Datopotamab Deruxtecan: First Approval.

e13073 Background: After radical surgery for breast cancer, routine laboratory or imaging studies for metastases screening are not indicated in the absence of clinical signs and symptoms suggestive of recurrence. While the goal of therapy is the extension of survival and maintenance of quality of life (QOL), therapies themselves could induce adverse events, resulting in deterioration of QOL. We evaluated quality adjusted life years (QALYs), which is survival adjusted by QOL, of the patients with recurrent breast cancer retrospectively and adequate follow-up measures. Methods: Fifty seven patients with recurrent breast cancer who died already were included. Survival curves were partitioned into two health states: time with ≥ grade 2 chemotherapy-related toxicity (TOX) and time without toxicity (TWiST). QALYs were acquired as follows: QALYs = TWiST + 0.7 * TOX. We compared clinical factors in the patients between with (symptomatic group, n = 32) and without symptoms (asymptomatic group, n = 25). Results: The median age of the patient at diagnosis of recurrence was 57 years. Luminal (hormone receptors (HR) - and human epidermal growth factor receptor-2 (HER2) -), HER2 (HER2 +), triple negative (TN) (HR - and HER2 -), and unknown were 29, 7, 15, and 6 cases, respectively. The proportion of HER2 and TN was significantly higher in the symptomatic group than that in the asymptomatic group (58.6, 21.7 %, p < 0.05). 44.6 % of the patients had visceral metastases at diagnosis of recurrence and the proportions were not different between the groups. Although post recurrent survival (PRS) was shorter significantly in the symptomatic group (22.5, 42,0 months, p < 0.01), overall survival from diagnosis of primary breast cancer (OS) was identical (60.5, 91.0 months). Additionally, QALYs after recurrence was shorter in the symptomatic group (23.0, 41.1 months, p < 0.01) and QALYs from diagnosis of primary breast cancer was identical (58.7, 91.0 months). Conclusions: Although there was no significant difference in OS between the both groups, the duration of therapy received was longer in the symptomatic group. In the present study, we acquired limited information due to retrospective manner. Prospective evaluation of QALYs, including patient reported outcome and symptoms derived from cancer itself, would turn out adequate measures of follow-up after radical surgery for primary breast cancer.

[This corrects the article on p. 192 in vol. 20, PMID: 28690656.].

Background: ARX788 is a next-generation, site-specific ADC composed of a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2) conjugated via a non-natural amino acid linker to a potent tubulin inhibitor payload AS269. The phase I ACE-Breast-01 and ACE-Pan Tumor-01(NCT03255070) studies previously evaluated the safety and efficacy of ARX788 in patients with HER2-positive breast cancer and pan tumor types respectively, with promising efficacy results and with associated ocular adverse events. The clinical benefit of HER2-targeted ADCs for patients with HER2-low breast cancer (HER2 IHC 1+ or 2+ and FISH/ISH negative) has been established for other HER2-targeted ADCs; novel treatment strategies in this population remain an area of high unmet clinical need. Therefore, we hypothesized that ARX788 will also be safe and efficacious for the treatment of patients with HER2-low locally advanced unresectable or metastatic breast cancer, including in patients who have progressed on prior chemotherapies and ADCs. Methods: This is a single-arm, open-label, Phase II clinical trial of ARX788 monotherapy in patients with HER2-low locally advanced unresectable or metastatic breast cancer (NCT06224673). Key eligibility criteria include patients with locally advanced unresectable or metastatic breast cancer, measurable disease, local confirmation of HER2-low status, and receipt of at least one prior line of chemotherapy or ADC therapy in the metastatic setting (no limit on prior lines of therapy). ARX788 monotherapy will be administered at a dose of 1.5mg/kg intravenously every three weeks until progressive disease or intolerable side effects. A total of 30-36 patients will be enrolled in one of two cohorts: 1) hormone receptor (HR) positive/HER2-low (n=20-24) and 2) HR-negative/HER2-low (n=10-12). The primary endpoint is objective response rate (ORR); The proposed sample size will provide ORR estimates with margin of error of 14% and 18% in each cohort respectively at 90% confidence level with anticipated 25% ORR. Secondary endpoints include duration of response (DOR), best overall response (BOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and efficacy of an eye toxicity prevention regimen to prevent grade 2 or higher ocular toxicity. Exploratory endpoints include blood- and tumor-based biomarker analyses and patient-reported outcomes (PROs). Enrollment to all cohorts will begin in the third quarter of 2025. Citation Format: L. A. Huppert, N. D. Pasricha, K. Nathalie, C. Galia, J. Rossi, A. DeLuca, K. Natsuhara, H. Batra-Sharma, M. Majure, M. Melisko, J. Chien, H. Rugo. Trial in Progress: Phase II Open-Label Study of ARX788 (anti-HER2 Antibody Drug Conjugate (ADC)) for Patients with HER2-Low Locally Advanced Unresectable or Metastatic Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-08-11.

Background: Most patients with metastatic cancer request information regarding their prognosis, most notably when death is clearly approaching. Several clinical indices are used to predict the prognosis of end-stage cancer based on performance status and clinical factors. For example, the Palliative Prognostic Index (PPI) includes a range of scores from 0-15 based on factors that include performance status, oral intake, presence of edema, dyspnea at rest, and delirium. For scores greater than six, survival for an additional three weeks was predicted with a sensitivity of 80% and a specificity of 85%. However, the predictive power of these indices is currently insufficient; the quality of life of end-stage breast cancer patients would be markedly improved with a more accurate prediction model. Breast cancer subtypes based on the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) statuses are important prognostic factors with respect to the outcome of initial breast cancer therapy; the subtype defined by these parameters was also identified as an independent prognostic factor for outcomes in cases of metastatic breast cancer. However, the prognostic impact of breast cancer subtype with respect to end-stage disease remains unclear. In this retrospective observational study, we evaluated the relationship between survival time and associated clinicopathological factors, including breast cancer subtype, in order to develop a more accurate prognostic model for end-stage breast cancer patients. Methods: Seventy-three patients with end-stage breast cancer who were admitted to our hospice care unit from January 2014 to December 2018 were enrolled in the study. Patients in this unit were not provided with anticancer therapy but did receive highest-quality supportive care. The primary endpoint was survival time from the admission. Patient information, including age, PPI, disease-free interval (DFI), the number of treatments for the metastatic disease, metastatic site, and breast cancer subtypes were collected from medical records. Breast cancer subtypes included Luminal (Lum), Lum-HER2, HER2, and triple negative (TN) with respect to those that were HR+HER2−, HR+HER2−, HR−HER2+, and HR−HER2−, respectively. The study was approved by the ethical committee of the Oikawa Hospital (OHCT022). Results: The median survival time was 23 days (1-359 days). From the univariate analysis, PPI scores of less than six were associated with significantly shorter survival (14 days vs. 36.5 days, P = 0.001). Patients diagnosed with Lum-HER2 subtype, those who were older and were without liver metastasis, those with a shorter DFI, and those who underwent fewer treatments for metastatic disease showed a tendency toward a favorable prognosis, although these findings did not reach statistical significance. Multivariate logistic regression analysis revealed that a PPI score less than six (P = 0.001), Lum-HER2 subtype (P = 0.003), absence of liver metastasis (P = 0.001), and DFI lower than the median (33 months; P = 0.028) all contributed to longer survival time. Discussion & Conclusion: In addition to the PPI, breast cancer subtype can be used to provide more precise prognoses for end-stage breast cancer patients. Survival of patients diagnosed with the Lum-HER2 subtype was longer than that observed among those with any of the other subtypes who had not undergone any anticancer treatment for metastatic disease; these results suggest that anti-HER2 therapy may be associated with critical immunological modifications. Taken together, our results indicate that breast cancer subtype should be included to provide a more accurate prognostic model for end-stage breast cancer patients. Citation Format: Masahiro Oikawa, Yumika Setoguchi, Yasuko Enomoto, Kazuhumi Hisamatsu, Tetsuaki Inamitsu, Tatsuji Oikawa. The prognostic impact of breast cancer subtype based on hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) statuses for end-stage disease [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-43.

Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial

Residual cancer burden (RCB) based on pathologic characteristics is the most powerful prognostic factor in breast cancer (BC) which received neoadjuvant chemotherapy (NAC) followed by surgery. According to RCB classification, class III predicted short survival duration regardless of BC subtypes according to hormone receptor (HR) and human epidermal growth factor receptor-2 (HER-2) state. However, up to 20-40% of BCs with RCB class III did not experience BC recurrence and had long term survival without disease recurrence. In our study, we evaluated genomic characteristics of BC which had high RCB class. We collected 96 fresh frozen BC specimens which had undergone surgery after NAC between 2010 and 2018 from Samsung Medical Center Biobank. We performed whole genome or exome sequencing, RNA sequencing and high-plex single-cell spatial transcriptomics. Of 96 BCs, 65 BCs had experienced BC recurrence and 31 BCs have not been BC recurrence. Of 65 BCs with dismal prognosis, 12 were HR+HER2-, four in HR+HER2+, 39 in triple negative breast cancer (TNBC) and 10 in HR-HER2+ BC. Of 31 BCs without recurrence, 11 were HR+HER2-, two in HR+HER2+, 14 in TNBC and four in HR-HER2+ BC. In HR+HER2- BC, ten of 12 BCs with dismal prognosis were categorized into basal like intrinsic subtype and two were into luminal B subtype compared that six of luminal A and five of luminal B subtype categorization in good prognosis BC group. Age associated mutation signature were enriched in HR+HER2- BC with good prognosis (p=0.027). Tumor microenvironment (TME) analysis using Kassandra suggested that high monocytes were associated with BC with dismal prognosis (p=0.00031). In single-cell spatial transcriptome analysis, T-cell abundance in the tumoral niche is associated with dismal prognosis in HR+HER2- BC (p=0.039). In TNBC, almost BCs (88.7%) were categorized into basal-like intrinsic subtype regardless of their prognosis. TME analysis presented that immune cells including macrophages and lymphocytes with CD4 and CD8 T cells were significantly enriched in TNBC with good prognosis (ps <0.05, respectively). In HER2+ BC, intrinsic subtypes were heterogeneous in both groups. Focal amplification in HER2+BC patient harbored DNA segments from different chromosomes more frequently than in those with good prognosis (p=0.00091), which was prominent in oncogenic extrachromosomal DNA amplifications compared to other oncogenic amplifications. In TME analysis, there were no specific cell enrichments according to BC prognosis but sing-cell spatial transcriptome analysis revealed that higher T-cell abundance in the tumoral niche was associated with HR+HER2+ BC with good prognosis (p=0.047). In conclusion, each BC subtype had their own genomic characteristics to determine their prognosis. Our study also suggested that TME characteristics was common prognostic factor for survival outcome of BC with residual tumor after NAC. Citation Format: Ji-Yeon Kim, Sabin Park, Sepil Ahn, Eun Seop Seo, Soyeon Kim, Mark Gregory, Emily Killingbeck, Eun Yoon Cho, Jeong Eon Lee, Jin Seok Ahn, Yeon Hee Park, Woong-Yang Park, Hoon Kim, Semin Lee, Young-Hyuck Im. Prognostication of genomic characteristics of residual breast cancer after neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7644.

To evaluate hormone receptor status on survival and recurrence of the human epidermal growth factor receptor 2-positive breast cancer treated with Trastuzumab in the adjuvant setting. The retrospective study was conducted in 2017 at the Breast Cancer Research Centre, Tehran University of Medical Sciences, Tehran, Iran, and comprised data of women aged >20 years with stage I-III of human epidermal growth factor receptor 2-positive breast cancer who were treated with Trastuzumab from 2008 to 2017. The patients were divided into two groups. Group P had patients who were triple positive for human epidermal growth factor receptor 2, oestrogen receptor and progesterone receptor. Group N had patients positive for only human epidermal growth factor receptor 2. All patients in group P were treated with hormone therapy. Overall survival, disease-free survival, and distant metastasis rates were measured. SPSS 22 was used for data analysis. Of the 263 patients, 169(%) were in group P with a mean age of 46.86 ± 10.92 years, and 94(%) were in group N with a mean age of 48.53±12.33 years (p>0.05). There were no unfavourable predictors for overall survival and disease-free survival except for stage (p<0.05). The difference on both counts between the groups was not significant (p>0.05 each). The impact of hormone receptor positivity on survival and progression of human epidermal growth fac tor receptor 2-positive breast cancer remains an area of debate.

Background: LIV-1 is a highly prevalent transmembrane protein in breast cancer cells. Ladiratuzumab vedotin (LV), SGN-LIV1A, is an investigational antibody-drug conjugate (ADC) that targets LIV-1 via a humanized IgG1 monoclonal antibody conjugated to monomethyl auristatin E (MMAE) by a protease-cleavable linker. LV is internalized when it binds LIV-1 on cell surfaces and MMAE is released, which binds tubulin and induces apoptosis. LV has been shown to be active and tolerable in metastatic breast cancer (mBC) at a recommended dose of 2.5 mg/kg every 21 days (Modi 2017). More frequent, fractionated dosing has improved the activity and/or safety of other ADCs. Thus, this study is actively accruing subjects with metastatic triple negative breast cancer (mTNBC; estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) receptor-negative) and endocrine-resistant ER+ or PR+ (hormone receptor [HR+])/HER2-negative mBC to test weekly dosing of LV (Days 1, 8, and 15 of every 3-week cycle). Methods: This study is enrolling up to 82 subjects (42 HR+/HER2-negative and 40 mTNBC) into dose escalation and dose expansion cohorts (NCT01969643). Eligible subjects are females ≥18 years old with pathologically and radiologically confirmed metastatic HR+/HER2-negative or mTNBC with at least 1 measurable lesion per RECIST v1.1. Subjects with HR+/HER2-negative disease must have received no more than 1 prior line of cytotoxic chemotherapy in the locally advanced (LA)/mBC setting, either as single agent or combination therapy. Subjects with mTNBC must have received 1 prior line of cytotoxic chemotherapy in the LA/mBC setting. Progression within 6 months of completion of neoadjuvant or adjuvant therapy is considered an LA/mBC regimen. Subjects must have adequate organ function, ECOG status of ≤1, and no ≥ Grade 2 peripheral neuropathy. Subjects with brain lesions must have received definitive treatment of the lesions. Prior therapy with MMAE-containing agents is not allowed. Dose escalation follows the modified toxicity probability interval method (Ji 2010). Dose expansion cohorts will provide data about activity and tolerability. Tumor assessments will be conducted every 2 cycles per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed. Primary safety endpoint is the incidence of adverse events and dose-limiting toxicities. Key efficacy endpoints include confirmed overall response rate, duration of response, and progression-free survival. Citation Format: Heather C Beckwith, Diana C Medgyesy, Jame Abraham, Rita Nanda, Katherine HR Tkaczuk, Ian E Krop, Lajos Pusztai, Shanu Modi, Monica M Mita, Jennifer M Specht, Sara A Hurvitz, Hyo S Han, Kevin Kalinsky, Sharon Wilks, Joyce O’Shaughnessy, Lowell L Hart, Hope S Rugo, Zahi I Mitri, Phillip M Garfin, Howard A Burris III. SGNLVA-001: A phase 1 open-label dose escalation and expansion study of SGN-LIV1A administered weekly in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-03-03.

Discovery and development of novel therapies in advanced breast cancer: rapid development of ribociclib

The use of trastuzumab in patients with breast cancer that overexpresses human epidermal growth factor receptor 2 has significantly improved treatment outcomes. However, a substantial proportion of this patient group still experiences progression of the disease after receiving the drug. Evaluation of the changes in expression of the human epidermal growth factor receptors could be of interest. Monoclonal antibodies against the extracellular domain of the human growth factor receptors, 2, 3, and 4, have been raised, and specific and sensitive immunoassays have been established. Sera from healthy individuals (Nordic Reference Interval Project and Database) were analyzed in the human epidermal growth factor receptor 2 assay (N = 805) and the human epidermal growth factor receptor 3 and 4 assays (N = 114), and reference limits were calculated. In addition, sera from 208 individual patients with breast cancer were tested in all three assays. Finally, the human epidermal growth factor receptor 2 assay was compared with a chemiluminescent immunoassay for serum human epidermal growth factor receptor 2/neu. Reference values were as follows: human epidermal growth factor receptor 2, <2.5 µg/L; human epidermal growth factor receptor 3, <2.8 µg/L; and human epidermal growth factor receptor 4, <1.8 µg/L. There were significant differences in human epidermal growth factor receptor 2 and human epidermal growth factor receptor 3 serum levels between the patients with tissue human epidermal growth factor receptor 2-positive and tissue human epidermal growth factor receptor 2-negative ( p = 0.0026, p = 0.000011) tumors, but not in the serum levels of human epidermal growth factor receptor 4 ( p = 0.054). There was good agreement between the in-house human epidermal growth factor receptor 2 assay and the chemiluminescent immunoassay. Our new specific antibodies for all the three human epidermal growth factor receptors may prove valuable in the development of novel anti-human epidermal growth factor receptor targeted therapies with sensitive immunoassays for measuring serum levels of the respective targets and in monitoring established treatment.

535 Background: Frail health status impacts clinical decision making for older cancer patients and their families, and frailty is independently associated with increased risks of mortality. Our objective was to describe differences in treatment and rates of recurrence by frailty status among older women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. Methods: We performed a large, population-based retrospective cohort study of women aged 65 years and older diagnosed with first primary stage I-III HR+/HER2-breast cancer using the Surveillance, Epidemiology, and End Results Medicare-linked database between 2007 and 2015. Using administrative health claims, we ascertained information on breast cancer treatment and utilized validated claims-based algorithms to determine frailty status (robust, pre-frail, and frail) and identify subsequent invasive breast cancer recurrences. Relative hazards of recurrence were determined using Fine and Gray competing risks regression models with estimated subdistribution hazard ratios (SHR) and robust 95% confidence intervals (CI). Results: From an overall cohort of 46,027 women, most women (56%) were classified as robust at breast cancer diagnosis, whereas 37% and 7% were identified as pre-frail and frail, respectively. Compared to robust patients, frail patients were more likely to have stage III disease (10% vs. 7%) and receive mastectomy (27% vs. 18%), and less likely to receive radiation (35% vs. 57%) or chemotherapy (5% vs. 9%). Five-year cumulative incidences of recurrence were 15%, 18% and 22% among robust, pre-frail, and frail women, respectively. In multivariable competing risks models adjusted for age, race, stage, and treatment, frail (SHR 1.28, 95%CI 1.17-1.41) and pre-frail (SHR 1.15, 95%CI 1.09-1.21) women had a significantly increased risk of breast cancer recurrence. Conclusions: Independent of differences in treatment, frailty was associated with increased breast cancer recurrence risk in this population-based cohort of older women. However, the vast majority of older women living with HR+/HER2- early breast cancer were not identified as frail. These study results suggest that age alone is not an adequate indicator of physical resilience and underscores the need to consider additional factors when assessing the benefits and risks of treatments for the prevention of recurrence among HR+/HER2- early breast cancer patients.

Background: ZN-c5 is an orally bioavailable selective estrogen receptor degrader (SERD) that binds potently to the estrogen receptors alpha and beta. It shows improved activity over fulvestrant in human tumor xenograft models and activity in tumor models that are resistant to tamoxifen. This is a Phase 1/2, open-label, multicenter, dose-escalation and expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), and clinical activity of ZN-c5 in subjects with advanced/metastatic estrogen receptor (ER) positive/ human epidermal growth factor receptor (HER2) negative breast cancer, both as monotherapy and in combination with palbociclib. The results from the ongoing monotherapy dose escalation are reported. Methods: Single agent ZN-c5 is being evaluated at sequentially escalating doses starting at 50 mg/day, administered orally, once daily (QD). The endpoints are to determine a maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D), preliminary clinical activity and to characterize the PK profile. Subjects must be intolerant to or have breast cancer refractory to established therapies and to have received up to 2 prior lines of chemotherapy for the treatment of advanced breast cancer. Subjects must have a documented prior response to endocrine therapy for advanced/metastatic disease (SD, PR, or CR) lasting &amp;gt; 6 months or disease recurrence after at least 24 months of adjuvant endocrine treatment. Results: A total of 15 female subjects (median age 57 years, range 51 - 89 years) were enrolled across 5 cohorts (3 subjects/dose level). The dose levels were 50, 75, 100, 150, and 300 mg/day. The subjects had a median of 4 prior therapies for advanced/metastatic disease, with a median of 3 prior hormonal-based therapies and a median of 1 prior chemotherapy. Eleven of 15 subjects (73%) received prior fulvestrant. The cut off-date for this analysis was 30 June 2020. There was no increase in incidence or severity of TEAEs with increase in dose level. The most frequent TEAEs reported in &amp;gt; 1 subject were nausea (33%), arthralgia, cough, musculoskeletal pain and vomiting (20% each), alanine aminotransferase increased, anemia, back pain, blood alkaline phosphatase increased, breast pain, diarrhea, fatigue, gamma-glutamyl transferase increased, headache, hypophosphatemia, myalgia and skin mass (13% each). Grade 3 events were COVID-19, hypercalcemia, arthralgia, back pain musculoskeletal chest pain, pain in extremity and hypertension, none were deemed related to ZN-c5. Grade 4 events were not reported. No bradycardia was observed. A single subject reported a Grade 1 visual field defect, not deemed related to ZN-c5. No DLTs were reported. ZN-c5 demonstrated a best response of stable disease (SD) in 10/15 subjects (66.5%), while progression of disease (PD) was reported in 5/15 subjects (33.5%). The clinical benefit rate (CBR, SD ≥ 24 weeks) was 40%. In addition, the progression free survival (PFS) was a median of 3.8 months (95% [CI], 1.6 to 6.3). The preliminary PK was characterized by fast absorption with median Tmax values of 1 - 2 hrs. The exposures were approximately dose-proportional at the dose levels of 50 - 100 mg and less than dose-proportional between 100 - 300 mg. No ZN-c5 accumulation after 15 days of QD dosing was observed. The estimated mean elimination half-lives ranged between 11 - 18 hrs. Conclusion: This monotherapy dose escalation study demonstrates that ZN-c5 is very well-tolerated and has promising clinical activity in patients with ER+/HER2-negative advanced breast cancer who have disease that progressed on standard therapies. The trial with ZN-c5 in monotherapy and with palbociclib is ongoing and the RP2D has not been determined yet. Citation Format: Pavani Chalasani, Vandana Abramson, Joanne Mortimer, Julie R Nangia, Jose Suarez, Matt Suster, Mieke Ptaszynski, Kevin Kalinsky. A dose escalation study of the novel oral SERD-ZN-c5 in women with ER-positive, HER2-negative advanced/metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-20.

Background: In the 2013 ASCO/CAP HER2 update, new recommendations for HER2 diagnostic criteria in breast cancer organized in situ hybridization (ISH) results into five categories; group1 (amplified), group 2 (monosomy), group 3 (co-amplified), group 4 (equivocal) and group 5 (non-amplified). Patients falling into groups 2, 3 and 4 were potentially eligible for HER2 targeted therapy, however, there is uncertainty from limited prospective clinical trials that show patients in these uncommon groups would receive the same benefit as group 1. Concern over whether the interpretation criteria should be modified for these uncommon groups led to the recent publication of the 2018 HER2 focused update. This update has modified ISH criteria for groups 2, 3 and 4, recommending the final diagnosis take into consideration both immunohistochemistry (IHC) and ISH results. The publication of this new guideline has prompted us to investigate what impact this would have on our institution. Materials &amp; Methods: A retrospective review of the URMC pathology database revealed 2,281 cases that had undergone HER2 FISH analysis since the 2013 update. IHC for initial HER2 screening was used, followed by reflex testing of all 2+ results and cases with histopathologic discordance. All 2,281 FISH cases were sorted into their 5 HER2 categories based on the 2013 guidelines. The final HER2 diagnosis for groups 2, 3 and 4 were then re-determined after applying the new criteria presented in the 2018 focused update. Results: The results from the 2,281 HER2 FISH cases are shown in Tables 1 and 2. The results for group 1 and group 5 cases remained the same. However, for ISH cases in groups 2, 3 and 4, there were alterations in the final HER2 results. All 25 monosomy cases, originally interpreted as HER2 positive by the 2013 guidelines, were now considered HER2 negative. All group 3 (co-amplified) cases remained positive (due to IHC 2+ results). The largest change was that the original 199 equivocal cases, based on the 2013 guidelines, became split into 198 HER2 negative (99.5%) and 1 HER2 positive (0.5%). Conclusion: Comparison of the HER2 FISH cases between 2013 and 2018 revealed differences in the final HER2 status. Using the 2018 guideline, 13.72% (313 cases) of the 2281 cases were HER2 positive in contrast to 14.77% (337 cases) from 2013. While that is only a difference of 1.05%, the reclassification of 198 of 199 equivocal cases to negative indicates that 9.82% of the final HER2 results for the entire patient cohort was affected. With 266,000 new cases of breast cancer annually, the final HER2 status of approximately 26,000 patients and their potential eligibility for targeted-therapy would change. Further study of the clinical significance of these changes is warranted. Final ISH HER2 Status (2013)AmplifiedMonosomyCo-AmplifiedEquivocalNon-Amplified272 cases (11.93%)25 cases (1.10%)40 cases (1.75%)199 cases (8.72%)1,745 cases (76.50%) Citation Format: Hicks DG, D'Aguiar M, Henry J, McMahon L, Buscaglia B, Turner B. Impact of the 2018 ASCO/CAP HER2 focused update on human epidermal growth factor receptor-2 (HER2) testing in breast cancer: A retrospective review of a single institutional cohort [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-02-03.

Background: A combination of a taxane, trastuzumab, and pertuzumab (THP) is the standard-of-care (SOC) 1L treatment for patients (pts) with HER2+ mBC; THP demonstrated median progression-free survival (mPFS) of 18.7 mo and overall survival (OS) of 56.5 mo (Swain et al. N Engl J Med. 2015;372:724-734). However, pts eventually develop resistance to treatment. Novel treatment options are necessary in order to delay the emergence of resistance and provide better clinical outcomes, improve quality of life (QOL), and prolong survival in the 1L setting. T-DXd has demonstrated efficacy in pts with heavily pretreated HER2+ mBC, with an objective response rate (ORR) of 61.4%, duration of response (DOR) of 20.8 mo, and mPFS of 19.4 mo (Modi et al. Cancer Res. 2021. Abstract PD3-06). Data from DESTINY-Breast01 supported global approvals of T-DXd in HER2+ mBC. Here we describe a phase 3 trial evaluating the efficacy and safety of T-DXd ± pertuzumab compared with THP in the 1L treatment of HER2+ mBC. Trial design: DESTINY-Breast09 (NCT04784715) is a global, multicenter, randomized, phase 3 trial assessing the efficacy and safety of T-DXd with or without pertuzumab compared with SOC THP as 1L treatment in pts with HER2+ (IHC 3+ or ISH+ assessed locally per ASCO-CAP guidelines and centrally confirmed) advanced or mBC. This study consists of 3 treatment arms: arm A (T-DXd + placebo), arm B (T-DXd + pertuzumab), and arm C (THP). Randomization is 1:1:1 and pts will be stratified by prior treatment status (de novo vs recurrent), hormone receptor status (positive vs negative), and PIK3CA mutation status (detected vs not detected). Pts (N≈1134) must have had no prior chemotherapy or HER2-targeted therapy for advanced or mBC (1 prior line of endocrine therapy is allowed for mBC). The primary endpoint is PFS by blinded independent central review. Secondary endpoints include PFS by investigator assessment, OS, ORR, DOR, PFS2, health-related quality of life (QOL), pharmacokinetics, immunogenicity, and safety. Citation Format: Sara M Tolaney, Romualdo Barroso-Sousa, Zefei Jiang, Yeon Hee Park, Mothaffar Rimawi, Cristina Saura, Andreas Schneeweiss, Masakazu Toi, Tinghui Yu, Jagdish Shetty, Pia Herbolsheimer, Sibylle Loibl. Phase 3 study of trastuzumab deruxtecan (T-DXd) with or without pertuzumab vs a taxane, trastuzumab and pertuzumab in first-line (1L), human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC): DESTINY-Breast09 [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 OT1-14-02.

e12621 Background: Human epidermal growth factor receptor-2 (HER2) overexpression is a defining feature of roughly 20% of localized breast cancer and represents a critical target for therapy. Since the demonstration that residual disease (RD) after neo adjuvant therapy (NAT) is associated with worse prognosis and that adjuvant ado trastuzumab emtansine (tDM1) improves survival, NAT has become the standard of care for localized HER2+ breast cancer. Retesting for HER2 overexpression post resection is variable, and data is conflicting regarding the prognostic significance of changes in HER2 expression pre and post therapy. The objective of this study was to evaluate the association of pre and post neo adjuvant therapy HER2 immunohistochemistry (IHC) expression on breast cancer outcomes in our institutional database. Methods: After IRB approval, data was gathered for patients with localized HER2+ breast cancer receiving NAT including trastuzumab/pertuzumab at Yale Cancer Center between 2012 and 2022. Pathologic complete response (pCR) was defined as no residual invasive tumor in breast and lymph nodes. Patients were divided into 3 cohorts by response and HER2 IHC: Cohort 1 pCR Cohort 2 pre-treatment 3+/post treatment 1-2+, and Cohort 3 pre-treatment 3+/post treatment 3+. A Kaplan-Meier survival analysis was done to assess recurrence free survival at 36 months. Results: Within the specified time interval, we identified 104 patients with localized HER2-IHC 3+ breast cancer who received neoadjuvant therapy. The pCR rate was 62.5% (65/104), while 37.5% (39/104) of patients had RD. Among patients with RD, 58.9% (23/39) remained HER2 IHC 3+ and 41% (16/39) had decreased HER2 expression IHC1+/IHC 2+. Median follow-up was 27.9 months at time of analysis. In patients with HER2 3+ RD 26% (6/23) developed local recurrence or distant metastasis while none of patients with HER2 IHC 1+ or 2+ RD had relapse ( p= 0.0309). In patients with pCR, 6.15% (4/65) had recurrence. Kaplan-Meier survival analysis showed a significant difference between the 3 groups (log rank p= 0.004). Conclusions: In our retrospective cohort, decreased HER2 expression by IHC following neoadjuvant treatment was associated with lower recurrence rates. If confirmed, RD HER2 IHC expression could be used as a prognostic biomarker to select patients for more or less aggressive adjuvant therapy, stratify patients in adjuvant trials, and identify patients who may benefit from more intensive post therapy surveillance.