Boughey, Judy C.

Abstract Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR). Cemiplimab (Cemi) is a PD-1 inhibitor approved for the treatment of NSCLC, cutaneous basal, and squamous cell cancer. Here, we report current efficacy rates of Cemi in combination with paclitaxel followed by AC. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment; HR positive (HR+) patients had to be MP high risk. Treatment included paclitaxel 80 mg/m2 IV weekly x 12 and Cemi 350 mg IV given q3weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. All patients undergo serial MRI imaging; and imaging response (at 3 weeks, 12 weeks and prior to surgery) were used along with accumulating pCR data to continuously update and estimate pCR rates for trial arms. Analysis was modified intent to treat. Patients who switched to non-protocol therapy count as non-pCR. The goal is to identify (graduate) regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 neoadjuvant trial with a pCR endpoint within responsive signatures. Cemi was eligible to graduate in 3 pre-defined signatures: HER2-, HR-HER2-, and HR+HER2-. To adapt to changing standard of care, we constructed “dynamic controls” comprising ‘best’ alternative therapies using I-SPY 2 and external data and estimated the probability of Cemi being superior to the dynamic control. Results: 60 HER2- patients (28 HR+ and 32 HR-) received Cemi arm treatment. The control group included 357 patients with HER2- tumors (201 HR+ and 156 HR-) enrolled since March 2010. Cemi graduated in HR-/HER2- signature. Estimated pCR rates (as of June 2022) are summarized in the table. Immune-related endocrine disorders include: hypothyroid (14.5%), adrenal insufficiency (10%), hyperthyroid (4.8%),) and thyroiditis (3.2%). Only one grade 3 adrenal insufficiency was observed. All immune related AE’s were manageable. Additional biomarker analyses are ongoing and will be presented at the meeting. Response predictive subtypes (Immune+ vs Immune-) and additional predictive biomarkers were assessed. Associations with pCR will be presented at SABCS. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial. Anti-PD-1 therapy with Cemi resulted in a higher predicted pCR rate in HR-/HER2- 55 rate% disease compared to control at 29%. Immune-mediated AE’s were observed. This data is consistent with previously published data using check point inhibitors in early-stage HR-/HER2- breast cancer. Estimated pCR rates Citation Format: Erica Stringer-Reasor, Rebecca A. Shatsky, Jo Chien, Anne Wallace, Judy C. Boughey, Kathy S. Albain, Hyo S. Han, Rita Nanda, Claudine Isaacs, Kevin Kalinsky, Zahi Mitri, Amy S. Clark, Christos Vaklavas, Alexandra Thomas, Meghna S. Trivedi, Janice Lu, Smita Asare, Ruixiao Lu, Maria Pitsouni, Amy Wilson, Jane Perlmutter, Hope Rugo, Richard Schwab, W. Fraser Symmans, Nola M. Hylton, Laura Van ’t Veer, Douglas Yee, Angela DeMichele, Donald Berry, Laura J. Esserman, I-SPY Investigators. PD11-01 Evaluation of the PD-1 Inhibitor Cemiplimab in early-stage, high-risk HER2-negative breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-01.

Abstract Background: The role of chemotherapy in node positive (N+) luminal breast cancer (BC) is often debated, given low total pathologic complete response (pCR) rates following neoadjuvant chemotherapy (NAC) and discrepancy in adjuvant chemotherapy benefit. A prior single institution study of cN+ luminal BC showed that pts age < 50 and tumor Ki-67 ≥ 20% had high nodal pCR (> 35%). This study’s goals were 1) to validate Ki-67 and age in relation to nodal pCR and 2) evaluate the prognostic impact of nodal pCR on overall survival (OS). Methods: We queried the National Cancer Database 2010-2019 for pts with cN+ ER+/HER2- BC treated with NAC and surgery. Breast pCR was defined as ypT0/ypTis and nodal pCR as ypN0/ypN0i+. Ki-67 was available in 2018 & 2019 only and was used to evaluate Ki-67 and nodal pCR. 2010-2018 data were used to evaluate nodal pCR and OS. OS was analyzed using multivariable Cox proportional hazards regression. Results: In 2018-2019, 4,801 pts were identified and 2,473 (51.5%) had Ki-67 available. Nodal pCR was 23.7% and was higher in pts < 50 years old (28.1% vs 21.1%) and in those with Ki67 ≥ 20% (28.4% vs 12.7%), both p < 0.001. Pts < 50 with Ki67 ≥ 20% had the highest nodal pCR at 31.7%, followed by age ≥ 50 with Ki67 ≥ 20% at 26.3%. With Ki67 < 20%, nodal pCR was 15.4% (in age < 50) and 11.3% (in age ≥ 50). From 2010-2018, we identified 20,084 cN+ ER+/HER2- BC pts treated with NAC. Total pCR was 7.4%, 14.3% had nodal pCR only, 3.8% had breast pCR only, and 74.5% had residual disease in breast and nodes. OS at 5 years was 79.1% and varied by NAC response: 90.8% with total pCR, 83.8% with nodal pCR only, 80.7% with breast pCR only, and 76.9% with residual disease in breast and nodes. Specifically nodal pCR (with or without breast pCR) was seen in 22.0% and was associated with 5-year OS rate of 86.4% compared to 77.1% without nodal pCR, p < 0.001. On multivariable analysis adjusted for other clinical and treatment factors, nodal pCR was associated with better OS (adjusted HR 0.56, 95% CI: 0.50-0.61, p < 0.001) in all ages combined and within both the age < 50 and age ≥ 50 subgroups (see Table). In a subgroup of pts approximating RxPonder entry criteria (defined as cT1-3, N1, Grade I or II, ER+/PR+), results were consistent with the overall cohort: nodal pCR varied by both age (17.5% in age < 50 and 13.6% in age ≥ 50, p < 0.001) and by Ki67 ≥ 20% vs < 20% (16.8% vs 7.9%, p < 0.001) and nodal pCR remained prognostic for OS with adjusted HR 0.63 (95% CI: 0.50-0.81, p < 0.001). Conclusion: In cN+ ER+/HER2- BC treated with NAC, nodal pCR is more common in pts< 50 and those with high Ki-67 and is highly prognostic for OS. These data strongly suggest that NAC chemotherapy benefit should not be evaluated using total pCR rates in isolation, but for N+ pts to also consider nodal response. Given that nodal pCR is highly prognostic for OS, future neoadjuvant strategies should consider nodal pCR as a potential intermediate biomarker for long term survival. Multivariable analysis of factors associated with overall survival, including the adjusted effect of nodal pCR Citation Format: Dan Moldoveanu, Matthew P. Goetz, Tanya L. Hoskin, Courtney N. Day, Judy C. Boughey. Age, Ki-67, Nodal pCR and overall survival following Neoadjuvant Chemotherapy for Node Positive ER+/Her2- Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-22.

Abstract Background: Triple-negative breast cancers (TNBC) exhibit high rates of recurrence and mortality. However, recent studies suggest that a subset of patients (pts) with early-stage TNBC enriched in tumor-infiltrating lymphocytes (TILs) have excellent clinical outcomes even in the absence of systemic therapy. Additional histological biomarkers that could identify pts for future systemic therapy escalation/de-escalation strategies are of great interest. TNBC are frequently highly proliferative with abundant mitoses. However, classic markers of proliferation (manual mitosis counting and Ki-67) appear to offer no prognostic value. Here, we evaluated the prognostic effects of automated mitotic spindle hotspot (AMSH) counting on RFS in independent cohorts of systemically untreated early-stage TNBC. Methods: AMSH counting was conducted with a state-of-the-art deep learning algorithm trained on the detection of mitoses within 2 mm2 areas with the highest mitotic density (i.e. hotspots) in digital H&E images. Details of the development, training and validation of the algorithm were published previously [1] in a cohort of unselected TNBC. We obtained AMSH counts in a centrally confirmed TNBC cohort from Mayo Clinic [2] and focused our analysis on pts who received locoregional therapy but no systemic therapy. Using a fractional polynomial analysis with a multivariable proportional hazards regression model, we confirmed the assumption of linearity in the log hazard for the continuous variable AMSH and evaluated whether AMSH counts were prognostic of RFS. We corroborated our findings in an independent cohort of systemically untreated TNBC pts from the Radboud University Medical Center in the Netherlands (Radboud Cohort). Results are reported at a median follow-up of 8.1 and 6.7 years for the Mayo and Netherlands cohorts, respectively. Results: Among 182 pts with who did not receive systemic therapy in the Mayo Cohort, 140 (77%) with available AMSH counts were included. The mean age was 61 (range: 31-94), 71% were postmenopausal, 67% had tumors ≤ 2cm, and 83% were node-negative. As expected, most tumors were Nottingham grade 3 (84%) and had a high Ki-67 proliferation index (54% with Ki-67 >30%). Most tumors (73%) had stromal TILs ≤ 30%. The median AMSH count was 18 (IQR: 8, 42). AMSH counts were linearly associated with grade and tumor size, with the proportion of pts with grade 3 tumors and size > 2 cm increasing as the AMSH counts increased (p=0.007 and p=0.059, respectively). In a multivariate model controlling for nodal status, tumor size, and stromal TILs, AMSH counts were independently associated with RFS (p< 0.0001). For every 10-point increase in the AMSH count, we observed a 17% increase in the risk of experiencing an RFS event (HR 1.17, 95% CI 1.08-1.26). We corroborated our findings in the Radboud Cohort (n=126). The mean age was 68 (range: 40-96), and 81% were node-negative. While the median AMSH count was 36 (IQR: 16-63), higher than in the Mayo Cohort (p=0.004), the prognostic impact was similar, with a significant association between AMSH count and RFS (p=0.028) in a multivariate model corrected for nodal status, tumor size, and stromal TILs. For every 10-point increase in the AMSH count in the Netherlands cohort, we observed a 9% increase in the risk of experiencing an RFS event (HR 1.09, 95% CI 1.01-1.17). RFS rates according to AMSH counts for both cohorts are shown in the Table. Conclusions: AMSH counting is a new proliferation biomarker that provides prognostic value independent of nodal status, tumor size, and stromal TILs in systemically untreated early-stage TNBC. Plans are underway to evaluate AMSH counts in additional cohorts of systemically untreated TNBC, and in other disease settings such as prior to neoadjuvant systemic therapy. If validated, this biomarker should be prospectively evaluated as a potential selection biomarker in clinical trials of systemic therapy de-escalation. References: 1. PMID: 29994086 2. PMID: 28913760 Table RFS according to AMSH counts in the Mayo and Radboud Cohorts Citation Format: Roberto A. Leon-Ferre, Jodi M. Carter, David Zahrieh, Jason P. Sinnwell, Roberto Salgado, Vera Suman, David Hillman, Judy C. Boughey, Krishna R. Kalari, Fergus J. Couch, James N. Ingle, Maschenka Balkenkohl, Francesco Ciompi, Jeroen van der Laak, Matthew P. Goetz. Mitotic spindle hotspot counting using deep learning networks is highly associated with clinical outcomes in patients with early-stage triple-negative breast cancer who did not receive systemic therapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-34.

Abstract Background: Adjuvant endocrine therapy (ET) in ER+ breast cancer (BC) reduces local, distant, and contralateral BC events and improves overall survival (OS). Furthermore, decreased adherence or omission of ET increases the risk of death. However, in ER+ pts with early-stage BC treated with NAC who have a pathologic complete response (pCR), the importance of adjuvant ET may be called into question. We sought to examine the impact of ET omission on the survival of pts with ER+ BC treated with NAC, according to pCR vs residual disease. Methods: We queried the National Cancer Database (NCDB) 2010-2018 for female pts with stage I-III ER+ BC treated with NAC followed by surgery. pCR was defined as ypT0/ypTis, ypN0. The percent receiving adjuvant ET and the impact of adjuvant ET omission on overall survival (OS) in patients with and without pCR were assessed separately based on HER2 expression. OS was analyzed with adjuvant ET as a time-dependent covariate using Cox proportional hazards regression. Results: We identified 34,394 pts treated with NAC for ER+ BC (28,434 ER+/HER2-, 5960 ER+/HER2+). Pts with ER+/HER2+ BC were less likely than pts with ER+/HER2- BC to have received adjuvant ET (61.6% vs 88.8%, p< 0.001). Overall, 4505 (13.1%) had pCR (9.1% of ER+/HER2- and 32.0% of ER+/HER2+). Within each subtype, pts with pCR were significantly less likely to start adjuvant ET after surgery than pts with residual disease (78.4% vs 89.8% for ER+/HER2- and 46.5% vs 68.7% for ER+/HER2+, each p< 0.001), Table 1. Regarding those with residual disease, pts with ER+/HER2+ BC were less likely than ER+/HER2- BC to receive adjuvant ET (68.7% vs 89.8%, p< 0.001). Median follow-up was 4.4 years. Among pts with pCR, 5-year OS was 93.2% (95% CI: 92.1-94.4%) for ER+/HER2- BC and 94.3% (95% CI: 93.1-95.5%) for ER+/HER2+ BC (p=0.08), while among patients with residual disease 5-year OS was 81.7% (95% CI: 81.1-82.2%) and 85.7% (95% CI: 84.5-86.9%) for the two subtypes respectively (p< 0.001). On multivariable analysis, omission of adjuvant ET was significantly associated with poorer OS in patients with residual disease for both ER+/HER2- BC (adjusted HR 1.72, p< 0.001) and ER+/HER2+ BC (adjusted HR 1.63, p< 0.001). In contrast, omission of adjuvant ET was not significantly associated with OS in patients with pCR, regardless of HER2 status (ER+/HER2- adjusted HR 1.28, p=0.20; ER+/HER2+ adjusted HR 1.13, p=0.54), Table 1. Conclusions: In pts receiving NAC for ER+ BC, those with ER+/HER2+ disease were less likely to have received adjuvant ET compared to ER+/HER2- patients, regardless of pCR. In pts with residual disease after NAC, omission of adjuvant ET was associated with significantly higher risk of death. These data provide strong support for interventions to increase utilization of ET, especially for patients with residual disease following NAC. The observation that ET omission did not impact OS in pts with ER+ BC who achieve pCR following NAC is hypothesis generating and may have implications for future de-escalation trials for this subset of patients. Table 1. Differential use of adjuvant endocrine therapy by subtype and pCR and the impact on overall survival Citation Format: Grace M. Choong, Judy C. Boughey, Tanya L. Hoskin, Courtney N. Day, Matthew P. Goetz. Impact of adjuvant endocrine therapy (ET) omission in ER+ breast cancer (BC) treated with neoadjuvant chemotherapy (NAC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-03-12.

Abstract Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR). Cemiplimab is an anti-PD-1 inhibitor approved for the treatment of NSCLC and cutaneous basal and squamous cell CA. Lymphocyte activation gene 3 (LAG-3) binds MHC class II leading to inhibition of T-cell proliferation and activation and is often co-expressed with PD-1. REGN3767 is a fully humanized mAb that binds to LAG-3 and blocks inhibitory T-cell signaling. Concurrent blockade of LAG-3 with an anti-PD-1 may enhance efficacy of an anti-PD-1. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment; HR positive (HR+) patients had to be MP high risk. Treatment included Paclitaxel 80 mg/m2 IV weekly x 12 and Cemiplimab 350 mg and REGN3767 1600 mg both given q3weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. Cemiplimab/REGN3767 was eligible to graduate in 3 of 10 pre-defined signatures: HER2-, HR-HER2-, and HR+HER2-. The statistical methods for evaluating I-SPY 2 agents has been previously described. To adapt to changing standard of care, we constructed “dynamic controls” comprising ‘best’ alternative therapies using I-SPY 2 and external data and estimated the probability of Cemiplimab/REGN3767 being superior to the dynamic control. Response predictive subtypes (Immune+ vs Immune-) were assessed using pre-treatment gene expression data and the ImPrint signature. Results: 73 HER2- patients (40 HR+ and 33 HR-) received Cemiplimab/REGN3767 treatment. The control group included [357 patients with HER2- tumors (201 HR+ and 156 HR-) enrolled since March 2010. Cemiplimab/REGN3767 graduated in both HR-/HER2- and HR+/HER2- groups; estimated pCR rates (as of June 2022) are summarized in the table. Safety events of note for Cemiplimab/REGN3767 include hypothyroidism 30.8%, adrenal insufficiency (AI) 19.2%, hyperthyroidism 14.1%, pneumonitis 1.3%, and hepatitis 3.8%. All were G1/2 except for 6 (7.7%) G3 AI and 3 (3.8%) G3 colitis. Rash occurred in 62.8%, 9% G3 and 2 pts (2.6%) had pulmonary embolism. X% of adrenal insufficiency cases required replacement therapy. 40 patients (11 HR+ and 29 HR-) in Cemiplimab/REGN3767 were predicted Immune+; 32 (29 HR+ and 3 HR-) were predicted Immune-. In the HR+ group pCR was achieved in 10/11 (91%) patients with Immune+ subtype compared with 8/29 (28%) with Immune- subtype. Additional biomarker analyses are ongoing and will be presented at the meeting. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial. Dual immune blockade with a LAG-3 inhibitor and anti-PD1 therapy resulted in a high predicted pCR rate both in HR-/HER2- (60%) and HR+/HER2- (37%) disease. The novel Imprint signature identified a group of HR+ patients most likely to benefit from this active regimen. Table 1: Estimated pCR rates Citation Format: Claudine Isaacs, Rita Nanda, Jo Chien, Meghna S. Trivedi, Erica Stringer-Reasor, Christos Vaklavas, Judy C. Boughey, Amy Sanford, Anne Wallace, Amy S. Clark, Alexandra Thomas, Kathy S. Albain, Laura C. Kennedy, Tara B. Sanft, Kevin Kalinsky, Hyo S. Han, Nicole Williams, Mili Arora, Anthony Elias, Carla Falkson, Smita Asare, Ruixiao Lu, Maria Pitsouni, Amy Wilson, Jane Perlmutter, Hope Rugo, Richard Schwab, W. Fraser Symmans, Nola M. Hylton, Laura Van’t Veer, Douglas Yee, Angela DeMichele, Donald Berry, Laura J. Esserman, I-SPY Investigators. Evaluation of anti-PD-1 Cemiplimab plus anti-LAG-3 REGN3767 in early-stage, high-risk HER2-negative breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-03.

Abstract Purpose/Objectives: Proton therapy is under investigation in breast cancer as a strategy to reduce heart and lung exposure, which is associated with late cardiopulmonary adverse events and secondary malignancy. To date, studies investigating postmastectomy radiotherapy (PMRT) with protons have used conventional fractionation. We hypothesized that condensing treatment to 15 fractions would be safe based on evidence that breast cancer is more sensitive to higher dose fractions than surrounding normal tissues. Materials/Methods: We conducted a randomized non-inferiority phase II trial comparing conventional and hypofractionated proton PMRT with primary endpoint of 24-month complication rate (defined as grade 3 or higher late adverse events using CTCAE, v 4.0 and/or unplanned surgical intervention in patients undergoing mastectomy with reconstruction). With a 10% non-inferiority margin the study ensured 80% power and had a one sided-type I error rate of 0.05. Cardiotoxicity was assessed with serial transthoracic conventional and 2-dimensional speckle tracking echocardiography (2D-STE). Eligibility included age ≥ 18 years with non-inflammatory breast cancer resected by mastectomy with indications for PMRT. Assignment of treatments was balanced with respect to immediate breast reconstruction (IBR). Conventional fractionation group received 50 Gy in 25 fractions of 2 Gy, and hypofractionation group received 40.05 Gy in 15 fractions of 2.67 Gy (RBE 1.1). Target volume included the chest wall and axillary, supraclavicular, and internal mammary lymph nodes. All patients were treated with multi-field optimized pencil beam scanning (intensity modulated proton therapy). Results: Between 2016 and 2018, 82 patients were enrolled and randomized (41 conventional, 41 hypofractionation). Median patient age was 52 years. 32.9% were staged T3-T4 and 79.3% node positive at diagnosis. 57 of 82 patients (69.5%) elected IBR. The median mean heart dose was 0.49 Gy and the median ipsilateral lung volume receiving 40% of prescription or greater (V40%) was 13.6%. No significant changes on conventional or 2D-STE at end-of-treatment or 3-month follow-up compared to baseline were observed. The rate of ≥ grade 2 acute dermatitis was lower with hypofractionation (44% vs 15%, p = 0.006). Other ≥ grade 2 acute adverse events including esophagitis (0 vs 5%), infection (5% vs 2.4%) and skin hyperpigmentation (7.3% vs 4.8%) were not significantly different between the two arms. With a median follow-up of 38.3 months, the 24-month complication rate was conventional 14.6% vs hypofractionation 17.1% (absolute difference 2.4%, p=0.17, 95% CI [-, 15.7%]). In patients with IBR, 6 of 28 (21.4%) conventional and 7 of 29 (24.1%) hypofractionated patients developed complications (p =0.80). There was no significant difference in 3-year disease-free survival between the conventional (89.4%; 95% CI 80.0 – 99.8%) and hypofractionated (92.4%, 95% CI 84.5 – 100.0%) arms (p = 0.91). One local recurrence occurred in the hypofractionated arm simultaneous with regional and distant relapse. The remaining 6 recurrences were isolated distant events. Conclusions: Proton PMRT provided excellent locoregional control and normal tissue sparing. There were no subclinical echocardiographic changes indicative of radiation-induced cardiac dysfunction. Hypofractionation resulted in comparable disease control, tolerability and reconstruction outcomes as conventional fractionation. Although non-inferiority of hypofractionation could not be established based on the upper bound of the 95% confidence interval for complication rate being greater than 10%, both conventional and hypofractionation may be considered appropriate regimens for ongoing phase 3 randomized trials comparing photon and proton radiotherapy. Citation Format: Robert Mutter, Sharmila Giri, Briant Fruth, Nicholas Remmes, Aman Anand, Kathryn Ruddy, Hector Villarraga, Sebastian Santos Patarroyo, Elizabeth Yan, Kenneth Merrell, Lisa McGee, Tamara Vern-Gross, Bradley Stish, Robert Gao, Judy C. Boughey, Sean Park, Kimberly Corbin, Carlos Vargas. Phase II randomized trial of conventional versus hypofractionated post-mastectomy proton radiotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-05.

Abstract Background: Data on the oncologic safety of omission of axillary lymph node dissection (ALND) in node positive (N+) patients who downstage to ypN0 with neoadjuvant chemotherapy (NAC) is sparse. Additionally, there is no consensus on which axillary staging procedure should be used in this setting, sentinel lymph node biopsy (SLNB) alone or in combination with localization and retrieval of the clipped positive node, also known as targeted axillary dissection (TAD). Whether the reduction in the false negative rate observed with TAD translates into a significant reduction in the rate of axillary recurrence is unknown. We sought to evaluate oncologic outcomes after omission of ALND in a large, real-world cohort of breast cancer (BC) patients and to compare rates of axillary recurrence after SLNB with dual tracer mapping vs. TAD. Methods: Data were collected from 19 centers in the Oncoplastic Breast Consortium (OPBC) and EUBREAST networks. Patients with T1-4 biopsy-proven N1-3 BC who underwent NAC followed by axillary staging with either SLNB with dual tracer mapping or TAD and who were pathologically node negative (ypN0) were included. ypN0 was defined as the absence of any tumor or isolated tumor cells. Competing risk analysis was performed to assess the cumulative incidence rates of axillary recurrence, locoregional recurrence, and any invasive (locoregional or distant) recurrence. Two-year cumulative incidence rates were compared between TAD and SLNB using the Gray’s test. Type I error rate was set to 0.05 (α). Results: We included 785 patients (565 treated with SLNB and 220 with TAD) treated with NAC followed by surgery from 01/2014-12/2020. Median patient age was 50 years. The majority (57%) of patients had clinical T2 tumors, and 95% had N1 disease. Most (55%) were HER2+, and 21% were triple negative. Most patients (81%) received anthracycline and taxane-based chemotherapy regimens, but NAC regimens differed between patients treated with TAD and those treated with SLNB (Table 1). All patients with HER2+ tumors received anti HER2 therapy. Nodal radiotherapy was administered to 76% of patients, and was more common in patients who underwent TAD (82% TAD vs 74% SLNB, p=0.017). Breast pathologic complete response (ypT0/is) was more frequent among those patients that had TAD (80% TAD vs. 66% SLNB, p< 0.001). TAD localization was with wire in 46%, radioactive seed in 40%, ultrasound in 5%, tattoo in 2%, and with a combination of these techniques in 7%. The clipped node was successfully retrieved in 94% of TAD cases. The median number of lymph nodes removed was lower in the TAD group compared to the SLNB group [3 (IQR 3-5) vs 4 IQR 3-5), p< 0.001], as was the median number of sentinel lymph nodes [3 (IQR 2-4) vs 4 IQR 3-5), p< 0.001] (Table 1). The 5-year rates of any axillary recurrence, locoregional recurrence, and any invasive recurrence in the entire cohort were 1.1% (95%CI 0.39-2.4%), 3.1% (95%CI 1.6-5.3%) and 10% (95%CI 7.6-13%), respectively. The two-year cumulative incidence of axillary recurrence did not differ between patients treated with TAD compared to SLNB (0% vs 0.9%, p=0.19). Conclusion: Early axillary recurrence after omission of ALND in patients who successfully downstage from N+ to ypN0 with NAC is a rare event following both SLNB or TAD, and was not significantly lower in TAD than SLNB. Although longer follow-up is needed to confirm these findings, the main advantage of TAD seems to be a reduction in the number of lymph nodes removed. Overall, these results support omission of ALND in patients who successfully downstage to node negative disease after NAC. Table 1: Clinicopathological Features of the Study Cohort, Stratified by Axillary Staging Technique Citation Format: Giacomo Montagna, Mary Mrdutt, Astrid Botty, Andrea V. Barrio, Varadan Sevilimedu, Judy C. Boughey, Tanya L. Hoskin, Laura H. Rosenberger, E Shelley Hwang, Abigail Ingham, Bärbel Papassotiropoulos, Bich Doan Nguyen-Sträuli, Christian Kurzeder, Danilo Diaz Aybar, Denise Vorburger, Dieter Michael Matlac, Edvin Ostapenko, Fabian Riedel, Florian Fitzal, Francesco Meani, Franziska Fick, Jacqueline Sagasser, Jörg Heil, Konstantin J. Dedes, Laszlo Romics, Maggie Banys-Paluchowski, Maria Del Rosario Cueva Perez, Marcelo Chavez Diaz, Martin Heidinger, Mathias K. Fehr, Mattea Reinisch, Nadia Maggi, Nicola Rocco, Nina Ditsch, Oreste Davide Gentilini, Regis Resende Paulinelli, Sebastian Sole Zarhi, Sherko Küemmel, Simona Bruzas, Simona Di Lascio, Tamara Parissenti, Uwe Güth, Valentina Ovalle, Christoph Tausch, Monica Morrow, Thorsten Kühn, Walter P. Weber. Oncological Outcomes Following Omission of Axillary Lymph Node Dissection in Node Positive Patients Downstaging To Node Negative with Neoadjuvant Chemotherapy: the OPBC-04/EUBREAST-06/OMA study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-02.

Abstract Background Breast conserving therapy (BCT) is accepted as a preferred option for unifocal breast cancer. However, the oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC), has not been demonstrated in a prospective study. The ACOSOG (Alliance) Z11102 phase II single arm prospective trial was designed to evaluate outcomes with BCT for MIBC. Methods Women age 40+ with 2 or 3 foci of biopsy proven breast cancer (BC) (each site < 5cm in size with at least 1 site invasive) separated by >2-3 cm of normal breast tissue and disease limited to two quadrants of the breast with cN0 or cN1 disease were eligible. All patients had pre-operative mammogram and breast MRI was initially required and subsequently made optional. Neoadjuvant therapy was not allowed. Patients were treated with lumpectomy resected to negative margins followed by whole breast radiation with boost to all lumpectomy beds. The primary endpoint of Z11102 is the cumulative incidence of local recurrence (LR, defined as histologic evidence of ductal carcinoma in situ or invasive BC in the ipsilateral breast or chest wall) at 5 years (treating death and distant and nodal/regional recurrence as competing risks) to assess whether the rate is greater than 8%. Data were frozen 5/25/2022. Results From 11/2012-8/2016, 270 women were enrolled. Of these, 33 were ineligible, 14 converted to mastectomy, 11 were unable to meet protocol-specific radiation endpoints, 1 had no definable tumor, 1 had 4 sites of cancer and 16 withdrew before completing surgery and radiation, leaving 194 patients [median age 61 (range 40-87)] eligible who completed breast conserving surgery and radiation therapy. With median follow-up of alive patients of 66.6 months (range: 4.1, 90.6), 6 patients have developed LR (5 ipsilateral breast and 1 chest wall), corresponding to an estimated cumulative incidence of local recurrence of 3.2% (95% CI: 1.3, 6.4) at 5 years. No patients have developed regional recurrence, 5 patients developed distant recurrence, 0 patients developed local and distant recurrence, 5 patients developed contralateral BC, 3 new non-BC primaries and 8 patients have died (1 related to BC). The rate of local recurrence in patients without a breast pre-op MRI (n=14) was 22.6% at 5 years compared to 1.7% among the 180 patients with a preop MRI (p=0.002). Patient age, number of sites of preoperative biopsy proven BC, HER2 status, pathologic T and N category were not statistically significantly associated with risk of LR. Conclusion The Z11102 clinical trial demonstrates that for women with MIBC breast conserving surgery with adjuvant radiation with lumpectomy site boosts has an acceptably low LR rate (3.2% at 5 years), making this a reasonable consideration for women with 2-3 ipsilateral foci. The LR rate was significantly higher in the small cohort of patients without preoperative breast MRI. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT01556243 Table 1: Factors associated with LR after BCT for MIBC Citation Format: Judy C. Boughey, Kari M. Rosenkranz, Karla V. Ballman, Linda McCall, Bruce G. Haffty, Laurie W. Cuttino, Charlotte D. Kubicky, H. T. Carisa Le-Petross, Kimberly Van Zee, Armando E. Giuliano, Olwen M. Hahn, Kelly K. Hunt, Lisa Carey, Ann Partridge. Impact of Breast Conservation Therapy on Local Recurrence in Patients with Multiple Ipsilateral Breast Cancer – Results from ACOSOG Z11102 (Alliance) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-01.

Adolescents and young women (AYA) with breast cancer represent a unique patient population, compared to the general population with breast cancer. We performed a literature review to evaluate the factors that influenced the surgical outcomes in this patient population. Fifty-two studies were identified, which evaluated breast surgery type, axillary surgery, contralateral prophylactic mastectomy (CPM), surgical timing, psychological factors, disparities, and imaging use. AYA patients had equivalent oncologic outcomes with breast conserving surgery (BCS) or mastectomy. CPM did not improve survival. There are limited data on axillary management in the AYA population, and while more data would be beneficial, this is currently extrapolated from the general breast cancer population. A shorter time to initiate treatment correlated to better outcomes, and disparities need to be overcome for optimal outcomes. AYA patients appreciated involvement in clinical decisions, and shared decision making should be considered whenever possible. Providers must keep these factors in mind when counseling AYA patients, regarding the surgical management of breast cancer.

Abstract Androgen receptor (AR) is expressed in 80% to 90% of estrogen receptor α–positive (ER+) breast cancers. Accumulated evidence has shown that AR is a tumor suppressor and that its expression is associated with improved prognosis in ER+ breast cancer. However, both a selective AR agonist (RAD140) and an AR inhibitor (enzalutamide, ENZ) have shown a therapeutic effect on ER+ breast cancer, so the potential for clinical application of AR-targeting therapy for ER+ breast cancer is still in dispute. In this study, we evaluated the efficacy of ENZ and RAD140 in vivo and in vitro in AR+/ER+ breast cancer models, characterizing the relationship of AR and ER levels to response to AR-targeting drugs and investigating the alterations of global gene expression and chromatin binding of AR and ERα after ENZ treatment. In the AR-low setting, ENZ directly functioned as an ERα antagonist. Cell growth inhibition by ENZ in breast cancer with low AR expression was independent of AR and instead dependent on ER. In AR-high breast cancer models, AR repressed ERα signaling and ENZ promoted ERα signaling by antagonizing AR. In contrast, RAD140 activated AR signaling and suppressed AR-high tumor growth by deregulating ERα expression and blocking ERα function. Overall, analysis of the dynamic efficacies and outcomes of AR agonist, and antagonist in the presence of different AR and ERα levels reveals regulators of response and supports the clinical investigation of ENZ in selected ER+ tumors with a low AR/ER ratio and AR agonists in tumors with a high AR/ER ratio. Significance: The ratio of androgen receptor to estrogen receptor in breast cancer dictates the response to AR-targeted therapies, providing guidelines for developing AR-directed treatment strategies for patients with breast cancer.