Primary Surgical Considerations

Terry Mamounas, M.D., M.P.H., F.A.C.S.Professor of Surgery

Northeastern Ohio Universities College of MedicineMedical Director, Aultman Cancer Center

Canton, OHIO

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• Breast Cancer Diagnosis/Preoperative Local Staging• Primary Surgical Management of Invasive/Non-Invasive BC

– RCT of Lumpectomy vs. Mastectomy– Lumpectomy Utilization/Indications/Contraindications – Technical Considerations/Margin Assessment– Contralateral Prophylactic and Nipple-Sparing Mastectomy

• Special Circumstances in Primary Surgical Management– Family History/BRCA 1 or 2 mutation carriers – Presence of EIC– Lobular Histology/Presence of LCIS– Occult Breast Cancer– Large Tumors/Neoadjuvant Chemotherapy– Management of Patients Presenting with Stage IV Disease

Outline 2

Breast Cancer Diagnosis/

Preoperative Local Staging

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Breast Cancer Diagnosis

• Currently, minimally invasive proceduresconstitute the standard of care for diagnosis in the majority of patients

• Needle biopsies can be directed by whichever method assures easiest access and best accuracy for obtaining a true positive or true negative result

• Core needle biopsy is the optimal method for BC diagnosis and can be performed by palpation, ultrasound guidance or stereotacticguidance

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Core Needle Biopsy • Advantages:

• Differentiates between invasive and non-invasive cancer• Leads to one-stage surgical procedures (including SNB

before lumpectomy)• Provides adequate material for biomarkers (ER/PR/HER2) • Neoadjuvant chemo can be given with invasive ca on core

• Limitations:• False negative rate 1-2 %• With non-invasive cancer on core, invasive cancer may

still be present in 10-25% of cases• With atypical hyperplasia on core, invasive or non-

invasive cancer may be present in 15-40 % of cases and open biopsy should follow

Dershaw DD: Breast J 2003, Rao A, et al: Am J Surg 2002, Shin SJ, et al: Arch Pathol Lab Med 2002, Renshaw AA, et al: Am J Clin Pathol 2001, Berg WA, et al: Radiology 2001,Darling ML, et al: AJR 2000, Tocino I, et al: Ann Surg Oncol 1996, Liberman L, et al: AJR 1995, Jackman RJ, et al: Radiology 1994, Adrales G, et al: Am J Surg 2000

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MRI in Preoperative Local Staging• Because of its high sensitivity in BC diagnosis and

screening, MRI is being increasingly utilized in the preoperative local staging of BC

• Multiple studies (and a meta-analysis) have shown that MRI identifies additional cancer foci, otherwise undetected by clinical assessment and conventional imaging (in both breasts)

• No consensus on whether MRI improves patient outcomes in terms of rates of margin positivity, reoperation, IBTR or DFS and OS

• On the other hand there remains concern that MRI can increase unnecessary mastectomy rates

Houssami N et al: J Clin Oncol 2008; Schnall M et al: Magn Reson imaging Clin N Am, 2006; Liberman L et al: Magn Reson Imaging Clin N Am, 2006; Smith RA et al: N Engl J Med 2007; Morrow M et al: Magn Reson Imaging Clin N Am 2006

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UK COMICE Randomized Trial: MRI Planning for Breast-Conserving Treatment

• 1623 women with biopsy-proven primary BC• Scheduled for WLE based on triple assessment

• Randomized to receive MRI (n = 816) or no MRI (n = 807)

Turnbull L et al: Lancet 2009

MRI N (%) No MRI N (%)Initial Surgery

Mastectomy 58 (7%) 10 (1%)Pathologically

Avoidable Mastectomy

16 (2%) 2 (0.2%)

PathologyMF/MC disease 101 (14%) 78 (11%)

• Change in management based on MRI = 50/816 (6%)

• Reoperation rates: • MRI: 18.75%• no MRI: 19.33% P = NS

• No significant differences in DFS of QOL (distress/anxiety)

MRI in Preoperative Local StagingPotential Candidates

• Not necessary for all patients who undergo BCS• Can be helpful in:

• Patients with mammographically dense breasts and ill-defined tumors

• Patients with invasive lobular carcinoma• Patients with multi-centric disease• Patients who are candidates for neoadjuvant

chemotherapy• MRI is essential in patients who present with axillary

adenopathy and clinically and radiographically occult breast lesions

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Primary Surgical Management in Patients

with Invasive and Non-Invasive BC

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Primary Surgical Management

• Evolution in the paradigm of surgical management over the past 30 years

• Trend towards increasing use of breast conserving procedures without compromising patient outcome

• Breast conserving surgery has become the preferred surgical treatment for the majority of early-stage BC patients

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Invasive Breast CancerBreast Conserving Surgery vs. Mastectomy

• From 1973-1989, six randomized trials• Two overview analyses• Compared mastectomy to BCS + XRT• Maximum tumor size for entry: 2-5 cm• No differences in overall survival• XRT significantly reduced the rates of IBTR

Fisher B, et al: N Engl J Med 1985, 1989, 1995, 2002, Veronesi U, et al: Eur J Cancer 1990, 1995, World J Surg 1994, N Engl J Med 1981, 2002Van Dongen JA, et al: Eur J Cancer 1992, J Natl Cancer Inst 2000, Lichter AS, et al: J Clin Oncol 1992, Sarrazin D, et al: Radiother Oncol 1989Blichert-Toft M, et al: J Natl Cancer Inst 1992, EBCTCG: N Engl J Med 1995, Morris AD, et al: Cancer J Sci Am 1997

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Breast Conserving SurgeryUtilization

• 1990: NIH CDC Statement: – Breast Conservation Treatment is an

appropriate method of primary therapy for the majority of women with stage I and II breast cancer and is preferable because it provides survival equivalent to total mastectomy while preserving the breast.”

• Despite this and the increase in detection of early-stage disease, BCS is underutilized as a surgical option

NIH CDC: JAMA 1991, Newman LA, et al: Surg Clin North Am 2003, Swanson GM, et al: SG&O 1990, Nattinger AB, et al: N Engl J Med 1992Samet JM, et al: Cancer 1994, Johantgen ME, et al: Am J Public Health 1995, Ayanian JZ, et al: BCRT 1996, Morrow M, et al: J Clin Oncol 2001

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Frequency of Lumpectomy in NSABP Studies

0

10

20

30

40

50

60

70

80

90

B-13 B-15 B-14 B-16 B-19 B-22 B-20 B-25 B-23 B-28 B-29 B-30 B-36 B-32

Node-Positive TrialsNode-Negative Trials

%

NSABP unpublished data 2/17/05

*

*26% node-positive

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Breast Conserving SurgeryFactors Associated with Increased Rates

• Young age• Treatment in the North-East US• Economic affluence• Treatment in a metro area/cancer center• Treatment in a teaching hospital• White ethnic background• T1 tumors• Absence of EIC

Newman LA, et al: Surg Clin North Am 2003, Swanson GM, et al: SG&O 1990, Nattinger AB, et al: N Engl J Med 1992, Samet JM, et al: Cancer 1994, Johantgen ME, et al: Am J Public Health 1995, Ayanian JZ, et al: BCRT 1996, Morrow M, et al: J Clin Oncol 2001

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Optimal Lumpectomy Candidates

• Tumors < 5 cm in diameter• Limited to one quadrant• Breast size/tumor size ratio permitting

lumpectomy with acceptable cosmetic result• Patient is desirous of breast preservation• Negative margins following resection• No contraindications to breast XRT

Newman LA, et al: Surg Clin North Am 2003, Winchester JD, et al: CA Cancer J Clin 1998

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Lumpectomy ContraindicationsAbsolute

• Multi-centric disease in more than one quadrant

• Diffuse suspicious microcalcifications• Inability to obtain clear margins after

multiple resections• First or second trimester of pregnancy• History of therapeutic radiation to the region

Hooning MJ, et al: Neth J Surg 1991, Morrow M, et al: Ann Surg 1998, Jakesz R, et al: Chirurg 1999

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• Large tumor size/breast size ratio for acceptable cosmesis

• History of collagen vascular disease (relative contraindication to XRT)

• Tumor location beneath nipple

• Unavailability of radiotherapy

Lumpectomy ContraindicationsRelative

Hooning MJ, et al: Neth J Surg 1991, Morrow M, et al: Ann Surg 1998, Jakesz R, et al: Chirurg 1999

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Lumpectomy TechniqueChoice of Incision

• Incision over mass• Adequate length• Always curvilinear• Keep in mind possible

future mastectomy• Do not combine with

axillary incision

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• Thick flaps unless mass is superficial

• Keep in mind possible future PBI

• Remove piece of skin if mass is fixed

• Use sharp dissection• Orient specimen and tag

before removing

Lumpectomy TechniqueExcision and Specimen Orientation

Sutures

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• Inking of specimen by pathologist

• Gross margin inspection

• Resection of additional tissue if necessary

InkNormal BreastTissue

Tumor

Lumpectomy TechniqueIntraoperative Margin Assessment

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Subcutaneous Stitch

Cavity

• Do not re-approximate breast tissue

• Advancement flaps can be used to minimize defect

• No drains in breast• Subcutaneous and

subcuticular closure

Lumpectomy TechniqueWound Closure

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• 21 studies reporting LR by quantified final microscopic margin status and the distance for negative margins

• 14,571 pts, 1,026 LRs• Odds of LR were significantly

associated with margin status:– OR = 2.02 for (+)/close vs. (-)

(P < 0.001)– OR = 1.80 for close vs. (-)– OR = 2.42 for (+) vs. (-)

(both P < 0.001)

What Constitutes Adequate Margin for IBC?Meta-Analysis: Effect of Margin Status on LR

Houssami et al: Eur J Cancer 2010

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• No significant association with margin width: 1 vs. 2 vs. 5 mm , P > 0.10

• Weak evidence that the OR of LR decreased as margin width increased:–OR for 1 mm, 2 mm, 5 mm: 1.0, 0.75, 0.51–P = 0.097 for trend in one model NS in

another model

• Conclusions:–Margin status has a prognostic effect

in women with IBC–Adoption of wider margins, relative

to narrower is unlikely to a have impact on LR

Houssami et al: Eur J Cancer 2010

What Constitutes Adequate Margin for IBC?Meta-Analysis: Effect of Margin Width on LR

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• 4,660 patients from trials of BCS + XRT for DCIS • Pts with (-) margins significantly less likely to experience

IBTR than pts with (+) margins (OR 0.36)• A (-) margin significantly reduced risk of IBTR compared

with a close (OR 0.59) or unknown margin (OR 0.56)

What Constitutes Adequate Margin for DCIS?Meta-Analysis: Effect of Margin Status on LR

Dunne et al: J Clin Oncol, 2009

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Dunne et al: J Clin Oncol, 2009

• 2-mm margin was superior to a margin < 2 mm (OR 0.53)• No significant difference in IBTR between 2 mm and more

than 5 mm (OR 1.51; P .05)• A margin of 2 mm seems to be as good as a larger margin

What Constitutes Adequate Margin for DCIS?Meta-Analysis: Effect of Margin Width on LR

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A Recently Observed Trend:Increase in the Incidence of

Contralateral Prophylactic Mastectomy

Tuttle et al: J Clin Oncol 2007

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Nipple-Sparing MastectomyBackground

• In most mastectomy techniques the NAC is removed:• Contains terminal ducts• Centripetal lymphatic drainage towards the

subareolar plexus of Sappey• In early mastectomy studies the likelihood of

occult NAC involvement was relatively high (8-50%)• Increased risk with tumor proximity to NAC, poorly

differentiated tumors, lymph node positivity, size >2 cm

Lagios MD, et al: Am J Surg 1979; Fisher ER et al: Cancer 1975; Smith J, et al: Surg Gynecol Obstr 1976; Kissin MW, et al: Br J Surg 1987

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Nipple-Sparing MastectomyRationale

• In more recent mastectomy series NAC involvement is seen in 6-11%

• In the majority not appreciated preoperatively• Careful intraoperative evaluation of the NAC

by FS or touch prep is necessary for NSM• Several series have demonstrated the

feasibility of NSM but long term FU is needed• Main advantages: cosmesis and preservation

of nipple sensation (variable)• Potential concerns: nipple necrosis, long-term

oncologic safetyLaronga C, et al: Ann Surg Oncol 1999; Simmons RM, et al: Ann Surg Oncol 2002; Klimberg et al: Ann Surg Oncol 1998; Crowe et al:Arch Surg 2004, Pennisi VR, et al: Aesth Plastic Surg 1989

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Nipple-Sparing MastectomyAppropriate Candidates

• Tumor size 3 cm or less• Tumor location at least 2 cm from the nipple-

areola complex• Absence of multicentricity• Absence of segmental malignant calcifications

extending to the nipple-areola complex• Clinically negative nodes• Negative intraoperative biopsy of nipple-areola

complexSpear SL, et al: Plast Reconstr Surg 2009; Golshan M: Diseases of the Breast, 2009

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Nipple-Sparing MastectomyTechnical Aspects

• Incisions:• Peri-areolar with lateral extension• Trans-areolar, peri-nipple with lateral

extension• Trans-areolar, trans-nipple with medial and

lateral extensions• Inferior-lateral mammary crease incision• Nipple-sparing omega (mastopexy) incision• Vertical incision

Laronga C, et al: Ann Surg Oncol 1999; Simmons RM, et al: Ann Surg Oncol 2002; Klimberg et al: Ann Surg Oncol 1998; Crowe et al: Arch Surg 2004, Pennisi VR, et al: Aesth Plastic Surg 1989

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Special Circumstances in Breast Cancer Primary Surgery

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Family History/BRCA Status and IBTR• Family history is not an independent predictor

of IBTR in case-control studies• Whether BRCA mutations increase IBTR rates

after BCS is controversial:• Pierce et al : No significant increase in 10-year IBTR

rate for BRCA+ pts (12%) vs. BRCA- pts (9%)• Robson et al : Non-significant increase in IBTR

rate for BRCA+ Ashkenazi Jewish pts vs. BRCA- pts (RR=1.79; 95% CI=0.64-5.03)

• Hafty et al : Significant increase in 12-year IBTR rate for BRCA+ pts (49%) vs. BRCA- pts (21%). No oophorectomy or tamoxifen used

Pierce LJ, et al: J Clin Oncol 2006, Robson M, et al: J Natl Cancer Inst 1999, Haffty BG, et al: Lancet 2002

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Surgical Approach of BRCA+ Patients

• Known Mutation Carriers:- Discuss BCS vs. bilateral mastectomy- XRT is effective without excess toxicity- High rate of IBTR and CBC

• Suspected Mutation Carrier:- Proceed with surgery as planned based on

tumor presentation (consider neoadjuvant Rx)- Proceed with genetic counseling and testing- Revisit the surgical management after

systemic therapy is given and before XRT

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Extensive Intraductal Component (EIC)DCIS in > 25% of the tumor area

• In early studies, EIC has been found to be associated with increase in IBTR rates after BCS

• Most of these studies included patients with involved margins and margin involvement generally correlates with the presence of EIC

• Subsequent studies that included patients with negative or focally positive margins, showed that presence of EIC does not significantly predict for IBTR

Schnitt SJ, et al: Cancer 1984 Boyages J, et al: Radiother Oncol 1990, Voogd AC, et al: Eur J Cancer 1999, Abner AL, et al: Cancer 2000, Leborgne F, et al: Int J Radiat OncolBiol Phys 1995 Voogd AC, et al: J Clin Oncol 2001, Burke MF, et al: Int J Radiat Oncol Biol Phys 1995, Touboul E, et al: Int J Radiat Oncol Biol Phys 1999,Schnitt SJ, et al: Cancer 74:1746-51, 1994, Anscher MS, et al: Ann Surg 1993, Smitt MC, et al: Cancer 1995, Wazer DE, et al: Int J Radiat Oncol Biol Phys 1999

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Presence of Lobular Histology

• Invasive lobular carcinoma can present in an insidious fashion making margin assessment often challenging

• Several studies have shown no significant differences in IBTR rates between pts presenting with lobular vs. ductal histology

• In one study, presence of LCIS increased IBTR rates at 10 but not at 5 years and mostly in younger women

Voogd AC, et al: Eur J Cancer 1999, Abner AL, et al: Cancer 2000,Elkhuizen PH, et al: Int J Radiat Oncol Biol Phys 1999, Wazer DE, et al:. Int J Radiat Oncol Biol Phys 1998

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Occult Breast CancerIncidence and Diagnosis

• 0.3%-1% of breast cancers present with clinical axillary adenopathy with an occult breast primary

• Breast MRI identifies the occult primary in 75-85 % of the cases

• In the majority of cases with negative MRI, no tumor can be identified in the mastectomy specimen

Baron PL, et al: Arch Surg 1990, Merson M, et al: Cancer 1992, Patel J, et al: Cancer 1981, Sakorafas GH, et al: Surg Oncol 1999, Orel SG, et al: Radiology 1999, Henry-Tillman RS, et al: Am J Surg 1999, Morris EA, et al: Radiology 1997, Tilanus-Linthorst MM, et al: BCRT 1997, Baker DR: Clin Breast Cancer 2000

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Occult Breast CancerLoco-Regional Management

• Traditionally, MRM followed by L-R XRT has been the standard approach

• Acceptable approaches with proven safety (in small series) include:• Axillary node dissection followed by breast

XRT (and regional nodal XRT as appropriate)• Neoadjuvant chemotherapy followed by either

one of the above options• If mastectomy is not performed, omission of

breast XRT increases the rates of IBTR (from about 12-33% to about 14-83%)Baron PL, et al: Arch Surg 1990, Merson M, et al: Cancer 1992, Patel J, et al: Cancer 1981, Sakorafas GH, et al: Surg Oncol 1999, Ellerbroek N, et al: Cancer 1990, Kemeny MM, et al: Am J Surg 1986, Vlastos G, et al: Ann Surg Oncol 2001, Foroudi F, et al: Int J Radiat Oncol Biol Phys 2000

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Neoadjuvant ChemotherapyLoco-Regional Effects

• NC in operable breast cancer induces clinical response in 80-90% of the pts

• pCR rates range from 15-40%

• NC increases the rates of BCS without significantly increasing IBTR

• Potential to increase cosmetic result by decreasing the amount of breast tissue needed to be removed at lumpectomy

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• Sometimes difficult to define the extent of residual tumor and as a result the amount of breast tissue to be removed at lumpectomy

• Ideally one would want to remove less than originally required

Challenges in Decreasing the Size of the Lumpectomy Specimen

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How Do Tumors Shrink in Response to NC?

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What is Adequate Surgical Resection after NC?

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1 2 3 4 51: Single predominant mass with identifiable rim, displacing 2: Nodular pattern, irregular borders 3: Diffuse infiltrative pattern 4: Patchy enhancement 5: Septal spread

MRI Phenotypes

Esserman L, et al:. Ann Surg Oncol 2001

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MRI Can Overestimate the Amount of Residual Disease

Before NC After NC

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• Identification of the exact tumor location in cases of cCR– Preoperative titanium clip placement

Neoadjuvant ChemotherapySurgical Planning

Kuerer HM, et al: Am J Surg 2001 Kaufmann M, et al: J Clin Oncol 2003, Baron LF, et al: AJR 2000, Edeiken BS, et al: Radiology 1999, Dash N, et al: AJR 1999

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Before NC After NC

Ensuring Adequate Surgical Resection after NC

• Identify pattern of shrinkage and the extent of residual tumor preoperatively (mammogram, US, MRI)

• Accurately localize tumor bed area in cases of clinical/radiologic CR

• Thoroughly evaluate margins (intraoperatively and postoperatively)

• Perform additional resection if necessary

Delille JP, et al: Radiology 2003, Wasser K, et al: Eur Radiol 2003, Tiling R, et al: Onkologie 2003, Partridge SC, et al: AJR 2002, Esserman L, et al: Ann Surg Oncol 2001

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Invasive Lobular Carcinoma and NC• Particular attention when planning BCS

in pts with ILC after NC

• ILC often multicentric and can extensively involve the breast without significant clinical or mammographic findings

• MRI is useful in defining the extent in the breast (but not in the axilla)

• Very low pCR rates with ILC (0-3%)

• ILC predicts for ineligibility of BCS

• Unlikely that pts with extensive ILC will be converted to BCS candidates by NC

Lesser, ML, et al: Surgery 1982, Cocquyt VF, et l: Eur J Surg Oncol 2003, Newman LA, et al: Ann Surg Oncol, 2002

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• Conventional wisdom is that once metastases have occurred, aggressive local therapy provides no survival advantage and should not be pursued except to prevent local complications (bleeding, ulceration, infection)

• Several retrospective studies have shown significantly better outcome for women who had surgical removal of their tumor vs. those who did not (particularly for those who had negative margins)

Primary Surgical Therapy in Patients Presenting with Stage IV BC

Khan SA, et al: Surgery 2002; Rapiti E, et al: J Clin Oncol 2006; Gnerlich J et al: Ann Surg Oncol 2007; Bafford AC et al: Br Ca Res Treat 2009; Babiera GV et al: Ann Surg Oncol 2006; Blanchard DK et al: Br Ca Res Treat 2006; Le Scodan R et al: J Clin Oncol 2009;Ruiterkamp J et al: Eur J Surg Oncol 2009; Shien T et al: Oncol Rep 2009; Cady B et al: Ann Surg Oncol 2008; Fields RC et al: Ann Surg Oncol 2007;

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• Most studies adjusted for imbalances in known prognostic factors (such as number of mets, location of mets, type of systemic therapy or use of radiotherapy)

• Most studies concluded that unrecognized selection bias may have accounted for the observed benefit of surgery and only a large prospective RCT could reliably answer the question (ECOG 2108)

Primary Surgical Therapy in Patients Presenting with Stage IV BC

Khan SA, et al: Surgery 2002; Rapiti E, et al: J Clin Oncol 2006; Gnerlich J et al: Ann Surg Oncol 2007; Bafford AC et al: Br Ca Res Treat 2009; Babiera GV et al: Ann Surg Oncol 2006; Blanchard DK et al: Br Ca Res Treat 2006; Le Scodan R et al: J Clin Oncol 2009;Ruiterkamp J et al: Eur J Surg Oncol 2009; Shien T et al: Oncol Rep 2009; Cady B et al: Ann Surg Oncol 2008; Fields RC et al: Ann Surg Oncol 2007;

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• In the absence of RCT data, not removing the primary tumor remains the standard

• Surgery can be entertained in selected cases (before or after systemic therapy) for local control if local manifestations are more likely to contribute to morbidity than distant ones

• In such cases, breast conserving surgery is preferable if it can encompass the scope of the surgical resection

• Axillary node surgery or breast XRT are generally not advisable

Primary Surgical Therapy in Patients Presenting with Stage IV BC

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• Core needle biopsy is the standard diagnostic procedure for primary BC

• MRI is not indicated for all pts who undergo BCS• Lumpectomy + breast XRT is the preferred

surgical option in the absence of absolute contraindications

• An increase in the use of CPM has been recently reported

• Use of nipple-sparing mastectomy requires careful consideration and patient selection

Summary/Conclusions (1)50

• Family history of breast cancer, presence of EIC (with negative margins), lobular histology and presence of LCIS do not increase the rates of IBTR and are not contraindications to BCS

• In patients presenting with “occult” BC and axillary metastases, MRI plays an important role in identifying the primary in the breast. Breast XRT is an acceptable alternative to mastectomy, if MRI does not identify a distinct lesion.

Summary/Conclusions (2)51

• In patients undergoing neoadjuvant chemotherapy, unique primary surgical issues relate to the assessment of the extent of residual disease and the exact location of residual tumor (or tumor bed) in patients with complete clinical and/or radiologic response

• There is currently no definitive evidence that the use of primary breast surgery in patients presenting with stage IV disease improves overall survival

Summary/Conclusions (3)52