1 Ongoing Controversies in Surgical Management Terry Mamounas, M.D., M.P.H., F.A.C.S. Medical Director, Comprehensive Breast Program UF Health Cancer Center at Orlando Health Professor of Surgery, University of Central Florida College of Medicine Clinical Professor of Clinical Sciences, Florida State University College of Medicine
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Ongoing Controversies in Surgical Management · Ongoing Controversies in Surgical Management Terry Mamounas, M.D., M.P.H., F.A.C.S. Medical Director, Comprehensive Breast Program
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Ongoing Controversies in Surgical Management
Terry Mamounas, M.D., M.P.H., F.A.C.S.Medical Director, Comprehensive Breast Program
UF Health Cancer Center at Orlando HealthProfessor of Surgery, University of Central Florida College of Medicine
Clinical Professor of Clinical Sciences,Florida State University College of Medicine
Outline
• Optimal Management of the Clinically Negative Axilla with Positive SLN(s)
• Optimal Management of the Axilla in Patients Treated with Neoadjuvant chemotherapy
• Adequate Margin Width in Breast Conserving Surgery
• Role of Surgical Excision of the Primary Breast tumor in Patients Presenting with Stage IV Disease
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Clinically Negative Axillary NodesN=5611
GROUP 1Sentinel Node
Biopsy
Axillary Dissection
GROUP 2Sentinel Node
Biopsy*
Randomization
Stratification• Age
• Clinical Tumor Size• Type of Surgery
*Axillary node dissection only if the SN is positive
NSABP B-32: RCT of SLNB +/- ALND
• ID Rate: 97%• FN Rate: 9.8%
• Average # SLNS: 2.9• Factors significantly
affecting ID rate:– Age, Tumor Size and Tumor Location
• Factors significantly affecting FN rate:
– Type of Biopsy and Number of Removed SNs
Krag D et al: Lancet Oncology 2007
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NSABP B-32: False-Negative Rate According to Number of Removed SNs
Krag D et al: Lancet Oncology 2007
_
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NSABP B-32 Sentinel Node-Negative PatientsDFS, OS and LRR
• Conclusion: SLN surgery after NC is as accurate as SLN surgery prior to chemotherapy, results in fewer positive SLNs and decreases unnecessary axillary dissections
• Retrospective studies: Variability in SLN IR (78%-98%) and SLN FNR (5%-30%)
• Three prospective trials were recently published (ACOSOC Z1071, SENTINA, SN FNAC)–IRs were lower with SLNB after NC (80-93%)
compared to upfront SLNB (>95%)–FNRs ranged between 9.6%-14% and were
mainly affected by number of removed SNs
SLNB After NC in Patients with Documented (+) Axillary Nodes
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SLNB After NC in Patients with + NodesFNR According to Number of Removed SLNs
ACOSOG Z1071
FN SNAC SENTINA Across studies
# of patients 756 153 592 1501
FNR withsingle SLN
31.5%17/54
18.2%4/22
24.3%17/70
26.0%38/146
FNR if 2 or more SLNs
12.6%39/310
4.9%3/61
9.6%15/156
10.8%57/527
FNR with dual tracer
10.8%27/251
- 8.6%6/70
10.3%33/321
FNR if >2 SLNs 9.1%20/220
- 4.9%5/102
7.8%25/322
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Re-Analysis of Z1071: Role of IHCBoughey J: SABCS 2014
• Re-analysis of 470 patients (90% of total) with cN1 and ≥ 2 SNs for which pathologic evaluation with IHC was available
• The FNR was 8.7% (95%CI, 5.6-11.8)• Increase in unnecessary CLND (dissecting
the nodes because of a (+) SN with ITCs and not finding non-SNs with metastases > 0.2 mm) was only 2.1% (10/470)
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Re-Analysis of Z1071: Role of IHCBoughey J: SABCS 2014
• An unplanned subgroup analysis of Z1071 examined patients who had a clip placed in the positive node at time of biopsy (32% of the total)
• FNR was 6.8% when the clip was retrieved in the SLNs
• If the clip was not identified in the SLNs, the FNR was much higher: 39%
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• Appropriate candidate selection for SLNB (T1-3,N1)• Dual agent lymphatic mapping (isotope + dye)• Identification and removal of >2 SNs
• Clip placement in the positive node with radiologic clip localization and retrieval
• Consideration of performing IHC staining in the SLN and consider completion ALND even with N0i+ disease
Optimizing SLNB After NC in Patients with Documented (+) Axillary Nodes Before NC
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• Helpful if the SN is negative• Patients with large operable breast cancer
have high likelihood of positive nodes• Does not take advantage of the down-staging
effects of neoadjuvant chemotherapy on nodes: 30-40% conversion from (+) to (-)
• May remove the only positive node(s) (interferes with direct assessment of chemosensitivity
• Requires two surgical procedures
SLNB Before NC: Pros and Cons30
• Breast XRT: Should be always given after lumpectomy
• Chest Wall and Regional Nodal XRT: Consider factors predicting local-regional recurrence after NC (baseline clinical characteristics + pathologic response to NC)
• These factors significantly predict rates of local-regional recurrence after NC
Can We Use Tumor and Nodal Response to NC in Order to
Individualize the Use of L-R XRT?
SNB Before NC:Selection of Loco-Regional XRT?
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Adequate Margin Width in Breast Conserving Surgery
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The Margin Width Controversy in BCS• This controversy is as old as the procedure itself• Two divergent techniques with diametrically
opposed approaches to margin width• Lumpectomy (NSABP): Removal of tumor with limited
normal surrounding tissue; path negative margins: “no ink on tumor” on microscopic assessment
• Quadrantectomy (Milan Group): Removal of the affected quadrant + overlying skin + underlying fascia en block; generally wider margins; originally intended to avoid XRT
• Benefit from XRT demonstrated with both procedures, further fueling the margin width debate
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SSO-ASTRO: Margins Consensus Guideline
• A multidisciplinary consensus panelconsidered:• Large, study level meta-analysis of margin
width and IBTR (33 studies, 28,162 pts)• Results of randomized trials• Reproducibility of margin assessment• Current patterns of multimodality care
Moran M, et al: J Clin Oncol, 2014
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SSO-ASTRO:Margins Consensus Guideline
• Recommendations:• Use of no ink on tumor as the standard for
an adequate margin in IBC in the era of multidisciplinary Rx results with low rates of IBTR
• This approach has the potential todecrease re-excision rates, improve cosmetic outcomes, and decrease healthcare costs
Moran M, et al: J Clin Oncol, 2014
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• Clinical observations that provide assurance when applying the recommendations:• Dramatic decline in the rates of IBTR• 5-year IBTR: 5.3% in the meta-analysis
SSO-ASTRO: Margins Consensus Guideline
Strengths
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• Applies to invasive BC treated with whole breast XRT
• The findings cannot be extrapolated to patients with pure DCIS or after neoadjuvant chemo
• Based on study-level meta-analysis• Close margins: increased risk of IBTR• Strength of evidence: “no tumor on ink” vs.
> 1 mm
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SSO-ASTRO: Margins Consensus Guideline
Limitations
• 235 patients, stage 0 to III BC• BCS +/- resection of selective margins• Intraoperative Randomization:
• Cavity Shave Margins vs. Not• Primary Outcome: Rate of (+) margins• Secondary Outcomes: Cosmesis and
Volume of tissue resected
A Randomized, Controlled Trial of Cavity Shave Margins
Chagpar A, et al: N Engl J Med 2015
• Results: Shave group associated with: • Lower rates of (+) margins: 19% vs. 34%, P = 0.01
Lower re-excision rates: 10% vs. 21%, P = 0.02 • No differences in complications, cosmesis and rates of
complex tissue rearrangements
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Management of the Breast Primary in Patients Presenting
with Stage IV BC
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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 outcomes 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
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• Surgery of the primary tumor appeared to be an independent factor for an improved survival in the multivariate analyses from the individual studies, with an HR of 0.69 (p<0.00001)
• 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 large prospective RCTs could reliably answer the question
Primary Surgical Therapy in Patients Presenting with Stage IV BC
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Tata Memorial Center Randomized Phase III Trial
R
Loco-Regional
Treatment*Anthracyclines +/- Taxanes
(CR /PR ) No Loco-Regional
Treatment
Stage IV BC At Presentation
Stratification by: • Hormone-Receptor Status• Site of metastases (visceral vs. bone vs. both)• Number of metastatic lesions (< 3 vs. > 3)
*LRT: BCS or Mastectomy + AND followed by radiation therapy (RT), as per standard adjuvant guidelines
Badve R et al: SABCS 2013, Abstract S2-02
N=350
Median F/U:17 mos
Tata Memorial Center Phase III TrialResults: Overall Survival
• The median OS in LRT and No-LRT arms were 18.8 and 20.5 months (HR=1.04, p=0.79)
• Corresponding 2-year OS were 40.8% and 43.3%, respectively
• No significant difference in OS between the two groups after adjusting for age, ER status, HER2 status, site and number of mets (HR=1.00, 95%CI=0.76-1.33, p=0.98).
Badve R et al: SABCS 2013, Abstract S2-02
MF07-01 Turkish Study: Design
Soran A, et al: SABCS 2013, Abstract S2-03
• Chemotherapy to all patients either after randomization in the ST treatment arm or after surgical resection the surgery arm
• Hormone therapy for HR positive BC and trastuzumab for HER-2 positive BC
• Surgery-RT at discretion of investigator
MF07-01 Turkish Study: ResultsOverall Survival
Soran A, et al: SABCS 2013, Abstract S2-03
Atilla Soran, MD, MPH, FACS, Magee-Womens Hospital of UPMC Vahit Ozmen, Serdar Ozbas, Hasan Karanlik, Mahmut Muslumanoglu, Abdullah Igci, Zafer Canturk, Zafer Utkan, Cihangir Ozaslan, Turkkan Evrensel, Cihan Uras, Erol Aksaz, Aykut Soyder, Umit Ugurlu, Cavit Col, Neslihan Cabioğlu, Betül Bozkurt, Efe Sezgin, Ronald Johnson, Barry LemberskyOn behalf of the Turkish Federation of Societies for Breast DiseasesClinicalTrials.gov identifier number is NCT00557986
A Randomized Controlled Trial Evaluating Resection of the Primary Breast Tumor in Women Presenting with de Novo Stage IV
Follow-up Time (months)LR progression Surgery=1% (2) ST=11% (15) P=0.001
Soran A. et al., ASCO 2016
• Survival was similar in 36 months with or without primary breast surgery
• Longer follow up revealed statistically significant improvement in median survival with surgery (46 vs 37 months; HR:0.66) and 5 year OS was 41.6% vs 24.4%, respectively
• Patients with a more indolent form of metastatic BC such as ER (+), HER2 neu (-), solitary bone metastasis, and patients < 55 years old have a significant survival benefit with initial surgery
MF07-01: Summary
Soran A. et al., ASCO 2016
A Prospective Analysis of Surgery and Survival in Stage IV Breast Cancer (TBCRC 013)
King TA, Lyman JP, Gonen M, Reyes S, Boafo C, Plichta J, Hwang ES, Rugo HS, Liu M, Boughey JC, Jacobs LK, Krontiras H, McGuire K, Storniolo A, Nanda R, Golshan M, Isaacs C, Meszoely IM, Van Poznak C, Babiera G, Norton L, Morrow M, Wolff AC, Winer EP, Hudis CA
Translational Breast Cancer Research Consortium
King TA. et al., ASCO 2016
TBCRC 013: Prospective Registry
• Characterize patients presenting with stage IV breast cancer in the modern era:– Response to first-line therapy– Proportion of patients who undergo surgery of
the primary tumor– Surgical decision-making process*
Presented by:
*Presented ASBrS 2016
King TA. et al., ASCO 2016
TBCRC 013: Prospective Registry
• Correlate molecular characteristics of the primary tumor with conventional prognostic factors, surgery and survival
• Determine the incidence of uncontrolled local disease and the frequency with which surgical palliation is needed
• Perform correlative molecular studies
Presented by: King TA. et al., ASCO 2016
TBCRC 013: Cohort A
• 112 pts with de novo Stage IV disease and intact primary
• 1st line systemic therapy per treating physician
• Responders to 1st line therapy offered opportunity to discuss elective surgery (absence of local symptoms or need for local control)
Presented by: King TA. et al., ASCO 2016
TBCRC 013 Cohort APatient Characteristics
Presented by:
Tumor Subtype
HR+HER2‐ 71 (63%)
HR+HER2+ 24 (21%)
HR‐HER2+ 9 (8%)
Triple Negative 8 (7%)
Site of Mets at dx
Bone Only 51 (46%)
Visceral Only 26 (23%)
Both 27 (24%)
Other 8 (7%)
# Met Sites at dx
Single Organ 64 (57%)
>1 Organ 48 (43%)
Median Patient Age: 51 yrs (21-77yrs)
Median Tumor Size: 3.2cm (0.8-15cm)
ECOG score 0: 56 (50%)1: 51 (46%)>1: 5 (4%)
King TA. et al., ASCO 2016
TBCRC 013 Cohort AOverall Survival
Presented by:
N=112
3yrs OS 70% (95%CI 63-79%)
Median Survival69 mos (51 – NR)
Median follow‐up 54 mos (34‐78mos)
King TA. et al., ASCO 2016
TBCRC 013 Cohort AResponse to 1st line therapy
Presented by:
N=112*
94 (85%)Responders (R)
17 (15%)Non‐Responders (NR)
*1 lost to f/u
• ER + was the only baseline difference between Responders (88%) and Non‐Responders (65%), p=0.02
King TA. et al., ASCO 2016
Survival: Responders vs Non-RespondersLandmark Analysis at 6 months
Presented by:
Non-responders (NR)
Responders (R)
N median survival, mos 30 mo survival (95%CI) P
R 90 65 mos (52‐NR) 78% (70‐87) < 0.001
NR 16 13 mos (9‐31) 24% (10‐55)
6 mos, surrogate for time to response assessment after 1stline therapy, per treating physician
King TA. et al., ASCO 2016
TBCRC 013: Surgical Uptake
Presented by:
N=112*
94 (85%)**responders
39 (43%) elective surgery
51 (57%) no surgery
17 (15%)non‐responders
* 1 lost to f/u** 4 lost to f/u
Median time to elective surgery 7 mos (3‐20mos)
King TA. et al., ASCO 2016
TBCRC 013 Cohort A Characteristics by Surgery
Presented by:
Surgery N=39
No SurgeryN=51
p
Median Age 49yrs (21-73) 52yrs (29-74) 0.17
Tumor Size 3.8cm (1.6-12) 3.2cm (0.8-15) 0.01
Tumor Subtype (ER+ vs other) 34 (87%) 46 (90%) 0.26
Site of Mets at Dx (bone vs other) 19 (49%) 22 (43%) 0.45
Single Organ Metastatic Disease 30 (77%) 21 (41%) 0.001
1st line chemotherapy 15 (39%) 9 (17%) 0.002
Race, marital status, employment status, income level, education and co-morbidities did not differ by use of surgery
King TA. et al., ASCO 2016
Multivariate Analysis: Survival
Presented by:
Stepwise Cox regression: includingage, size, ECOG, HR, Her2, tumor grade, response and surgery
N Median Survival, mos 30 mos survival (95%CI)
Non‐Responders 16 13 mos (9‐31) 24% (10‐55)
Responders, No Surgery (red) 51 65 mos (50‐NR) 76% (66‐89)
Responders, Surgery (green) 39 71 mos (46‐NR) 77% (65‐91)
King TA. et al., ASCO 2016
TBCRC 013: Palliative Surgery
Presented by:
N=112*
94 (85%)**responders
39 (43%) elective surgery
51 (57%) no
surgery
Palliative surgery 2 (4%)
17 (15%)non‐
responders
Palliative surgery 3 (18%)
* 1 lost to f/u** 4 lost to f/u
Median time to palliative surgery 17 mos (8-35 mos)
King TA. et al., ASCO 2016
TBCRC 013: Conclusions• In this prospective registry study, 3yr overall survival
among patients presenting with de novo stage IV disease is 70%
• The majority of patients (85%) responded to 1st line therapy and response was significantly associated with survival
• Among patients who respond to systemic therapy – the need for palliative surgery is uncommon– progression free survival is not negatively impacted
by surgery
Presented by: King TA. et al., ASCO 2016
• Until more RCT data become available showing improved outcomes with surgical resection of the primary, 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, BCS 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