Neoadjuvant HER2-targeted Therapy Research Articles

Poor response of HER2-positive mucinous carcinomas of breast to neoadjuvant HER2-targeted therapy: A study of four cases

BackgroundBreast mucinous carcinoma (MC) is typically positive for estrogen receptor (ER) and progesterone receptor (PR) expressions and negative for human epidermal growth factor receptor (HER2) overexpression. HER2 positive MC is a rare entity; its response to neoadjuvant HER2-targeted therapy remains unclear. MethodsFour cases of HER2 positive MC and seven cases of HER2 positive invasive ductal carcinoma with mucinous features (MCF) were identified. Clinicopathologic features were collected. Patients' germline data was gathered if available. Tumor's response to HER2-directed treatment were recorded and compared. ResultsTwo HER2 positive MCs were treated with neoadjuvant HER2-directed treatment and showed no response in the subsequent surgical resection specimens including one positive lymph node showing no treatment effect. One patient had upfront surgery. The fourth patient presented with advanced stage and showed progression on HER2-directed treatment. Six HER2 positive MCFs received neoadjuvant HER2-directed therapy; two cases showed complete pathologic response and four had only minimal residual carcinomas in the breast. Two cases with positive lymph nodes had complete response in the lymph nodes. The seventh patient presented at an advanced stage and was stable on HER2-directed treatment. ConclusionsOur findings suggest that HER2 positive MCs may be resistant to HER2-directed treatment. This is in contrast with the excellent treatment response observed in HER2 positive MCFs. It is important to report mucinous carcinoma percentage in biopsies on HER2 positive tumors as it may be related to treatment response. Further investigation of the underlying mechanisms may help optimize clinical management in this patient population.

Abstract A107: Be Part of the Cure Clinical Trials Campaign: Koreans, Hispanic/Latino/a/e/x, and Black/African Americans living in Los Angeles County

Abstract Background. There is negative perception and lack of participation in clinical trials among Koreans, Hispanic/Latino/a/e/x, and Black/African Americans living in Los Angeles County, which may be attributed to cultural beliefs, language barriers, historical mistrust of medical research, and lack of awareness about the benefits of participation. Without representation from diverse groups, there may be missed opportunities to develop personalized treatment approaches tailored to specific genetic, cultural, and lifestyle factors. Methods. Cedars Sinai Cancer Community Outreach and Engagment (COE) developed a multi-level approach to increase representation of minority populations in clinical trials. With active Community Advisory Board involvement in the development and implementation, a culturally sensitive clinical trials awareness campaign, “Be Part of the Cure”, was developed to offer in-language cancer information, education on clinical trials, and navigation through the cancer care continuum. To support patients and facilitate access to trials, COE has developed bi-directional engagement between CCSC physicians, nurses and Clinical Trials Office representatives, FQHCs, and community and faith-based organizations to ensure a seamless navigation process to care. Additionally, our multicultural and multilingual COE staff have trained Community Health Workers and navigators to expand our outreach efforts and effectively engage our target communities. Results. In total, COE has facilitated 7 health education workshops and attended 3 community outreach events with 501 people educated (37% or 184 Black/African American; 25% or 123 Asians; 17% or 87 Hispanic/Latinx; and 21% or 107 White). Pre/post-tests administered to 73 Koreans during health education workshops showed significant increase in positive perception on clinical trials from 57% to 95%. Korean (n=9) cancer patients have expressed interest in clinical trials, and 1 have been enrolled in Neoadjuvant HER2-Targeted Therapy and Immunotherapy with Pembrolizumab clinical trial. Among Hispanic/Latinx/a/o community, 1 clinical trials health awareness workshop was convened with clinicians who presented to promotores, patients, caregivers, survivors and community members. There were 25 people who completed the pre/post test. There was an increase in positive perception on clinical trials from 52% to 100%, willingness to participate from 60% to 96%, and likelihood of encouraging others to participate from 60% to 96%. In the Black/African American community, 1 clinical trials health awareness workshop was also convened. Among attendees, 21 people completed Pre/Post Test and positive perception on clincal trials increased from 47% to 85%, willingness to participate from 43% to 81%, and likehood on encouraging others to participate from 52% to 81%. Conclusion. Efforts to increase diversity and inclusion in clinical trials should focus on culturally sensitive recruitment strategies, language accessibility, community engagement, and building trust between researchers and communities. Citation Format: Ghecemy Lopez, Dong Hee Kim, Zul Surani, Lourdes Barajas. Be Part of the Cure Clinical Trials Campaign: Koreans, Hispanic/Latino/a/e/x, and Black/African Americans living in Los Angeles County [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A107.

Abstract PO3-20-01: ASTEFANIA: a Phase III study of ado-trastuzumab emtansine plus atezolizumab or placebo as adjuvant therapy in patients with residual invasive breast cancer after neoadjuvant HER2-targeted therapy and chemotherapy

Abstract BACKGROUND Ado-trastuzumab emtansine (T-DM1) is the standard of care for adjuvant treatment of patients (pts) with HER2-positive early breast cancer (eBC) who have invasive residual disease after preoperative treatment with taxane and HER2-targeted therapy. However, a high unmet need remains in some higher risk subgroups (e.g., inoperable or lymph node-positive, hormone receptor-negative disease) who have 3-year invasive disease-free survival (IDFS) rates of 76%. Exploratory analyses suggest that addition of the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab to T-DM1 results in longer progression-free survival compared with T-DM1 alone in pts with previously treated PD-L1-positive metastatic BC. PD-L1/programmed death-1 inhibitors may have a different effect in eBC, as they result in improved pathologic complete response in early triple-negative BC regardless of PD-L1 status. ASTEFANIA evaluates atezolizumab plus T-DM1 in PD-L1-unselected pts with higher risk residual invasive breast cancer after neoadjuvant treatment. TRIAL DESIGN ASTEFANIA is a Phase III, randomized, double-blind, multicenter, study in pts with centrally confirmed HER2-positive eBC with residual invasive disease at surgery after neoadjuvant chemotherapy and HER2-directed treatment including ≥9 weeks of taxane and ≥9 weeks of trastuzumab. Within 12 weeks of primary surgery, pts are randomized 1:1 to intravenous (IV) T-DM1 3.6 mg/kg every 3 weeks (q3w) plus atezolizumab 1200 mg IV q3w or T-DM1 3.6 mg/kg IV q3w plus placebo IV q3w for 14 cycles. Radiotherapy and/or endocrine therapy is administered per local standards. Randomization is stratified by clinical stage at presentation, hormone receptor status, preoperative HER2-directed therapy, and PD-L1 status. ELIGIBILITY CRITERIA Eligible pts have clinical stage cT4/any N/M0, any cT/N2–3/M0, or cT1–3/N0–1/M0 at presentation. Those with cT1–3/N0–1 disease must have pathologic evidence of residual invasive carcinoma in axillary lymph node(s) at surgery. Pts with cT1mi/T1a/T1b/N0 disease are not eligible. AIMS The primary endpoint is IDFS. Secondary endpoints include overall survival, safety, and patient-reported outcomes. STATISTICAL METHODS The log-rank test will be used to compare IDFS between the treatment arms, according to the protocol-defined stratification factors. The Cox proportional hazards model, stratified by the protocol-defined stratification factors, will be used to estimate the hazard ratio between the two treatment arms and its 95% confidence intervals. ACCRUAL As of Jun 28, 2023, 789 pts of the target of 1,700 have been enrolled. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number NCT04873362. Originally presented at the ESMO Congress 2021, 202TiP, Peter Schmid et al. – Reused with permission. Further information is available in Future Oncology 2022; 18:3563–3572. Submitted with permission from Future Medicine & Future Science, part of the Future Science Group. Citation Format: Peter Schmid, Thomas Bachelot, Giampaolo Bianchini, Nadia Harbeck, Sherene Loi, Yeon Park, Aleix Prat, Leslie Gilham, Thomas Boulet, Nino Gochitashvili, Estefania Monturus, Chiara Lambertini, Beatrice Nyawira, Adam Knott, Sara Hurvitz. ASTEFANIA: a Phase III study of ado-trastuzumab emtansine plus atezolizumab or placebo as adjuvant therapy in patients with residual invasive breast cancer after neoadjuvant HER2-targeted therapy and chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-20-01.

Abstract GS03-12: Phase III study of adjuvant ado-trastuzumab emtansine vs trastuzumab for residual invasive HER2-positive early breast cancer after neoadjuvant chemotherapy and HER2-targeted therapy: KATHERINE final IDFS and updated OS analysis

Abstract Background: Patients with HER2-positive early breast cancer (EBC) who have residual invasive disease after neoadjuvant chemotherapy + HER2-targeted therapy have a high risk of recurrence and death. The standard of care when KATHERINE was designed was continuation of the same HER2-targeted therapy in the adjuvant setting for 1 year. The primary analysis of KATHERINE in 2018 showed that the risk of recurrence of invasive BC or death was 50% lower with adjuvant ado-trastuzumab emtansine (T-DM1) than with trastuzumab. Methods: KATHERINE (NCT01772472/BO27938/NSABP B-50-I/GBG 77) is a phase III, open-label, global study of patients with centrally confirmed, HER2-positive (immunohistochemistry 3+ or in situ hybridization-positive) primary BC (T1–4, N0–3, M0) who received neoadjuvant chemotherapy + HER2-targeted therapy, which had to include a taxane and trastuzumab, followed by surgery, with pathologically documented residual invasive disease in the breast and/or axillary lymph nodes. Within 12 weeks of surgery, patients were randomized 1:1 to T-DM1 (3.6 mg/kg intravenously [IV] every 3 weeks [q3w]) or trastuzumab (6 mg/kg IV q3w) for 14 cycles. Randomization was stratified by clinical stage at presentation, hormone receptor status, single vs dual neoadjuvant HER2-targeted therapy, and pathologic nodal status after neoadjuvant therapy. Patients received radiotherapy and/or endocrine therapy per local standards. The primary endpoint was invasive disease-free survival (IDFS). We report the final IDFS analysis, which was to occur after ~384 events had been reported, and the preplanned second interim analysis of overall survival (OS); specified to occur at the same time. Results: With a median follow-up of 8.4 years (101 months), T-DM1 sustained the improvement in IDFS over trastuzumab (unstratified hazard ratio [HR] 0.54; 95% confidence interval [CI] = 0.44, 0.66; p < 0.0001). Landmark 7-year IDFS rates were increased from 67.1% with trastuzumab to 80.8% with T-DM1; a difference of 13.7%. At clinical cutoff for the final IDFS analysis, 215 deaths had been reported. T-DM1 significantly reduced the risk of death by 34% compared with trastuzumab (unstratified HR 0.66; 95% CI = 0.51, 0.87; p = 0.0027). Deaths had occurred in 89/743 patients (12.0%) in the T-DM1 arm and 126/743 (17.0%) in the trastuzumab arm. Landmark 7-year OS rates were increased from 84.4% with trastuzumab to 89.1% with T-DM1; a difference of 4.7%. OS and IDFS benefits were seen across key subgroups. A low incidence of adverse events (AEs) related to study treatment or to study procedures was observed during the post-treatment period: Grade ≥3 related AEs occurred in 3/740 patients (0.4%) in the T-DM1 arm and 3/720 (0.4%) in the trastuzumab arm; serious related AEs, in 2/740 (0.3%) and 4/720 (0.6%), respectively. Related AEs classed as “cardiac disorders” were rare in both arms with extended follow-up. Conclusions: After 8.4 years (101 months) median follow-up, T-DM1 significantly improved OS in patients with HER2-positive EBC with residual invasive disease after neoadjuvant therapy. The IDFS benefit of T-DM1 was sustained in the intention-to-treat population with longer follow-up, and no new safety issues emerged. Cardiac toxicity was rare in both arms. T-DM1 is the first therapy to show improved survival post-surgery in patients with HER2-positive EBC with residual invasive disease after neoadjuvant therapy. Follow-up is ongoing for the final OS analysis. Citation Format: Sibylle Loibl, Max Mano, Michael Untch, Chiun-Shen Huang, Eleftherios Mamounas, Norman Wolmark, Adam Knott, Asna Siddiqui, Thomas Boulet, Beatrice Nyawira, Eleonora Restuccia, Charles Geyer. Phase III study of adjuvant ado-trastuzumab emtansine vs trastuzumab for residual invasive HER2-positive early breast cancer after neoadjuvant chemotherapy and HER2-targeted therapy: KATHERINE final IDFS and updated OS analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS03-12.

Abstract PO5-19-08: Neoadjuvant HER2-targeted Therapy +/- Immunotherapy with Pembrolizumab (neoHIP): An Open Label Randomized Phase II Trial

Abstract Background: Immune checkpoint inhibition (ICI) is synergistic with HER2-directed therapy in pre-clinical models. Clinically, pembrolizumab (K)-mediated ICI plus HER2-directed therapy with trastuzumab (H) was safe and demonstrated modest activity in H-resistant HER2-positive (HER2+) metastatic breast cancer. Because ICI may confer more robust activity when administered earlier in the course of disease, H and K administered in the curative-intent, treatment-naive setting may allow for de-escalation of cytotoxics; confer life-long, tumor-specific immunity; and ultimately, improve cure rates. Moreover, the synergy of H and K with paclitaxel (T) may overcome the need for dual HER2-blockade with H plus pertuzumab (P). In this randomized, multicenter, phase II, open-label trial the efficacy and safety of neoadjuvant THP vs THP-K vs TH-K are explored. Methods: Patients (pts) ≥18y with previously untreated, stage II-III, HER2+ breast cancer are being randomized and stratified by clinical nodal status (positive vs. negative) and hormone receptor status (positive vs. negative). In arm A, pts receive T at 80mg/m2 weekly for 12 weeks, H at 8mg/Kg (loading dose) and then 6mg/Kg every 3 weeks x 3 doses, P at 840 mg (loading dose) and then 420mg/Kg every 3 weeks x 3 doses (THP). In arm B, pts receive THP plus K at 200mg every 3 weeks x 4 doses (THP-K). In arm C, pts receive TH-K. After enrollment of 22 pts to arm C, a prespecified interim efficacy analysis was conducted, and enrollment to this arm was subsequently terminated. Enrollment to the other arms continues with 32/58 pts enrolled to arm A and 33/58 pts enrolled to arm B as of 2/14/2023. Definitive surgery is 3-6 weeks after the last dose. After surgery, pts are treated per the treating physician’s discretion per local clinical standard. The primary end point is pathologic complete response (pCR) rate in the breast and axilla (ypT0/Tis ypN0). Secondary end points include pCR rate by ypT0ypN0 and ypT0/Tis, residual cancer burden index, event free survival, breast conserving surgery rate, safety and overall survival. Exploratory correlative studies will characterize potential immune biomarkers predictive of efficacy and/or toxicity. Funding sources: BCRF, Merck NCT03747120 Citation Format: Heather McArthur, Jorge Henrique Santos Leal, Isaac Chan, Nisha Unni, Stephen Shiao, Joshua Gruber, Samira Syed, Namrata Peswani, Navid Sadeghi, Glenda Delgado, Dawn Klemow, Reva Basho, Meredith Carter, Mai Badran, Nasir Qureshi, Jessica Curtin, Joshua Weese, Stephanie Rice, Michelle Phillips, David Chan, Hugo Hool, Dorothy Park, Mary El-Masry, Philomena McAndrew, Swati Sikaria, Laura Spring, Aditya Bardia, Mourad Tighiouart, Farnaz Dadmanesh, Armando Giuliano, Katherine Sanchez, David Page. Neoadjuvant HER2-targeted Therapy +/- Immunotherapy with Pembrolizumab (neoHIP): An Open Label Randomized Phase II Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-08.

A multicenter phase II study of vaccines to prevent recurrence in patients with HER-2–positive breast cancer.

532 Background: Patients (pts) with early stage HER2-positive breast cancer are commonly treated with neoadjuvant HER2-targeted therapy. Pts who have residual invasive disease have a less favorable outcome and increased risk of recurrent disease than pts with a complete pathologic response (pCR). It also has been observed that pts who do not achieve a pCR have low or absent anti-HER-2 CD4 Th1 responses. We hypothesized that correcting anti-HER-2 CD4 Th1 response using vaccines will be safe, induce anti-tumor immunity in HER2-positive breast cancer and reduce the risk of recurrence. We conducted a multi-center, phase 2, randomized study to determine the safety, immunogenicity and recurrence free survival of two HER2 vaccines (multivalent anti-oncodriver DNA vaccine (WOKVAC) or HER-2-pulsed dendritic cell vaccine (DC1)). Methods: Pts with HER2-positive early breast cancer were eligible if they had residual invasive disease at surgery after receiving neoadjuvant chemotherapy plus HER2-targeted therapy. Patients were randomly assigned in a 1:1 ratio, with stratification according to residual cancer burden (RCB) (1+2 vs 3) to receive adjuvant HER2 vaccination with either DC1 or WOKVAC. For the initial vaccination phase, DC1 was delivered via US guided inguinal lymph node administration, weekly x 6 weeks and WOKVAC was given intradermally on weeks 1, 4, and 7. Booster vaccines were given at months 6, 9 and 12. The primary end point is to evaluate the safety and tolerability of each vaccine and assess immune response rate as measured by ELISPOT. Each treatment arm will be assessed separately. Secondary endpoints include recurrence-free survival. Exploratory analyses include the assessment of prognostic and predictive biomarkers including circulating tumor cells, serum HER2 levels, and other immune correlative biomarkers. Here we are reporting the initial safety results. Results: Total of 110 eligible pts (55 WOKVAC vs 55 DC1) were enrolled from 2/2018 to 12/2022 and received at least one dose of treatment and 38 pts pending completion of the booster phase. Most pts had clinical stage II/III 56/35 (82%) and 50% had positive node disease at diagnosis. 82% had hormone receptor positive disease. 37/38/8 patients had RCB 1/2/3. For patients without known RCB status, ypTNM was used to randomize (yp stage I/II/III = 13/13/1 pts). The most frequently observed treatment related adverse events (TRAE) were injection site pain/reaction (38%) and chills (34%), fever (25%) and fatigue (40%) for DC1 arm. For WOKVAC, the most common toxicities included injection site reaction (68%) and fatigue (37%). All of these were grade 1 and 2. Nine patients had events including new primary cancer (1), local recurrence (2), metastatic disease recurrence (6). Conclusions: Both DC1 and WOKVAC HER2 vaccines were well tolerated without significant toxicities. Updated results will be presented at the meeting including correlatives. Clinical trial information: NCT03384914 .

Neoadjuvant therapy of HER2 directed conventional dendritic cell (DC1) intratumoral (IT) therapy plus weekly paclitaxel, trastuzumab, and pertuzumab in patients with HER-2 positive breast cancer: NATASHA trial.

596 Background: Early stage HER2 positive breast cancer (BC) patients (pts) are commonly treated with neoadjuvant HER2-targeted therapy. Optimizing neoadjuvant therapy by improving efficacy while reducing toxicity is a critical unmet need. IT DC 1 therapy combined with an IgG1 antibody mediating ADCC drives strong anti-HER-2 CD4 Th1 responses and complete tumor regression in preclinical models. We initiated a phase I/II neoadjuvant study to explore the efficacy and immune stimulation effects of an initial 6 weeks of immunotherapy phase (IP) using IT DC1 vaccine plus trastuzumab (H) and pertuzumab (P) (as source of IgG1) followed by 12 weeks of paclitaxel (T) and HP. Methods: Early stage HER2+ BC pts with tumor ≥ 1cm were eligible. Treatment included IT DC1 weekly x6 followed by paclitaxel 80 mg/m2 IV weekly x 12. Trastuzumab IV every (q) 3 weeks (8 mg/kg loading dose, then 6 mg/m2) and pertuzumab IV q 3 weeks (840 mg loading dose, then 420 mg) x 6 cycles starting from day 1. Two dose levels (DL) of IT DC1 (DL1 = 50 million and DL2 = 100 million cells) were evaluated including 6 pts in each DL. Once the optimal DL is determined based on toxicities, additional 22 patients will be enrolled in expansion phase 2 trial. The primary end point of the phase 1 is the safety, immune responses (measured by ELISPOT). MRI breast was performed at the baseline, post-immunotherapy and post-chemotherapy. Here we are reporting the safety and immune correlates in phase 1 study. Results: Twelve pts were enrolled between 10/2021 and 10/2022. Median age was 57 (range 34-74). Nine pts had hormone receptor positive disease with clinical stage I/II/III (5/5/2) and 4 pts had node positive disease. All pts completed IP and 10 patients completed THP chemotherapy as of 2/1/2023. Radiologic response per MRI breast on pre and post-IP showed 6 partial response, 3 complete response and 3 stable disease. Nine pts underwent surgery and 6 out of 9 pts had pCR (RCB 0). The most frequently observed toxicities were chills (50%), diarrhea (42%), nausea (42%), fatigue (42%), and headache (42%). ELISPOT demonstrated a significant decrease of HER2- specific T cell response following 6 weeks of DC1 IT injections in DL2 compared to DL1. Conclusions: The addition of IT DC1/HP to neoadjuvant chemotherapy was well tolerated with manageable toxicities. The 100 million DC1 led to a significant decrease in peripherally circulating anti-HER2 T cell response at week 6 following IP and improved radiologic tumor responses which correlates with a higher likelihood of pCR. Data from another IT DC1 trial suggests decreased circulating HER2 responsive T cells are due to increased trafficking of reactive T cells out of circulation into the tumor possibly leading to an enhanced anti-tumor effect. Updated results including correlative biomarkers will be presented at the meeting. Clinical trial information: NCT05325632 .

A phase II study of concurrent WOKVAC vaccination with neoadjuvant chemotherapy and HER2-targeted monoclonal antibody therapy.

TPS636 Background: HER2+ breast cancer (BCa) is an aggressive breast cancer subtype. The treatment of Stage I-III HER2+ BCa with neoadjuvant chemotherapy and HER2 monoclonal antibodies (trastuzumab and pertuzumab) induces a pathologic complete response in 43-67% of patients. Residual HER2+ disease (i.e. residual cancer burden) after neoadjuvant therapy is associated with a significantly higher risk of recurrence. Evidence supports that HER2 immunity is progressively lost in HER2 oncogenesis and that restoration of HER2 specific CD4+ Th1 immunity is associated with a lower risk of recurrence. Trastuzumab can partially restore HER2 specific immunity, but only in a minority of patients. We have demonstrated that HER2 specific vaccination can augment HER2 specific immunity. While taxane chemotherapy can deplete immunosuppressive cells (MDSCs) 13 – 17 days after treatment creating an optimal time for vaccination. The WOKVAC vaccine is a plasmid vaccine encoding Th1 selective epitopes from HER2 and two other high-risk cancer antigens IGFBP-2 and IGF-1R. The Phase I trial of this vaccine reported that it is safe and all doses induced antigen specific Type I immune responses. We hypothesize that addition of WOKVAC to neoadjuvant chemo/HER2 targeted therapy will induce a significant increase in the number of patients with Th1 CD4+ and CD8+ T cells after neoadjuvant vaccine/chemo/HER2 therapy. Methods: Trial Design: Phase II single arm trial of WOKVAC vaccination with concurrent neoadjuvant taxane based chemotherapy, trastuzumab, and pertuzumab in patients with Stage I-III HER2+ (HR+/-) breast cancer. Enrolled patients will receive WOKVAC vaccine 150mcg on day 13 of cycles 1-3. WOKVAC vaccination may be given with either TCHP or THP. A maximum of 16 patients will be enrolled in this study. Objectives: The primary objective is to evaluate whether concurrent WOKVAC vaccine with chemotherapy and HER2 antibody therapy can significantly increase T-bet+ CD4+ and CD8+ TIL. Secondary objectives are to determine: (1) whether concurrent WOKVAC with neoadjuvant chemo/HER2 therapy is safe, (2) if the magnitude of vaccine induced antigen specific Th1 immunity after neoadjuvant therapy is associated with pathologic response. Statistical Methods: (1) In order to detect a 30% increase in the number of patients with Tbet+ CD4+ and CD8+ TIL in the enrolled patients with 80% power and a one-side alpha of 0.05, our enrollment goal for this study will be 16 patients. (2) Safety will be assessed per CTCAE v5.0, Benchmarks for safety needed to advance this trial concept to a Phase III study will be a grade 3 toxicity rate of ≤13% and a grade 4 toxicity rate of ≤ 7%. (3) The induction of Th1 immunity will be compared against the presence or absence of a complete pathologic response to determine if there is a significant correlation using Pearson r correlation analysis. Targeted Accrual: The study will accrue up to 16 patients. Clinical trial information: NCT04329065 .

Incidence and prognostic impact of HER2-positivity loss after dual HER2-directed neoadjuvant therapy for HER2+ breast cancer.

Loss of HER2 "positivity" can occur in patients with residual disease after neoadjuvant treatment, but the incidence of HER2-positivity loss after neoadjuvant dual HER2-targeted treatment plus chemotherapy, the current standard-of-care for most early stage HER2-positive breast cancers, is not well described. Previous studies that report the HER2 discordance rate after neoadjuvant treatment also do not include the novel HER2-low category. In this retrospective study, we determine the incidence and prognostic impact of HER2-positivity loss, including the evolution to HER2-low disease, after neoadjuvant dual HER2-targeted therapy with chemotherapy. Clinicopathologic data for patients with stage I-III HER2+ breast cancer diagnosed between 2015 and 2019 were reviewed in this single institution retrospective study. Patients who received dual HER2-targeted treatment with chemotherapy were included, and HER2 status before and after neoadjuvant therapy was interrogated. A total of 163 female patients were included in the analysis with a median age of 50 years. A pathologic complete response (pCR as defined by ypT0/is) was achieved in 102 (62.5%) of 163 evaluable patients. Among the 61 patients with residual disease after neoadjuvant therapy, 36 (59.0%) had HER2-positive and 25 (41.0%) had HER2-negative residual disease. Of the 25 patients with HER2-negative residual disease, 22 (88%) of patients were classified as HER2-low. After a median follow-up of 3.3 years, patients who retained HER2-positivity after neoadjuvant treatment had a 3-year IDFS rate of 91% (95% CI, 91%-100%), while patients who lost HER2-positivity had a 3-year IDFS rate of 82% (95% CI, 67%-100%). Almost half of patients with residual disease following neoadjuvant dual HER2-targeted therapy plus chemotherapy lost HER2-positivity. The loss of HER2-positivity may not confer negative prognostic impact, although the results were limited by short follow-up time. Further research on the HER2 status after neoadjuvant treatment may help guide treatment decisions in the adjuvant setting.

Abstract P5-07-08: Evaluating the risk of cardiotoxicity associated with concurrent trastuzumab emtansine (TDM1) and radiation therapy in patients with early-stage HER2 positive breast cancer

Abstract BACKGROUND: HER2-positive breast cancers, which accounts for 20% of breast cancers, is associated with aggressive clinical behavior and inferior survival. The approval of HER2 targeted therapy has changed the landscape of this disease and has reduced disease recurrence by 50% and has improved survival by 33%. (1) However, cardiotoxicity is a well-recognized adverse event associated with HER2-targeted therapies. Adjuvant trastuzumab emtansine (TDM1) is the current standard of care for patients with residual breast cancer after neoadjuvant HER2-targeted therapy. TDM1 is associated with a risk of cardiotoxicity defined as a decline in left ventricular ejection fraction (LVEF). In a pooled analysis of data from seven metastatic breast cancer trials with TDM1, the incidence of cardiac events such as congestive heart failure (CHF), cardiac ischemia, cardiac arrhythmia or grade 1/2 LVEF drop was 3.37%. Adjuvant breast radiation (RT) is routinely offered for patients at high risk for recurrence. Breast RT is also associated with long-term increased risk of cardiac disease more than 10 years after RT. The HERA trial which studied use of adjuvant trastuzumab showed that rates of cardiotoxicity were higher in patients receiving concurrent RT with trastuzumab (left sided > right sided breast cancer) compared to those who did not receive adjuvant RT, although not statistically significant. In the multivariate analysis, no treatment or baseline cardiovascular risk factors were strongly correlated with LVEF, but radiation therapy showed a borderline correlation (adjusted HR, 1.258; 95% CI, 1.00-1.58; P = .049). The risk of cardiotoxicity with concurrent TDM1 and RT has not been well studied. With increasing use of TDM1 in the adjuvant setting, it is important to understand the cardiotoxic effects of combination therapy in early-stage breast cancer. METHODS: We undertook a review of our clinical database to identify patients who received adjuvant TDM1 with concurrent RT for Stage I-III breast cancer from 1/2020 to 01/2022. Clinical parameters including age, date of diagnosis, history of cardiac disorders, echocardiogram findings, radiation dose, final pathologic stage and molecular subtypes of cancer were extracted. All patients had ejection fraction to monitor cardiac fraction. Global longitudinal strain (GLS), which is a more sensitive and reproducible indicator of cardiac dysfunction than LVEF, was also collected, if available. RESULTS: Of 32 patients identified in our retrospective analysis, two patients (6%) developed a drop in ejection fraction post radiation. Median age of patients was 57y. Majority of the patients were Caucasian (44%) followed by Hispanic (28%). 19 (60%) patients had right sided breast cancers and 13(40%) patients had left sided cancers. The mean pre-radiation ejection fraction was 60% and post radiation was 61%. Using paired t-testing, there was no statically significant difference in ejection fraction after radiation (p=0.343). Comparative GLS measurements were available for 16 patients and there was no statical difference with concurrent radiation (p=0.18). All patients tolerated radiation with mostly grade 2 skin dermatitis except four patients who had grade 3 skin dermatitis. One patient had to discontinue radiation early given grade 3 skin dermatitis. CONCLUSION: This institutional review of 32 patients suggests that adjuvant TDM1 with concurrent RT did not result in a significant change in ejection fraction or GLS. Most patients tolerated radiation without significant skin toxicities. One of the limitations of the study is the small sample size. A larger study should look at more broader conclusions; however this data has strong clinical implications. Cardiac Parameters pre and post RT Citation Format: Faheem Farooq, Dillon Cason, Nisha Ohri, Shicha Kumar, Allison Grann, Anna Litvak, Shridar Ganesan, Bruce G. Haffty, Deborah Toppmeyer, Coral Omene, Mridula A. George. Evaluating the risk of cardiotoxicity associated with concurrent trastuzumab emtansine (TDM1) and radiation therapy in patients with early-stage HER2 positive 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 P5-07-08.

Abstract OT3-25-01: Neoadjuvant HER2-targeted Therapy +/- Immunotherapy with Pembrolizumab (neoHIP): An Open Label Randomized Phase II Trial

Abstract Background: Immune checkpoint inhibition (ICI) is synergistic with HER2-directed therapy in pre-clinical models. Clinically, pembrolizumab (K)-mediated ICI plus HER2-directed therapy with trastuzumab (H) was safe and demonstrated modest activity in H-resistant HER2-positive (HER2+) metastatic breast cancer. Because ICI may confer more robust activity when administered earlier in the course of disease, H and K administered in the curative-intent, treatment-naive setting may allow for de-escalation of cytotoxic chemotherapy; confer life-long, tumor-specific immunity; and ultimately, improve cure rates. Moreover, the synergy of H and K with paclitaxel (T) may overcome the need for dual HER2-blockade with H plus pertuzumab (P). In this randomized, multicenter, phase II, open-label, multi-center trial the efficacy and safety of neoadjuvant THP vs THP-K vs TH-K are explored. Methods: 174 patients (pts) ≥18y with previously untreated, stage II-III, HER2+ breast cancer will be randomized and stratified by clinical nodal status (positive vs. negative) and hormone receptor status (positive vs. negative). In arm A, pts receive T at 80mg/m2 weekly for 12 weeks, H at 8mg/Kg (loading dose) and then 6mg/Kg every 3 weeks x 3 doses, P at 840 mg (loading dose) and then 420mg/Kg every 3 weeks x 3 doses (THP). In arm B, pts receive THP plus K at 200mg every 3 weeks x 4 doses (THP-K). In arm C, pts receive TH-K; however, in a preplanned interim analysis, arm C did not meet the pre-defined efficacy threshold and this arm was subsequently closed. Enrollment to arms A and B continue. Definitive surgery is 3-6 weeks after the last dose. After surgery, pts are treated per the treating physician’s discretion including radiotherapy per local clinical standard. Pts whose tumors are hormone-receptor positive will receive hormone therapy per local standard-of-care. The primary end point is pathologic complete response (pCR) rate in the breast and axilla (ypT0/Tis ypN0). Secondary end points include pCR rate by ypT0ypN0 and ypT0/Tis, residual cancer burden index, event free survival, breast conserving surgery rate, safety and overall survival. Exploratory correlative studies will characterize potential immune biomarkers predictive of efficacy and/or toxicity. Funding sources: BCRF, Merck NCT03747120 Citation Format: Heather McArthur, Jorge Henrique Santos Leal, Christina DiLauro Abaya, Sangeetha Reddy, Meredith Carter, Reva Basho, Michelle Phillips, David Chan, Hugo Hool, Dorothy Park, Mary El-Masry, Philomena McAndrew, Swati Sikaria, Laura M. Spring, Aditya Bardia, Mourad Tighiouart, Farnaz Dadmanesh, Armando Giuliano, Stephen Shiao, David B. Page. Neoadjuvant HER2-targeted Therapy +/- Immunotherapy with Pembrolizumab (neoHIP): An Open Label Randomized Phase II 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 OT3-25-01.

Abstract P4-06-08: HER2-protein expression is a predictive marker for treatment response in patients with HER2-positive breast cancer who received neoadjuvant chemotherapy with dual HER2-blockade

Abstract Background In HER2-positive breast cancer, pathologic complete response (pCR) has been known to be a surrogate marker for favorable prognosis after neoadjuvant chemotherapy. We aimed to identify the clinico-pathologic factors related to pCR in patients with HER2-positive breast cancer treated with neoadjuvant dual HER2-targeted therapy. Methods Two-hundred ninty-five patients with HER2-positive breast cancer who received neoadjuvant chemotherapy with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) were included in this retrospective analysis. We assessed the association between age, clinical T, N stage, pathologic factors such as histologic grade, hormone receptor (HR), tumor-infiltrating lymphocytes, the membranous expression of HER2 protein evaluated by immunohistochemistry (IHC) and pCR. The fluorescent in situ hybridization (FISH) was performed in a tumor with HER2 score of 2+. Results Of the 295 patients, 195 (66.1%) achieved pCR (ypT0/is and ypN0). Besides, 240 (81.4%) patients were HER2 score of 3+, and 55 (18.6%) patients were HER2 score of 2+. The pCR was frequently observed in patients with HER2 score of 3+ (64 of 176 [73.3%]) than in those with HER2 score of 2+ (19 of 55 [34.5%]), regardless of HR status. After adjusting other clinicopathologic factors, the high HER2 protein expression was only an independent factor for pCR (adjusted OR 3.85, 95% CI, 1.66-8.91, p=0.002). Conclusions Our results suggest that high expression of HER2 protein assessed by IHC is important in predicting neoadjuvant TCHP response in HER2-positive breast cancer. Citation Format: Soong June Bae, Ji Soo Jang, Yoonwon Kook, Seung Ho Baek, Jee Hung Kim, Sung Gwe Ahn, Joon Jeong. HER2-protein expression is a predictive marker for treatment response in patients with HER2-positive breast cancer who received neoadjuvant chemotherapy with dual HER2-blockade [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 P4-06-08.

Abstract ED7-4: Beyond the lab: Clinical implications

Abstract During this talk, I will review the ever expanding repertoire of single cell and spatially resolved profiling techniques which enable the interrogation breast cancer pathlogy, immuno-biology and treatment response at unprecedented resolution. I will outline considerations for throughput, plex and resolution across different methods before providing several case studies in their application. As one example, I will outline the use of multi-omic single cell profiling and spatial proteomic profiling to characterize changes throughout the course of neoadjuvant Her2-targeted therapy and leading to the identification of candidate predictive biomarkers. I will go on to discuss translational and potential clinical applications of these techniques. Citation Format: Christina Curtis. Beyond the lab: Clinical implications [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 ED7-4.

Using the HER2/CEP17 FISH Ratio to Predict Pathologic Complete Response Following Neoadjuvant Anti-HER2 Doublet Therapy in HER2+ Breast Cancer.

Clinical trials of HER2-directed therapy that omit neoadjuvant conventional chemotherapy for HER+ breast cancer demonstrate that a subset of patients still obtains a pCR. Identifying tumor characteristics which predict pCR may help select patients for de-escalated neoadjuvant dual HER2-targeted treatment without chemotherapy. This is the first study evaluating the HER2/CEP17 ratio by FISH as a biomarker to predict pCR among patients who received neoadjuvant anti-HER2 regimens without chemotherapy. Data from patients with locally advanced HER2+ breast cancer who received neoadjuvant dual HER2-targeted therapy without conventional chemotherapy from a single center was retrospectively reviewed. All patients were enrolled in one of 3 clinical trials evaluating chemotherapy de-escalation. Logistic regression modeling assessed for a relationship between the HER2/CEP17 FISH ratio obtained from baseline tissue biopsy and pCR based on pathology at the time of definitive breast surgery following neoadjuvant treatment. Following neoadjuvant treatment with dual HER2-targeted therapies in 56 patients, the probability of pCR was 73% among patients with a HER2 ratio of 13.1 compared to a probability of 38% among patients with HER2 ratio of 5.5 (OR 4.14, 95% CI 1.44-11.89; P = .012). This positive association persisted after controlling for different treatment regimens administered (OR 2.87, 95% CI 0.9-9.18, P = .020). These data found a positive association between the HER2/CEP17 FISH ratio and pCR following neoadjuvant dual HER2-targeted therapy without chemotherapy. Larger prospective studies are needed to validate the HER2 ratio as a biomarker to select patients for neoadjuvant dual anti-HER2 therapy without chemotherapy.

EE599 Cost-Effectiveness Analysis of Trastuzumab Emtansine for the Adjuvant Treatment of Patients With Residual Invasive HER2+ Early Breast Cancer in Greece

Approximately 7,770 new patients are diagnosed annually with breast cancer in Greece and 25% of them have human epidermal growth factor receptor 2 (HER2+) disease. 49% of newly diagnosed HER2+ patients have early-stage breast cancer (eBC). Based on a physician survey (N=95), 44% of patients receive neo-adjuvant treatment, of whom 33.7% have residual disease and require additional treatment in the adjuvant setting. The objective of this study was to evaluate the cost-effectiveness of trastuzumab emtansine (T-DM1) for the adjuvant treatment of patients with residual invasive HER2+ eBC after neoadjuvant taxane-based and HER2-targeted therapy, from the third-party payer perspective (EOPYY) in Greece.

Antibody-Drug Conjugates for the Treatment of HER2-Positive Breast Cancer.

Human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase is overexpressed in 20-30% of breast cancers and is associated with poor prognosis and worse overall patient survival. Most women with HER2-positive breast cancer receive neoadjuvant chemotherapy plus HER2-targeted therapies. The development of HER2-directed therapeutics is an important advancement in targeting invasive breast cancer. Despite the efficacy of anti-HER2 monoclonal antibodies, they are still being combined with adjuvant chemotherapy to improve overall patient outcomes. Recently, significant progress has been made towards the development of a class of therapeutics known as antibody-drug conjugates (ADCs), which leverage the high specificity of HER2-targeted monoclonal antibodies with the potent cytotoxic effects of various small molecules, such as tubulin inhibitors and topoisomerase inhibitors. To date, two HER2-targeting ADCs have been approved by the FDA for the treatment of HER2-positive breast cancer: Ado-trastuzumab emtansine (T-DM1; Kadcyla®) and fam-trastuzumab deruxtecan-nxki (T-Dxd; Enhertu®). Kadcyla and Enhertu are approved for use as a second-line treatment after trastuzumab-taxane-based therapy in patients with HER2-positive breast cancer. The success of ADCs in the treatment of HER2-positive breast cancer provides novel therapeutic advancements in the management of the disease. In this review, we discuss the basic biology of HER2, its downstream signaling pathways, currently available anti-HER2 therapeutic modalities and their mechanisms of action, and the latest clinical and safety characteristics of ADCs used for the treatment of HER2-positive breast cancer.

Accuracy of ultrasonographic changes during neoadjuvant chemotherapy to predict axillary lymph node response in clinical node-positive breast cancer patients.

PurposeTo evaluate whether changes in ultrasound features during neoadjuvant chemotherapy (NAC) could predict axillary node response in clinically node-positive breast cancer patients.MethodsPatients with biopsy-proven node-positive disease receiving NAC between February 2009 and March 2021 were included. Ultrasound (US) images were obtained using a 5-12-MHz linear array transducer before NAC, after two cycles, and at the completion of NAC. Long and short diameter, cortical thickness, vascularity, and hilum status of the metastatic node were retrospectively reviewed according to breast imaging-reporting and data system (BI-RADS). The included population was randomly divided into a training set and a validation set at a 2:1 ratio using a simple random sampling method. Factors associated with node response were identified through univariate and multivariate analyses. A nomogram combining clinical and changes in ultrasonographic (US) features was developed and validated. The receiver operating characteristic (ROC) and calibration plots were applied to evaluate nomogram performance and discrimination.ResultsA total of 296 breast cancer patients were included, 108 (36.5%) of whom achieved axillary pathologic complete response (pCR) and 188 (63.5%) had residual nodal disease. Multivariate regression indicated that independent predictors of node pCR contain ultrasound features in addition to clinical features, clinical features including neoadjuvant HER2-targeted therapy and clinical response, ultrasound features after NAC including cortical thickness, hilum status, and reduction in short diameter ≥50%. The nomogram combining clinical features and US features showed better diagnostic performance compared to clinical-only model in the training cohort (AUC: 0.799 vs. 0.699, P=0.001) and the validation cohort (AUC: 0.764 vs. 0.638, P=0.027).ConclusionsUltrasound changes during NAC could improve the accuracy to predict node response after NAC in clinically node-positive breast cancer patients.

Real-world outcomes of patients with human epidermal growth factor 2 (HER2)–positive breast cancer receiving neoadjuvant therapy without adjuvant ado-trastuzumab emtansine (T-DM1).

584 Background: HER2-positive early-stage breast cancer (EBC) treated with neoadjuvant chemotherapy and HER2-targeted therapy has favourable outcomes, especially for those attaining pathologic complete response (pCR). Among those with residual invasive disease (RD), outcomes are variable. Replacing adjuvant trastuzumab with ado-trastuzumab emtansine (T-DM1) reduces the risk of recurrence, but increases toxicity and cost. The magnitude of benefit of T-DM1 may be small among patients with RD and favourable prognostic features. Here we report on real-world outcomes of patients with HER2-positive EBC treated with neoadjuvant therapy without adjuvant T-DM1. Methods: We performed a single institution, retrospective review of HER2-positive EBC treated with neoadjuvant chemotherapy and trastuzumab between January 1st, 2012 and February 1, 2021. We excluded patients who received adjuvant T-DM1. We collected clinical and pathologic characteristics, treatment data, and outcomes events. We estimated 3-year disease-free survival (DFS), a validated endpoint in HER2-positive EBC, using Kaplan-Meier with recurrence and/or death as events. Outcomes were reported in subgroups based on known prognostic factors. The study was approved by the University Health Network Research Ethics Board. Results: The study comprised 193 patients with a median follow-up of 30 months. The majority (n=160, 83%) received neoadjuvant anthracycline and taxane-based chemotherapy; 42 (22%) received neoadjuvant pertuzumab. All received adjuvant trastuzumab. Median age was 53 years (range 25-87), 113 (59%) patients had estrogen receptor (ER) positive disease, and 82 (42%) had pCR. In total, 16 events were observed, of which 13 (81%) were distant recurrences (including 5 (31%) in the brain) and 3 (19%) were locoregional. Of these, 14 (88%) occurred in the first 3 years of follow-up. Estimated 3-year DFS was 98.6% in patients with pCR, and 85.4% in patients with RD. Patients with ER positive disease had excellent outcomes, regardless of pathologic nodal (ypN) status. The highest risk of recurrence was in ER negative and ypN positive disease (Table). Conclusions: Real-world outcomes of patients with HER2-positive EBC treated with neoadjuvant therapy without adjuvant T-DM1 are favorable, including those with RD if ER positive. The expected benefit of adjuvant T-DM1 in this group is therefore likely to be small. Patients with ER- disease had poorer outcomes irrespective of nodal status. Further research to identify patients with RD for whom the benefit of T-DM1 is unlikely to merit its added toxicity and cost is warranted. [Table: see text]

Pathologic complete response and survival after neoadjuvant chemotherapy in cT1-T2/N0 HER2+ breast cancer

Women with small HER2+ breast cancers may have excellent prognosis with adjuvant single-agent chemotherapy and HER2-targeted therapy. The role of de-escalated therapy in the neoadjuvant setting, however, remains uncertain. We conducted a cohort study of adult women with T1-2/cN0 HER2+ breast cancer diagnosed 2013–2016 in the National Cancer Database treated with neoadjuvant chemotherapy (NAC) and HER2-targeted therapy. Factors associated with pathologic complete response (pCR) and overall survival were examined. In total, 6994 patients were included, 32% cT1 and 68% cT2. Multi-agent NAC was given to 90% of women while single-agent NAC was given to 10% of women. pCR was achieved in 46% of cT2 patients and 43% of cT1, and in 46% of patients treated with multi-agent versus 38% single agent. Patients receiving multi-agent chemotherapy were younger, had fewer comorbidities, and had higher cT stage and grade. In all patients, pCR was associated with improved survival (p < 0.01). Multi-agent chemotherapy (OR 1.3, p = 0.003), hormone receptor negative (OR 2.6, p < 0.001), higher grade (OR 2.2, p < 0.001), younger age (OR 1.4, p = 0.011), and later year of diagnosis (OR 1.3, p = 0.005) were associated with achieving pCR. Multi-agent chemotherapy was associated with higher likelihood of pCR, but this effect was modest compared to other factors. Single-agent NAC with HER2-directed therapy in selected patients may provide excellent outcome with reduced toxicity, while allowing escalated therapy in the adjuvant setting for patients with residual disease. Prospective studies are needed to determine effects of de-escalation in the neoadjuvant setting on survival and optimal selection strategies.

Abstract P3-12-20: Outcomes of patients with pathologic complete response following neoadjuvant HER2-targeted therapy in patients with HER2+ early stage breast cancer

Abstract BACKGROUND: Contemporary clinical trials of HER2-targeted therapies have shown benefits regarding recurrence and survival in patients (pts) with HER2+ early stage breast cancer. The outcomes of pts treated in community practice settings who had a pathologic complete response (pCR) to neoadjuvant therapy or who had residual disease at definitive surgery (non-pCR) have not been well characterized. This preliminary study aimed to describe the patient characteristics, disease-free survival (DFS) and overall survival (OS) in patients with and without pCR following neaoadjuvant HER2-targeted therapy in The US Oncology Network. METHODS: This retrospective cohort study identified pts diagnosed with stage I-III HER2+ breast cancer who initiated neoadjuvant HER2-targeted therapy in the community setting between April 1, 2014 - March 31, 2019. Pts were followed through the date of last visit, death, or study end (March 31, 2021), whichever occurred first. Data were collected from the US Oncology Network’s electronic medical record database, iKnowMed. Natural language processing/artificial intelligence was used to identify pts with pCR status and pts with disease recurrence during the study period. Patient profiles, risk of recurrence (RR), and time to recurrence (TTR) were assessed descriptively. Kaplan-Meier methods were used to evaluate DFS and OS from the start of neoadjuvant therapy. Results were stratified by pCR status. RESULTS: The study included 641 pts (median age, 55 years), 71% had non-pCR and 29% had pCR. The majority of pts were Caucasian (79%) or black (8%). At diagnosis, 78% of pts had stage I/II disease, and 21% stage III. Nearly 74% were HR+. With a median follow-up of 33 months, pts who had non-pCR had a higher risk of disease recurrence (10.3% vs 8.1%) and a shorter median TTR (18.6 vs 21.1 months) compared to pts with pCR. Three-year DFS (87.5% vs 92.2%) and OS (96.0% vs 98.8%) were lower in pts with non-pCR than with pCR. CONCLUSIONS:Findings from this real-world study of HER2+ early stage breast cancer pts who received neoadjuvant HER2-targeted therapy in the community setting suggested that pts with non-pCR had shorter DFS and OS outcomes than pts with pCR. Pts with non-pCR had a risk of recurrence of nearly 10% over approximately a 3-year time period . This residual risk of recurrence among non-pCR pts suggested a potential opportunity to improve long-term outcomes in this group. Future analyses, including HR subgroups, are planned as data mature and longer follow-up time is available. Results on additional pts with known pCR/non-pCR data, with longer follow-up, and outcomes by HR+ vs HR- status will be presented. Disclosure DeclarationThis study was funded by Puma Biotechnology, Inc. Outcomes of pts with pCR or non-pCR following neoadjuvant HER2-targeted therapyNon-pCRpCROverall CohortN=429N=185N=641Follow-up time, months, median (range)30.8 (0.0,81.6)38.4 (2.8,83.3)33.0 (0.0,83.3)Patients with recurrence, n (%)44 (10.3%)15 (8.1%)59 (9.6%)Time to recurrence, median (range)18.6 (0.0,42.4)21.1 (0.0,60.3)18.8 (0.0,60.3)Disease-free survival at 36 months87.5% (83.4,90.7)%92.2% (86.8,95.4)%89.0% (85.9,91.5)%Overall survival at 36 months96.0% (92.8,97.8)%98.8% (95.2,99.7)%97.0% (94.9,98.3)% Citation Format: Joyce O'Shaughnessy, Nina Oestreicher, Nicole Fulcher, Wan-Yu Tseng, April Beeks, Julia Moore, Deepa Lalla. Outcomes of patients with pathologic complete response following neoadjuvant HER2-targeted therapy in patients with HER2+ early stage breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-20.