1 Loco-Regional Management After Neoadjuvant Chemotherapy 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
Clinical Rationale for Neoadjuvant Chemotherapy 2 Neoadjuvant chemotherapy is the standard of care for patients with LABC and a reasonable alternative to adjuvant chemotherapy for those with large operable disease Several RCTs have shown no differences in outcome between neoadjuvant and adjuvant chemotherapy Achievement of pathologic complete response (pcr) correlates with excellent long-term outcome
Neoadjuvant Chemotherapy for Operable BC Loco-Regional Endpoints High clinical response rates (>90%) Increasing pathologic complete response rates: 10-15% with anthracyclines 25-30% with anthracyclines/taxanes 40-50% with chemo + trastuzumab in HER-2 (+) 50-60% with chemo + two anti-her agents Decrease in the rates of axillary positivity 30% with anthracyclines Up to 40% with anthracyclines/taxanes Probably > 50% with chemo + anti-her-2 therapies
Unique LR Management Issues in Patients Treated with Neoadjuvant Chemotherapy 4 Accurate assessment of the location and extent of the primary breast tumor before and after NC Accurate assessment of axillary nodal status before and after NC Appropriate surgical management of primary breast tumor and axillary lymph nodes Optimal use of radiotherapy following NC
How Can We Maximize the Clinical Impact of Neoadjuvant Chemotherapy? Develop more effective regimens that will further decrease rates of local and distant recurrence Use primary tumor/nodal response as a surrogate endpoint for long-term outcome (potential pathway for new drug approval) Identify better predictors of pcr : Baseline biomarkers Early changes in biomarkers with treatment Use primary tumor response as a guide for tailoring loco-regional and systemic therapy
Using Clinical and Pathologic Response to NC to Tailor Further Loco-Regional Treatment
Individualizing Loco-Regional Therapy with Neoadjuvant Chemotherapy Past Achievements Conversion of patients with inoperable tumors to operable candidates Conversion of mastectomy candidates to candidates for breast conserving surgery Improvement in cosmesis by reducing the size of lumpectomy in breast conserving surgery candidates with large tumors
Individualizing Loco-Regional Therapy with Neoadjuvant Chemotherapy Future Promises Reduction in the extent of axillary surgery by down-staging involved axillary nodes (SNB) Reduction in the extent of loco-regional XRT by down-staging primary tumors and axillary nodes Potential for eliminating some loco-regional therapy altogether (surgery or XRT) with use of more active regimens and/or appropriate patient selection (imaging/biomarkers)
Management of the Primary Breast Tumor
Challenges in Decreasing the Size of the Lumpectomy Specimen 10 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
How Do Tumors Shrink in Response to Neoadjuvant Chemotherapy? 11
What is Adequate Surgical Resection after Neoadjuvant Chemotherapy? 12
MRI Phenotypes 13 1 2 3 4 5 1: Single predominant mass with identifiable rim, displacing 2: Nodular pattern, irregular borders 3: Diffuse infiltrative pattern 4: Patchy enhancement 5: Septal spread Esserman L, et al:. Ann Surg Oncol 2001
MRI Can Overestimate the Amount of Residual Disease 14 Before Neoadjuvant Chemo After Neoadjuvant Chemo
Neoadjuvant Chemotherapy Surgical Planning Identification of the exact tumor location in cases of clinical and radiologic complete response Preoperative titanium clip placement 15 Before NC After NC
Ensuring Adequate Surgical Resection after Neoadjuvant Chemotherapy 16 Identify pattern of shrinkage and extent of residual tumor preoperatively (mammogram, US, MRI) Accurately localize tumor bed area in cases of clinical/radiologic complete response Thoroughly evaluate margins (intraoperatively and postoperatively) Perform additional resection if necessary
Local Recurrence with Neoadjuvant vs. Adjuvant Chemotherapy
NSABP B-18 Cumulative Incidence of In-Breast Recurrence 40 % 30 20 10 Postop: 7.6 % Preop: 10.7 % P = 0.12 0 YEAR 1 2 3 4 5 6 7 8 9 Wolmark N, et al: JNCI Monogr 2001
EBCTCG 2006 Overview Analysis: Neoadjuvant vs. Adjuvant Chemotherapy Local Recurrence All patients had surgery in the adjuvant chemo group Not all patients had surgery after neoadjuvant chemotherapy
Neoadjuvant Versus Adjuvant Systemic Treatment in Breast Cancer: A Meta-Analysis Loco-regional Recurrence Avril/Mauriac Danforth Gazet Makris NSABP B-18 Scholl Scholl/Broet Semiglazov Van der Hage ALL RR 1.22 p=0.015 Studies of XRT without Surgery: - RR 1.53 - p=0.009 Studies of Surgery + XRT: - RR 1.10 - p=0.44 Risk Ratio (95% CI) for Neoadjuvant vs. Adjuvant Treatment Mauri D. et al: J Natl Ca Inst 2005; 97:188-94
Tailoring Loco-Regional XRT with Neoadjuvant Chemotherapy
Rates and Predictors of LRR in the Adjuvant and Neoadjuvant Settings For pts with ESBC who receive surgery first there is abundant information on rates and predictors of LRR with or without adjuvant systemic therapy There is limited information on rates and predictors of LRR in patients who receive neoadjuvant chemotherapy
Limited Information on Rates and Predictors of LRR after NC Fewer patients with operable breast cancer are being treated with neo- vs. adjuvant chemo By the time NC became established as an alternative to adjuvant chemo, the role of LRR XRT in node+ BC was well established Thus, most available NC databases include patients who, at the discretion of the treating physician, were treated with postoperative XRT (either because of path + nodes at surgery or because of presumed node + status before NC)
NSABP B-18/B-27: Combined Analysis 24 B-18 B-27 Operable Breast Cancer Operable Breast Cancer R R Surgery AC x 4 AC x 4 AC x 4 AC x 4 AC x 4 Surgery Surgery Docetaxel x 4 Surgery Surgery Docetaxel x 4 3,088 Patients 356 LRR as First Events Mamounas EP et al: J Clin Oncol, 2012
NSABP B-18/B-27: Combined Analysis Independent Predictors of LRF 25 Lumpectomy + XRT (1890 Pts, 190 Events) Age (>50 years vs. <50 years) Clinical Nodal Status (+) vs. (-) Breast/Nodal Path Status Node(-)/No pcr vs. Node(-)/pCR Node(+) vs. Node(-) /pcr Mastectomy (1070 Pts, 128 Events) Clinical Tumor Size (>5 cm vs. <5 cm) Clinical Nodal Status (+) vs. (-) Breast/Nodal Path Status Node(-)/No pcr vs. Node(-)/pCR Node(+) vs. Node(-) /pcr Mamounas EP et al: J Clin Oncol, 2012
Nomogram for Prediction of 10-Year Rate of LRR After NC: Lumpectomy + XRT 26 Clin N (+) Clin N (-) pn+ pn0/no pcr Br pn+ pn0/pcr Br pn0/no pcr Br pn0/pcr Br Mamounas EP et al: J Clin Oncol, 2012
Nomogram for Prediction of 10-Year Rate of LRR After NC: Mastectomy 27 Clin N (-) Clin N (+) pn+ pn+ pn0/no pcr Br pn0/no pcr Br pn0/pcr Br pn0/pcr Br Mamounas EP et al: J Clin Oncol, 2012
Using Neoadjuvant Chemotherapy in Order to Tailor XRT These results indicate that node-positive patients at presentation (candidates for comprehensive XRT) who become pathologically node-negative after NC have low rates of LRR without XRT after mastectomy or breast XRT after lumpectomy and may not need additional XRT However, before such a strategy becomes the standard of care, randomized clinical trial data are needed to demonstrate that the use of XRT would not significantly improve breast cancer recurrence
NSABP B-51/RTOG 1304 (NRG 9353): Schema Clinical T1-3N1M0 BC Axillary Node (+) (FNA or Core Needle Biopsy) Neoadjuvant Chemo (+ Anti-HER-2 Therapy for HER-2 neu + Pts) Path Negative Axillary Nodes at Surgery (Axillary Dissection or SNB + Axillary Dissection) Randomization No Regional Nodal XRT with Breast XRT if BCS and No Chest Wall XRT if Mastectomy Regional Nodal XRT with Breast XRT if BCS and Chest Wall XRT if Mastectomy
Conclusions In pts with operable BC, neoadjuvant chemotherapy has several potential clinical advantages Information on outcome based on tumor response can be obtained on an individualized basis Loco-regional therapy can be tailored based on tumor response in the breast and axillary nodes This approach holds great promise as new neoadjuvant chemotherapy regimens (+ targeted biologics) become considerably more effective and as genomic and imaging technology allows for more accurate prediction and identification of pathologic complete responders