Neoadjuvant therapy for breast cancer: the Stoddard protocol Scott D. Hamling, MD General Surgeon The Iowa Clinic

Objectives Patient eligibility Patient eligibility Pretherapy evaluation Pretherapy evaluation Neoadjuvant systemic therapy (NAST) options Neoadjuvant systemic therapy (NAST) options Treatment response monitoring Treatment response monitoring Definitive surgical therapy Definitive surgical therapy Results Results The Stoddard protocol The Stoddard protocol

Multidisciplinary Team Approach

Cases 48yo, cT4d cN2 cM0, grade 3, IDC, -, -, +. 48yo, cT4d cN2 cM0, grade 3, IDC, -, -, +. 60yo, cT3 cN1 cM0, grade 2, ILC, +, +, -. 60yo, cT3 cN1 cM0, grade 2, ILC, +, +, -. 39yo, cT2 cN0 cM0, grade 2, IDC, -, -, +. 39yo, cT2 cN0 cM0, grade 2, IDC, -, -, yo, cT1c cN0 cM0, grade 3, IDC, -, -, yo, cT1c cN0 cM0, grade 3, IDC, -, -, yo, cT3 cN0 cM0, grade 1, IDC, +, +, yo, cT3 cN0 cM0, grade 1, IDC, +, +, -. Who would you offer NAST to? Who would you offer NAST to?

48yo, cT4d cN2 cM0, grade 3, IDC, ER-, PR-, Her 2+.

60yo, cT3 cN1 cM0, grade 2, ILC, ER+, PR+, Her 2-.

39yo, cT2 cN0 cM0, grade 2, IDC, ER-, PR-, Her 2 +.

37 yo, cT1c cN0 cM0, grade 3, IDC, ER-, PR-, Her 2-.

65 yo, cT2 cN0 cM0, grade 1, IDC, ER+, PR+, Her 2-.

NAST utilization: Stoddard registry results 2013: 15/52 (29%) patients with IBC/LABC were clearly documented as having been offered/given NAST 2013: 15/52 (29%) patients with IBC/LABC were clearly documented as having been offered/given NAST –Most patients went straight to mastectomy 2013: 1/14 (7.1%) patients had appropriate biospies, documented complete pretherapy staging, and routine image monitoring during NAST 2013: 1/14 (7.1%) patients had appropriate biospies, documented complete pretherapy staging, and routine image monitoring during NAST

NAST rational Systemic therapy intended to reduce the risk of distant disease recurrence Systemic therapy intended to reduce the risk of distant disease recurrence Improve surgical outcome when a primary surgical resection is not possible or the extent of resection is undersirable Improve surgical outcome when a primary surgical resection is not possible or the extent of resection is undersirable Allows in vivo treatment sensitivity assessment Allows in vivo treatment sensitivity assessment Novel research window Novel research window

Historical perspective Preoperative chemotherapy historically given to patients with inflammatory and noninflammatory unresectable LABC. Preoperative chemotherapy historically given to patients with inflammatory and noninflammatory unresectable LABC. To summarize large and muture literature, preoperative chemotherapy: (B-18, B-27) To summarize large and muture literature, preoperative chemotherapy: (B-18, B-27) –Capable of shrinking large primary tumors renduring many inoperable patients operable –Improves the survival of patients with IBC as part of multimodality therapy, compared to locoregional therapy alone –Equivalent survival in operable breast cancer, compared to adjuvant chemotherapy

Contemporary perspective Can NAST improve surgical outcomes in patients with operable breast cancer? Can NAST improve surgical outcomes in patients with operable breast cancer? –Increased rate of BCT –Decreased extent of axillary surgery Can NAST allow tailored therapy to avoid toxicities of ineffective therapy? Can NAST allow tailored therapy to avoid toxicities of ineffective therapy? –Biologic monitoring of new drugs –Neoadjuvant trials to avoid adjuvant trials Is NAST optimal for all patients? Is NAST optimal for all patients?

Patient eligibility Surgical eligibility Surgical eligibility –Unresectable disease: locally advanced breast cancer (LABC), inflammatory breast cancer (IBC) –Resectable disease: if BCT is not possible or cosmetic result is undesirable –Contraindication to surgery at the time of diagnosis: gestational breast cancer

Patient eligibility Tumor biology: NAST is most appropriate in patients predicted to have a good response Tumor biology: NAST is most appropriate in patients predicted to have a good response –Triple-negative breast cancer (TNBC) –Her 2 positive breast cancer

Tumor biology TNBC: TNBC: –Pathologic complete response rate with NAST 27-45%, compared to 10% for HR pos, Her 2 neg breast cancer (Carey, 2007) (Esserman, 2012) –Residual disease burden is predictive of early distant recurrence and lower overall survival (Liedtke, 2008)

Tumor biology Her 2 positive breast cancer Her 2 positive breast cancer –I-SPY 1 trial (2012): T > 3cm, looked at pCR and receptor status associations Relatively high pCR of 39% following treatment with neoadjuvant chemotherapy (NACT) in Her 2 pos patients, vs 18% for Her 2 neg patients. Relatively high pCR of 39% following treatment with neoadjuvant chemotherapy (NACT) in Her 2 pos patients, vs 18% for Her 2 neg patients. Relatively high pCR rate regardless of HR status Relatively high pCR rate regardless of HR status –HR pos, Her 2 pos: pCR of 33% –HR neg, Her 2 pos: pCR of 45% Significant increase in pCR to 60% in patients who also received adjuvant Her 2 directed therapy. Significant increase in pCR to 60% in patients who also received adjuvant Her 2 directed therapy. –TECHNO trial (2011): Her 2 + patients receiving NACT + traztusumab pCR rate was associated with improved disease free survival (DFS) and overall survival (OS) pCR rate was associated with improved disease free survival (DFS) and overall survival (OS)

Pretherapy evaluation Complete histopathologic diagnosis Complete histopathologic diagnosis Initial staging evaluation to rule out distant metastatic disease Initial staging evaluation to rule out distant metastatic disease Primary tumor evaluation Primary tumor evaluation Nodal evaluation Nodal evaluation

Diagnosis Pathologic evaluation Pathologic evaluation –Comprehensive histopathologic confirmation –Hormone receptor status (ER/PR) –Human epidermal growth factor receptor 2 status (Her 2)

Complete clinical staging Comprehensive clinical staging prior to NAST, as surgical pathologic stage in expected to be altered Comprehensive clinical staging prior to NAST, as surgical pathologic stage in expected to be altered –Exam –Regional imaging and biopsies –May include systemic scans to detect occult distant disease, which would alter surgical planning

Primary tumor evaluation Requires accurate radiopaque clip placement to mark the tumor location Requires accurate radiopaque clip placement to mark the tumor location Tumor size documentation Tumor size documentation –Exam –Imaging Mammogram Mammogram US US MRI MRI

Nodal evaluation Negative axillary exam Negative axillary exam –Axillary US with core needle biopsy (including clip placement) of suspicious nodes detected during imaging –SLN bx pretherapy although posttherapy N stage has greater prognostic significance although posttherapy N stage has greater prognostic significance

Nodal evaluation Positive axillary exam Positive axillary exam –US core biopsy preferred –Palpation FNA/core biopsy Consider SLN bx if discordant pathologic and clinical results Consider SLN bx if discordant pathologic and clinical results –Clip placement is advised (esp if posttherapy SLN bx is planned)

NAST Options Options –Neoadjuvant chemotherapy (NACT) –NACT with the incorporation of biologic therapy (NACT + Her 2 directed therapy) –Neoadjuvant hormonal therapy (NAHT) Limited data regarding the use of NAHT compared to NACT Limited data regarding the use of NAHT compared to NACT NACT generally offered preferentially NACT generally offered preferentially –Recommendations based on tumor biology

NACT Patients receiving NACT have a statistically higher likelihood of undergoing cosmetically desirable surgery (B-18, 27) Patients receiving NACT have a statistically higher likelihood of undergoing cosmetically desirable surgery (B-18, 27) DFS and OS are equivalent, compared to adjuvant systemic chemotherapy (B-18, 27) DFS and OS are equivalent, compared to adjuvant systemic chemotherapy (B-18, 27) –However, patients with a pCR at surgery have a significant improvement in both DFS and OS, compared to those with residual invasive disease

NACT Regimen: Regimen: –Choice of systemic therapy is based on tumor biology with similar efficacy expected to that seen in the adjuvant setting. Timing: Timing: –Since downstaging is the primary goal of NAST, all planned NACT should be administered prior to surgery. Provided no evidence of disease progression Provided no evidence of disease progression

NACT Anthracycline-taxane based regimens: Anthracycline-taxane based regimens: –Multiple studies have demonstrated increased response rates in the neoadjuvant setting, compared with non-taxane-containing regimen (ex. NSABP B-27) –ACT –TC if contraindication to anthracycline –May see carboplatin added to TNBC: (GeparSixto, CALGB 40603, I-SPY 2)

NACT + Her 2 directed therapy Patients with Her 2 pos cancers have a relatively high rate of pCR with NACT (I- SPY 1) Patients with Her 2 pos cancers have a relatively high rate of pCR with NACT (I- SPY 1) pCR increases with the addition of Her 2 directed therapy, esp if HR neg (I-SPY 2) pCR increases with the addition of Her 2 directed therapy, esp if HR neg (I-SPY 2) pCR after NACT plus Her 2 directed therapy is assoc. with recurrence and survival advantages (TECHNO) pCR after NACT plus Her 2 directed therapy is assoc. with recurrence and survival advantages (TECHNO)

NACT + trastuzumab Benefit of adding Her 2 directed therapy (NOAH trial): Benefit of adding Her 2 directed therapy (NOAH trial): –Improvement in pCR rate to 43% vs 20% –Reduction in relapse rate to 26% vs 39% –Trend to lower mortality rate of 13% vs 20% –Increased benefit in both event free survival and overall survival at 5 years compared to NACT alone.

NACT + trastuzumab + pertuzumab Pertuzumab (Perjeta) Pertuzumab (Perjeta) –Monoclonal antibody that inhibits the dimerization of Her 2 with other Her receptors –Designed to overcome trastuzumab resistance caused by the formation of Her 2:Her 3 heterodimers. –NeoSphere and TRYPHAENA trials: Increased pCR with addition of pertuzumab to trastuzumab Increased pCR with addition of pertuzumab to trastuzumab

Neoadjuvant hormonal therapy Limited data in premenopausal women Limited data in premenopausal women Often restricted to postmenopausal patients not fit to receive or refuse NACT Often restricted to postmenopausal patients not fit to receive or refuse NACT Comparing NACT and NAHT(AI) in postmenopausal stage II-III HR pos cancer (Semiglazov et al, 2007): Comparing NACT and NAHT(AI) in postmenopausal stage II-III HR pos cancer (Semiglazov et al, 2007): –No differences in response rates –Similar median time to observed response (57 vs 51 days) –Similar pCR (3 vs 6%) –Increased BCT rate with AI (33%) vs NACT (24%)

GEICAM study –Randomized HR + cancers to NACT vs 24 weeks of exemestane (plus luteinizing- hormone-releasing hormone analog goserelin every 4 weeks in premenopausal patients) NACT patients had higher clinical response (66 vs 48%) NACT patients had higher clinical response (66 vs 48%) pCR in 3 NACT patients, no pCR in NAHT pCR in 3 NACT patients, no pCR in NAHT Higher rate of BCT with NAHT (56 vs 47%) Higher rate of BCT with NAHT (56 vs 47%) Lower grade 3 and 4 toxicities with NAHT (9 vs 47%) Lower grade 3 and 4 toxicities with NAHT (9 vs 47%)

NAHT drug of choice Postmenopausal patients: AI > TAM Postmenopausal patients: AI > TAM –Letrozole vs tam: significantly higher overall response rate (55 vs 36%) and BCT rate (45 vs 35%) (Ellis, 2007) –PROACT study (Cataliotti, 2006): anastrozole vs tam; no significant difference in overall response rate (40 vs 35%), improved surgical option rate (43% vs 31%) No preferred AI : (ACOSOG) Z1031 trial No preferred AI : (ACOSOG) Z1031 trial –Exemestane, letrozole, anastrozole

Duration of NAHT Should be individualized to patients Should be individualized to patients Response to therapy may not be evident for 3 to 4 months and maximal response may take longer Response to therapy may not be evident for 3 to 4 months and maximal response may take longer –Strobel et al (2008) found 62% response rate by 4 months with AI for T2 or larger tumors Monitoring response to therapy to guide surgical timing Monitoring response to therapy to guide surgical timing

Treatment response monitoring No formal guidelines exist No formal guidelines exist NACT patients: exam prior to each cycle of treatment NACT patients: exam prior to each cycle of treatment NAHT patients: exam every 4-8 weeks NAHT patients: exam every 4-8 weeks Imaging: Imaging: –Midpoint of NAST and surgical scheduling –If disease progression suspected –MRI vs US depending on tumor and surgical plan

Tumor monitoring MRI: (Yuan, 2010) MRI: (Yuan, 2010) –highest specificity (91%) to predict pCR, sensitivity low (63%) –Sensitivity hampered by DCIS findings Chagpar, 2006: Chagpar, 2006: –Accuracy of exam 66%, mammo 70%, US 75%

Response monitoring Correlation between tumor measurements by PE, imaging, and final pathology are modest at best Correlation between tumor measurements by PE, imaging, and final pathology are modest at best Lack of concordance likely due to variable patterns of tumor response Lack of concordance likely due to variable patterns of tumor response –Symmetric shrinkage around a residual fibrotic scar vs residual cancer core –Complete mass resolution despite the persistence of microscopic foci

Surgical treatment Breast surgery Breast surgery –Indications for surgical approach are similar to patients who did not undergo NAST –Definitive surgery should take place as soon as the patient has recovered from NAST toxicities (3-6 week window) –NAHT patients do not need to cease treatment prior to surgery

Surgical treatment Nodal evaluation following NAST: Nodal evaluation following NAST: –Clinically negative (cN0): outside of trial, sln bx may be done prior to or after NAST. If neg, no further axillary evaluation is required. –Clinically positive (cN1/pN1): If remain clinically positive: ALND If remain clinically positive: ALND If convert to clinically negative: If convert to clinically negative: –ALND –Posttherapy sln bx if dual tracer used, at least two nodes are recovered, and removal of prior biopsied node confirmed by image confirmation of clip

SENTINA trial (2013) cN0 baseline: pre-NACT sln bx cN0 baseline: pre-NACT sln bx –pN0: no further axillary eval –pN1: post-NACT sln bx + ALND cN1 baseline: no pre-NACT bx cN1 baseline: no pre-NACT bx –cN0 post-NACT: sln bx + ALND –cN1 post-NACT: ALND

SENTINA trial (2013) Results: Results: –In those who underwent a post-NACT sln bx and ALND, patients who started out cN1 had a higher sentinel node detection rate (80 vs 61%) and a lower FN rate (14 vs 52%) compared to those who started out pN1 based on pre-NACT sln bx. Pre-NACT sln bx decreases success and accuracy of post-NACT sln bx. Pre-NACT sln bx decreases success and accuracy of post-NACT sln bx. NACT may adversely impact success of sln bx. NACT may adversely impact success of sln bx.

ACOSOG Z1071 trial (2012) Patients with cN1 disease at diagnosis underwent sln bx and ALND after NACT. Patients with cN1 disease at diagnosis underwent sln bx and ALND after NACT. Main results: Main results: –Sln detection rate was 93% –41% of cN1 patients converted to pN0 after NACT –FN rate in cN1 patients with at least 2 sln recovered was 12.6% and dropped to 9.1% for 3 sln. –FN rate lower with dual vs single agents (10.8 vs 20.3%) –Confirmed findings NSABP B-27 (dual agent) and B- 32 (FN rate decreases with more sln recovered)

Adjuvant therapy Radiation therapy: XRT recommendation typically based upon pretherapy clinical staging Radiation therapy: XRT recommendation typically based upon pretherapy clinical staging –BCT patients –LABC and IBC patients s/p mastectomy –Patients with post-NAST residual nodal disease

NSABP B-51 trial –Randomized phase III clinical trial evaluating post-mastectomy chestwall and regional nodal XRT and post-lumpectomy regional nodal XRT in patients with positive axillary nodes before NACT who convert pathologically to pN0 after NACT.

Adjuvant therapy Adjuvant chemotherapy Adjuvant chemotherapy –Typically not administer adjuvant chemo tx –May consider adjuvant chemo tx if: Residual TNBC is present and their NACT did not include both an anthracycline and a taxane. Residual TNBC is present and their NACT did not include both an anthracycline and a taxane. Patient treated with NAHT and is eligible for chemo tx. Patient treated with NAHT and is eligible for chemo tx. Patient did not complete planned NACT course. Patient did not complete planned NACT course.

Adjuvant therapy Her 2 directed therapy: Her 2 directed therapy: –Resumption of trastuzumab to complete full year course –Initiation of trastuzumab if not part of their NAST regimen Endocrine therapy: Endocrine therapy: –Recommended in HR positive patients following locoregional treatment

Results CTNeoBC (2012) CTNeoBC (2012) –Patients with pCR had significant improvement in EFS and OS –The pCR rate varied by breast cancer subtype HR +, Her 2 -, grade 1-2: 7% HR +, Her 2 -, grade 1-2: 7% HR +, Her 2 -, grade 3: 16% HR +, Her 2 -, grade 3: 16% HR +, Her 2 + (NACT + trastuzumab): 30% HR +, Her 2 + (NACT + trastuzumab): 30% HR -, Her 2 -: 34 % HR -, Her 2 -: 34 % HR -, Her 2 + (NACT + trastuzumab): 50% HR -, Her 2 + (NACT + trastuzumab): 50%

Working towards a central goal

The Stoddard Neoadjuvant Protocol Neoadjuvant therapy indications Neoadjuvant therapy indications –Absolute: Inflammatory breast cancer Inflammatory breast cancer Locally advanced T3/T4 tumors, particularly if Her 2 positive Locally advanced T3/T4 tumors, particularly if Her 2 positive –Relative: Patients younger than 40 with tumors larger than 2 cm regardless of nodal status Patients younger than 40 with tumors larger than 2 cm regardless of nodal status Her 2 + (T2 or N1) to allow use of pertuzumab Her 2 + (T2 or N1) to allow use of pertuzumab Stage II tumors not qualifying for de novo BCT Stage II tumors not qualifying for de novo BCT N2/N3 disease, esp if hormone negative N2/N3 disease, esp if hormone negative

The Stoddard Neoadjuvant Protocol Prior to starting neoadjuvant therapy: Prior to starting neoadjuvant therapy: –Clinically suspicious breast and nodal abnormalities should be biopsied and marked with radiopaque clips. –Clinical and pathological staging should be completed prior to starting therapy.

The Stoddard Neoadjuvant Protocol Imaging during NAST: Imaging during NAST: –Imaging at midpoint in therapy to assess response. Exact timing will depend on regimen and treating physicians. –For women with baseline US clearly demonstrating the tumor prior to NAST and choosing mastectomy, repeat US utilized to monitor response. –For women planning BCT after NAST, pre and post- NAST MRI should be used to assess extent of resection.

Cases 48yo, cT4d cN0 cM0, grade 3, IDC, +, -, +. 48yo, cT4d cN0 cM0, grade 3, IDC, +, -, +. 60yo, cT3 cN1 cM0, grade 2, ILC, +, +, -. 60yo, cT3 cN1 cM0, grade 2, ILC, +, +, -. 39yo, cT2 cN0 cM0, grade 2, IDC, -, -, +. 39yo, cT2 cN0 cM0, grade 2, IDC, -, -, yo, cT1c cN0 cM0, grade 3, IDC, -, -, yo, cT1c cN0 cM0, grade 3, IDC, -, -, yo, cT2 cN0 cM0, grade 1, IDC, +, +, yo, cT2 cN0 cM0, grade 1, IDC, +, +, -. Who would you offer NAST to? Who would you offer NAST to?

Summary All patients who are candidates for systemic therapy are candidates for NAST All patients who are candidates for systemic therapy are candidates for NAST If the indication for systemic therapy is uncertain, then surgical therapy should be completed first If the indication for systemic therapy is uncertain, then surgical therapy should be completed first NAST should be tailored to the biologic profile of the tumor NAST should be tailored to the biologic profile of the tumor Primary tumor and nodes must be measurable and monitored Primary tumor and nodes must be measurable and monitored A multidisciplinary team approach must be available A multidisciplinary team approach must be available