AHN-JHU Breast Cancer Symposium Novel Local Regional Clinical Trials March 22, 2019 Thomas B. Julian, MD, FACS Associate Medical Director, Cancer Program Development, ANH Cancer Institute Background In patients with large operable BC, neoadjuvant chemotherapy (NC) down-stages involved axillary nodes in up to 40% of pts (even higher proportion in TNBC or HER-2 neu + tumors) With increasing use of NC, a commonly encountered clinical scenario involves patients who present with involved axillary nodes, receive neoadjuvant chemotherapy and are found to be pathologically node-negative at the time of definitive surgery Neoadjuvant Chemotherapy Benefit Page 1 1
Background For such patients, there is an active debate on the appropriate use (and extent) of loco-regional XRT after mastectomy or BCS On one hand, since these patients presented with known Can positive We Use axillary Tumor nodes they and are Nodal at high-risk for LRR Response and should to receive NC comprehensive in Order to XRT On the other hand, sterilization involved axillary Individualize the Use of L-R XRT? nodes by NC lowers the risk for LRR making the need for comprehensive XRT questionable The decision of whether to add XRT after mastectomy is further complicated by the desire for immediate reconstruction 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 Existing (albeit limited) information on rates and predictors of LRR in patients who receive NC suggests that node-positive patients who convert to node-negative with NC have low rates of LRR and can potentially be spared the addition of XRT Using Response to NC to Tailor XRT Use However, before such a strategy becomes the standard of care, RCT data are needed to demonstrate that the use of XRT would not significantly improve breast cancer recurrence If so, this will produce a major paradigm shift in the LR management of early-stage BC De-escalate radiation therapy Page 2 2
Radiation Toxicities Radiation Toxicities Lymphedema Radiation dermatitis Delayed wound healing Fibrosis Pulmonary pneumonitis NRG/NSABP B-51/RTOG 1304 A Randomized Phase III Clinical Trial Evaluating the Role of Post-mastectomy Chest Wall and Regional Nodal XRT and Post-lumpectomy Regional Nodal XRT in Patients with Documented Positive Axillary Nodes Before Neoadjuvant Chemotherapy Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy Protocol Co-Chairs: Protocol Officer: Behavioral and Health Outcomes Officer: Protocol Statistician: Behavioral and Health Outcomes Statistician: KEY STUDY PERSONNEL Terry Mamounas, MD, MPH (NSABP) Julia White, MD (RTOG) Thomas Julian, MD Patricia Ganz, MD Joseph Costantino, DrPH Hanna Bandos, PhD Page 3 3
NSABP B-51/RTOG 1304 Clinical T1-3N1M0 BC Axillary Nodal Involvement (FNA or Core) NC (+ Anti-HER-2 Therapy for HER-2 +) Negative Axillary Nodes at Surgery Stratification Type of Surgery (Mastectomy vs. Lumpectomy) ER-Status (+ vs. -), HER-2 Status (+ vs. -) pcr in Breast (yes vs. no) 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 Objectives Primary objective: To evaluate whether the addition of comprehensive XRT will significantly reduce breast cancer recurrence in patients who present with histologically positive axillary nodes but convert to histologically negative axillary nodes following neoadjuvant chemotherapy Objectives Secondary objectives: To evaluate whether the addition of comprehensive XRT will significantly:» Prolong overall survival» Reduce loco-regional recurrence» Reduce distant recurrence To compare patterns of postmastectomy reconstruction and the effect of XRT on cosmetic outcomes following post-mastectomy reconstruction To compare the effect of adding XRT on QOL in patients who receive postmastectomy reconstruction Page 4 4
Eligibility Eligible pts must fulfill all of the following criteria: Clinical T 1-3 N 1 M 0 BC at presentation Histologic confirmation of axillary nodal involvement by FNA or CNB Completed at least 8 weeks of NC with an anthracycline and/or taxane-based regimen (+ neoadjuvant anti-her-2 therapy for HER-2 + pts) At the time of surgery, all removed axillary nodes must be histologically free from cancer (SNB, SNB+AND, AND alone. SNB Minimum 2-3, Dual Tracer) Known ER/PR and HER-2 neu status from the original CNB before NC B-51: Protocol Status Protocol activation: 8-22-13 Study sample size: 1636 Total Accrual as of 2/22/2019: 1178 (72%) Average monthly accrual*: 26.7 Close to Accrual: Mid 2020 *Over past 6 months Active and Accruing U.S. Clinical Trials for Local Regional Therapy after Neoadjuvant Chemotherapy NCI Sister Studies 15 ALLIANCE A11202 Page 5 5
ALLIANCE A11202 Same patient population as in B-51 for locally advanced node positive patients but who remain node positive after neoadjuvant chemotherapy Objective is to de-escalate surgical effects Lymphedema Decreased arm mobility Numbness/parasthesia Outcomes Primary Outcome Measures : 1.Invasive breast cancer recurrence-free interval (IBC-RFI) [ Time Frame: Up to 5 years after completion of radiation therapy ] Secondary Outcome Measures : 1.Overall survival [ Time Frame: Up to 5 years after completion of radiation therapy ] 2.Ipsilateral/local/regional invasive breast cancer recurrence (ILR-REC) [ Time Frame: Up to 5 years after completion of radiation therapy ] Outcomes Other Outcome Measures 1.Development of arm lymphedema if there is a 10% increase in the volume of the ipsilateral arm from its pre-surgery volume [ Time Frame: Up to 5 years after completion of radiation therapy ] 2.Breast lymphedema (in BCT patients) [ Time Frame: Up to 5 years after completion of radiation therapy ] 3.Adequacy of radiation fields, dose delivered to supraclavicular and axillary nodes [ Time Frame: Up to 5 years after completion of radiation therapy ] 4.Residual cancer burden (RCB) [ Time Frame: Up to 5 years after completion of radiation therapy Page 6 6
Eligibility Female or male 18 years old T1-3, N1, M0 clinical stage Axillary FNA or core biopsy documenting nodal disease Invasive breast cancer ER, PR, Her2 testing on breast tumor core biopsy Completed at least 4 cycles of neoadjuvant chemo Her2 positive disease must have received anti-her2 therapy Negative axilla on physical exam after completion of neoadjuvant chemotherapy (NAC) clarified : no bulky adenopathy Surgery performed 56 days after NAC completion Clips in axillary lymph nodes Placement of a clip in the lymph node at diagnosis Allowed / Not required Localization of the clipped lymph node at diagnosis Allowed / Not required If clipped node is localized Evaluate if blue and/or radioactive if yes document and submit as SLN If not submit as localized lymph node and counts as a sentinel node in terms of protocol requirements If clipped node is not localized X-ray specimen to document whether clipped node is excised Surgical / Pathology aspects Breast tumor: Require negative margins (no tumor on ink) around breast primary Sentinel Nodes: Minimum of 1 LN with a metastasis with largest dimension > 0.2 mm identified on intra-operative pathologic assessment. Maximum of 6 LN resected by surgeon Maximum of 8 LN seen by pathologist ALND: Arm 1 pts minimum of 8 LNs for SLN +ALND Page 7 7
Opened: 2/7/2014 Accrual target: 1576 Accrual: 1466 (93%) NRG-BR005 A Phase II trial assessing the accuracy of tumor bed biopsies in predicting pathologic response in patients with clinical/radiologic complete response after neoadjuvant chemotherapy in order to explore the feasibility of breast conserving treatment without surgery Mark Basik, M.D. Jennifer De Los Santos, M.D. Heidi Umphrey, M.D. Background Use of neoadjuvant chemotherapy (NAC) has increased. Pts with HER2+ or triple negative (TN) disease have high pcr rates to NAC +/- trastuzumab compared with ER+ (22-66.7%) (Buzdar et al., JCO, 2005; Gianni et al., Lancet, 2010; Liedtke et al., JCO, 2008) Lower rates of LR in pcr patients (7% at 10 years) (Mamounas, JCO, 2012) pcr predicts excellent survival Page 8 8
Randomized Trial in Women with complete response after neoadjuvant systemic therapy BCS + RT RT alone Can we define a group who can safely be treated with primary chemo-radiotherapy by developing a tool highly predictive of pcr? MRI alone insufficient to identify this group (NPV~60% HER2+ and TN subsets) MRI alone is insufficient to identify a group that may safely omit surgery MRI accuracy for residual disease ~ 0.69-0.91 (De Los Santos et al., Cancer, ; Marinovich et al., JNCI, 2013) What is the additive value of tumor bed/clip biopsy? Will breast cancer patients accept a trial omitting surgery? Trimodality Imaging Results 23/83 (28%) had pcr Using a cut-point of < 5 Sensitivity: 0.95 Specificity: 0.87 NPV: 0.87 PPV: 0.95 Accuracy: 0.93 Meban score for pts with pcr: 4.61 (range 3-10); 3 pts scored > 5 Mean score for pts with residual disease was 7.73 (range 5-11) Page 9 9
NRG-BR005 SCHEMA Operable focal or multifocal T1-T3, stage II and IIIA invasive ductal carcinoma (all receptor phenotypes) Neoadjuvant Systemic Therapy Complete Clinical Response (ccr) Tri-modality Imaging Near-Complete Response REGISTRATION (QOL Questionnaire) Image-guided Core Biopsy of Residual tumor bed FINAL SURGERY (lumpectomy) (QOL Questionnaire) Primary Objective Assess accuracy of post-nst image-directed tumor bed biopsy for pcr (resolution of both invasive disease and DCIS), in cases of clinical and radiologic complete response with standard of care (SOC) imaging. Secondary Objectives Determine patient and physician acceptability of foregoing lumpectomy and assess whether acceptability is conditioned by demographic or personal factors. Collect axillary pathology results, surgical staging methods (SLNBx and/or ALND), and management (surgery and/or radiation) to determine axillary nodal response to NAC and relationship to breast pcr Correlate imaging results with pathologic nodal status following neoadjuvant chemotherapy for future planning of axillary management in the next study. Page 10 10
Secondary Objectives To retrospectively assess the NPV of a trimodality imaging algorithm in combination with the tumor bed biopsy for predicting pcr, and to determine which combination of SOC imaging best identifies the group achieving pcr. To correlate the number of needle cores and tumor bed clip retrieval with the NPV of the tumor site biopsy. To determine the clinical, pathologic, and molecular tumor factors associated with the highest NPVs of post-nst tumor bed biopsies. Patient Eligibility Operable focal or multifocal (T1-T3, stage II and IIIA invasive ductal carcinoma [all receptor phenotypes]) who have completed NAC with a clinical complete response (ccr by clinical examination). rcr or near complete response by SOC imaging (DCE-MRI, mammography and ultrasound post-chemo) Trimodality imaging required Biopsy marker placed within the tumor bed with image confirmation of marker placement. Patients who are undergoing breast conserving therapy. Imaging Criteria for Eligibility are defined under Ineligibility Criteria Patients with one or more of the following imaging criteria from any of the 3 imaging modalities after completion of NCT are not eligible: Mammogram with malignant appearing calcifications or mass > 1 cm; or Ultrasound with a hypoechoic area > 2 cm; or Breast MRI demonstrating a residual mass with rapid rise and washout type III kinetics. Page 11 11
Study Design 6-8 imaging-guided cores: 3 at/near marker and 3 at a 1 cm radial distance from the marker Marker removed and replaced Cores placed in formalin Surgery proceeds normally Evaluation of residual tumor burden (RCB) Sample size N=175 futility analysis at 77% accrual (135 out of 175) If no more than 18 positive biopsies were observed among the initial 27 patients who fail to achieve pcr at surgery (no more than 72.2%), the study would be terminated early Current Status Activated: April 2017 On hold to obtain extra funding for the biopsies June 2017 - funding obtained for biopsies Accrual: 82/175 (46.9%) Page 12 12
NRG-CC006 (NRG BR005 Companion Survey) A Phase II Trial Assessing the Accuracy of Tumor Bed Biopsies in Predicting Pathologic Response in Patients with Clinical/Radiologic Complete Response after Neoadjuvant Chemotherapy in Order to Explore the Feasibility of Breast Conserving Treatment without Surgery Protocol Chair Reshma Jagsi, M.D., DPhil Quality of Life Chair Patricia A. Ganz, M.D. Funding: DCP/NCORP Thank you Page 13 13