age

History of Breast Cancer Surgery• Before15th century: Imbalance of black bile, local therapy futile;

patients died a slow painful death due to cancer progression• Systemic treatments (purging and bleeding) ineffective

• 1500-1700s: scientific thinking; observation of orderly spread of breast cancer to local lymph nodes

• Taste test: breast cancer ≠ bile

• Attempts to cure breast cancer through local therapy; lack of anesthesia did not prevent efforts to perform mastectomies

History of Breast Cancer Surgery1500-1800s

• Ambroise Paré (1500s): local, topical agents

• Andreas Versalius (1500s): wide local excision

• Lorenz Heister (1600-1700s): resected breast, muscle, ribs

• James Syme (1700-1800s): advocated wide and complete excision including axillary nodes

History of Breast Cancer Surgery

A German physician warned surgeons about the procedure: "Many females can stand the operation with the greatest courage and without hardly moaning at all. Others, however, make such a clamor that they may dishearten even the most undaunted surgeon and hinder the operation. To perform the operation, the surgeon should be steadfast and not allow himself to become discomforted by the cries of the patient."

Olson, J: “Bathsheba’s Breast: Women, Cancer and History”

Sir William Halsted• GENERAL ANESTHESIA

(1840’s)

• Halsted Radical mastectomy standard treatment from late 1890-1970s

• Halsted theory: breast cancer spread locally into muscle and regional nodes; then distant metastasis

CANCER

LYMPH NODES

LUNGS

LIVER

HALSTED THEORY

BONE

Radical Mastectomy

Radical Mastectomy

• Aggressive surgical treatment for what was often locally advanced disease

• Did not significantly improve (dismal) survival rate • High incidence of overall morbidity, lymphedema, arm paralysis

• Described in 1894• Procedure of choice until 1960-70s

• Halsted died in 1922

The 1970s

• Screening mammography became more prevalent

• Smaller cancers detected

• Increased public awareness – Betty Ford, Happy Rockefeller

Dr. Bernard FisherNSABP B04; Enrollment 1971-1974

www.NSABP.edu

CANCER

LYMPH NODE

FISHER THEORY

LUNGS

LIVER

BONE

BLOOD STREAM

Fisher B et al. N Engl J Med 2002;347:567-575.

NSABP B04 Results

• Preservation of the pectoral muscle new standard of care• 2 step procedure should be performed

Modified Radical Mastectomy

Modified Radical Mastectomy

NSABP B06; Enrollment 1976-1984

www.NSABP.edu

NSABP B06 Results

Fisher, et al N Engl J Med,Vol. 347, No. 16 · October 17, 2002

NSABP B06 Results

• No difference in survival at 20 years

• Lumpectomy without postoperative irradiation higher local recurrence 39.2% vs. 14.3%

• BCS New standard of care for Stage I/II

Fisher, et al N Engl J MedVol. 347, No. 16 · October 17, 2002

Goals of Breast Conservation

• Minimize local recurrence at the primary site

• Achieve an acceptable cosmetic result

• Eradicate microscopic foci of cancer with radiation

• Minimize risk of complications

• Maximize benefit in terms of quality of life

Targeting the Cancer

Can BCS be applied to larger cancers? NSABP B18; Enrollment 1988-1993

• 1523 patients randomized• 80% of NAC patients had

tumor size; 36% had pCR

• 12% more lumpectomies performed in NAC patients

• 175% increase in BCS if tumor >5.1cm

Mamounas, EP Clin Med Resv1(4); 2003 Oct

ACOSOG Z1031Neoadjuvant Endocrine Therapy

• Rationale:•Endocrine therapy has shown survival benefit in ER + patients

• Decreased toxicity of endocrine therapy compared to chemotherapy

•Aromatase inhibitors more effective than tamoxifen for post-menopausal, ER+ patients

ACOSOG Z1031 Cohort AEnrollment 2006 - 2009

• 60% complete or partial response• 6% of patients had progression of disease• 51% of patients slated for mastectomy were able to undergo

lumpectomy• Overall breast conservation rate 68% Ellis, Olson, et al J Clin Oncol

2011 Jun 10;29(17):2342-9

Goals of Neoadjuvant Therapy

• Convert “Inoperable” to “Operable”• Convert Mastectomy to Breast Conservation• Increase Breast Conservation Success

• Clear Margins• Cosmetic Outcome (tissue preservation)

• Further study is ongoing to identify subsets of patients which might not respond based on biological markers

Neoadjuvant TherapyImportance of Tumor Biology

• 20-25% of breast cancers over-express Her2/neu• Trastuzumab and Pertuzumab – anti-Her2 antibody; bind at different sites

• Trastuzumab: improves time to progression and OS in Stage IV; in women w/ operable disease improves DFS and OS; given for one year with chemotherapy

Gianni L, et al Lancet Oncol 2012; 13: 25–32

Neo-Sphere StudyNeoadjuvant Therapy for Her2/neu

• T+D, P+T+D, P+T, P+D• P+T+D significantly rate of pCR 45.8% vs. 14-29%• No significant difference in tolerability

• Pertuzumab only approved for neoadjuvant• Stresses need for surgeons to understand more than just surgery – molecular marker and pathway driven treatments

Gianni L, et al Lancet Oncol 2012; 13: 25–32

Importance of Axillary Lymph Node Status

• Node status determines stage, predicts outcome• ~ 5-30% Stage I & II breast cancer has positive nodes• Node status influences adjuvant therapy decisions:

- Chemotherapy, anti-estrogen therapy- Drug choice, dose, combination- Radiation therapy

• High rate of lymphedema, paresthesias, shoulder dysfunction. No benefit in node-negative patients

History of Axillary Lymphadenectomy

• Petit 1774

• Pancoast 1884

• Halsted 1895

• Patey 1948

• Krag, Morton, Giuliano, Tafra, Ross, Reintgen, 1990s

- Sentinel Node

Sentinel Lymph Node Dissection

Development and Validation of Sentinel Node Biopsy Technique

• Morton, D, et al. Technical Details of Intraoperative Lymphatic Mapping for Early Stage Melanoma Arch Surg. 1992;127(4):392-399

•Krag DN, et al. Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surg Oncol 1993;2:335-339

•Giuliano AE, et al.Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994;220:391

Sentinel Node BiopsyNSABP B32; Enrollment 1999-2004

Mamounas, EP Clin Med Resv.1(4); 2003 Oct

NSABP B32 Results• 5,611 patients, 80 sites, 232 surgeons• SN Identification rate 97%• 26% had positive node• 9.7% false negative rate ; less common with >1SN,

more common if excisional biopsy performed first• OS, DFS, Regional Control statistically equivalent

• SNB alone is safe, appropriate, and effective in patients with clinically negative nodes

Positive Sentinel Node (891 patients)Axillary

Dissection (445)

No axillary

Dissection (446)•All patients with +nodes received WBI and adjuvant

systemic therapy• Original goal = 1900•End Points: Overall & Disease Free Survival and Local-Regional Failure

Positive Sentinel NodeACOSOG Z0011 Trial

Giuliano AE, et alJAMA 2011;305:569-75

ACOSOG Z11 Results• Closed early due to slow accrual and lower mortality than

anticipated• No difference in OS or DFS• 70% vs. 25% (AXND vs. SNB) surgical morbidity: wound

infections, axillary seromas, paresthesias• Lymphedema 13% vs. 2%; longer term after SNB 5-8%

• In patients with limited SN disease who receive BCS with WBI and systemic therapy, SNB alone does not result in inferior survival

• Study limitations, but practice-changing Giuliano AE, et alJAMA 2011;305:569-75

ACOSOG Z0011 Change in Practice

Breast Conservation Patients•No intraoperative frozen section•No ALND if 1-2 positive nodes

Other Patient Populations?•Mastectomy, APBI, Neoadjuvant Therapy•AMAROS Trial - Radiation shown to be as effective as AXND, lower morbidity

Local Therapy Paradigm Shift: Less is MoreCurrent Treatment: Stage I/II

• Initial diagnosis by needle core biopsy• Absolute tumor size / location not a contraindication to breast

conservation• Consider molecular profile of tumor, neoadjuvant therapy• Sentinel node dissection even if positive sentinel node. Positive

node not a contraindication to breast conservation

• Mastectomy is an option based on patient preference, multicentric disease, contraindication to radiation, tumor size relative to breast size.

• Immediate reconstruction should be considered along with skin-sparing and/or nipple sparing approach

Immediate Reconstruction• Most patients are a candidate unless locally advanced or inflammatory cancer

• Implant or free flap (fat and skin); less commonly muscle flap used

• Skin-sparing mastectomy with reconstruction can result in minimal scarring

• Collaboration with breast surgeon, plastic surgeon, medical oncologist, and radiation oncologist is crucial for optimal results

Skin Sparing / Tissue Expander-Implant

NSM / Direct to Implant

Skin Sparing / Free Flap

The FutureAblative Therapy

• Majority of patients are candidates for breast conserving lumpectomy

• Still requires general anesthesia, scarring, potential for cosmetic deformity, and may require multiple operations (literature reports 25-40% re-excision for positive margins)

• Ablation involves destruction of the tumor without the need for surgery

• Used for liver, kidney and other cancers

Cryoablation - Probe Placement

Cryoablation - Iceball Formation

ACOSOG Z1072; Enrollment 2008-2013

Surgical resection

Imaging (breast MR)

Ablation therapy ( cryoablation)

Imaging ( Mammography, US, Breast MR)

Core biopsy for diagnosis including ER/PR, HER-2/neu, OncotypeDx

Invasive Ductal Breast Cancer (tumor ≤2cm)

Phase II Trial Evaluating the Efficacy of Pre and Post Treatment Imaging to Determine Residual Disease in Patients with Invasive Breast Carcinoma

Undergoing Cryoablation Therapy

ACOSOG Z1072 Case Study

• 62 year old woman• No family history, no prior biopsy• Screening mammogram: unifocal 10x10x13mm irregular

right upper outer quadrant mass• Core biopsy: Grade I IDC, ER/PR positive, Her2/neu not

over-expressed

ACOSOG Z1072 Case Study

ACOSOG Z1072 Case Study

S09-15441

ACOSOG Z1072 Case Study

ACOSOG Z1072 Results

• 99 Patients, 17 Sites• 87 cancers eligible for evaluation after cryoablation

• 81/87 (92%) successful ablation

Personal communication; Simmons, RM

Immune Response to Cryoablation

Likely cryo-induced immune response capable of inhibiting the growth of distant tumor foci

Sabel. Cryobiology.2006;53:360-366. Ablin RJ Arch Surg. 1998;133:106. Tanaka S. Cryobiology 1982;19:247-262.Suzuki Y. Skin Cancer. 1995;10:19-26.

Breast Cancer Treatment - The Future:Individualized and Targeted Approach

• Core biopsy to determine genomic profile and identify markers / pathways

• Specific tumor based therapy – target driven therapy, ablation

• Identify which patients even need surgery???

Research = Progress

Thank You!