HER2-positive Disease Research Articles

Automated radiofluorination of HER2 single domain antibody: the road towards the clinical translation of [18F]FB-HER2 sdAb

BackgroundWith the next generation of Human Epidermal Growth Factor Receptor 2 (HER2) -targeting therapies, such as antibody–drug conjugates, showing benefit in “HER2 low” and even “HER2 ultralow” patients, the need for novel methods to quantify HER2 expression accurately becomes even more important for clinical decision making. A HER2 PET/CT imaging assessment could evaluate HER2 positive disease locations while improving patient care, reducing the need for invasive biopsies. A single-domain antibody (sdAb)-based PET tracer could combine the high specificity of sdAbs with short-lived radionuclides such as fluorine-18 (18F) and gallium-68 (68Ga). SdAb-based PET tracers have clinically been used via a 68Ga-chelator approach. However, the distribution of 68Ga-labelled pharmaceuticals to peripheral PET centres is more challenging to organize due to the short half-life of 68Ga, most certainly when the available activity is limited by a generator. Cyclotron produced 68Ga has removed this limitation. Distribution of 18F-labelled pharmaceuticals remains less challenging due to its slightly longer half-life, and radiofluorination of sdAbs via N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) has shown to be a promising strategy for developing sdAb-based PET tracers. Although [18F]SFB automation has been reported, automating protein conjugation proves challenging. Herein we report the fully automated, cartridge-based production of [18F]FB-HER2 sdAb on a single synthesis module.Results[18F]FB-HER2 sdAb (> 6 GBq) was obtained after a fully automated production (95 min), with a RCP > 95%, apparent molar activity > 20 GBq/µmol and decay-corrected radiochemical yield (RCY d.c.) of 14 ± 2% (n = 4). Further upscaling amounted to production batches of 16 GBq with an apparent molar activity > 40 GBq/µmol and RCY d.c. of 8 ± 1% (n = 4). Ex vivo biodistribution and PET imaging showed specific HER2-positive tumour targeting and low kidney retention.ConclusionThe [18F]FB-HER2 sdAb tracer was produced with clinically relevant activities using a fully automated production method. The automated production method was designed to ease the translation to the clinic and has the potential to be used not only in mono-centre but also multi-centre clinical trials with one central production site. [18F]FB-HER2 sdAb showed a favourable biodistribution pattern and could be a valuable alternative to 68Ga-labelled sdAb-based PET tracers in the clinic.

Immune marker expression and prognosis of early breast cancer expressing HER3

IntroductionThere is a strong rationale for targeting HER3, as HER3 contributes to tumorigenesis and treatment resistance. However, the prognostic role of HER3 and their association with immunoregulatory protein expression has not been established. MethodsThe main objective of this study was to investigate the prognostic role of HER3 expression and identify immunoregulatory marker expression according to HER3 status. HER3 expression and 10 immunoregulatory protein (PD-1/PD-L1/PD-L2/IDO/TIM-3/OX40/OX40L/B7-H2/B7-H3/B7-H4) expression was identified in 320 stage I-III breast cancer patients who received curative surgery at Seoul National University Hospital in 2008. The median follow-up duration was 88.8 months. Criteria for HER3 IHC was adopted from HER2 IHC score and only those with 3 + was considered positive. ResultsAmong 320 patients, 213 (67.2 %) had luminal A disease, 30 (9.5 %) had luminal B disease, 28 (8.8 %) had HER2-positive disease, and 46 (14.5 %) had triple negative disease. HER3 expression was shown in 153 patients (47.8 %). Tumors with HER3-expression had more immunogenic tumor microenvironment compared to HER3-negative tumor. In addition, patients with HER3 expression had favorable 5-year relapse free survival compared to HER3-negative patients (5-year RFS 92.5 % vs. 85.2 %, p = 0.038). However, in the multivariate analysis, HER3 expression was not a prognostic factor, but expression of immunoregulatory protein was a prognostic factor. ConclusionsThis study identified immunoregulatory protein expression according to HER3 status in breast cancer patients. As tumor with HER3 expression have more immunogenic microenvironment, investigating combination treatment of HER3 targeting agent and immunotherapy in HER3 expressing breast cancer may be promising.

Neoadjuvant treatment with trastuzumab and pertuzumab plus fulvestrant in older patients with HER2-positive, ER-positive early breast cancer.

13 Background: The prevalence of breast cancer in older adults (≥70 years) is increasing and worse outcomes compared to younger patients could be explained by advanced presentation, late diagnosis, deterioration of organ function, and the presence of multimorbidities. Older patients are under-represented in clinical trials. Therefore, the risks and benefits of anticancer therapy should be carefully evaluated. The CREATE-X36 and KATHERINE37 trials enrolled few older individuals but did not show any new safety concerns, older patients should be considered for trastuzumab in case of residual HER2-positive disease following neoadjuvant systemic therapy; neoadjuvant endocrine therapy for at least 4-6 months is useful for older patients who are not immediately suitable for surgery and aromatase inhibitors are favored over tamoxifen in view of better response rate. Although adjuvant trastuzumab is beneficial regardless of age, anti-HER2 (neo)adjuvant strategies remain poorly investigated in patients age 65 years or older. Pertuzumab can be considered for high-risk individuals, but diarrhoea can be debilitating in older adults, similarly with adjuvant neratinib. Age is associated with increased cardiac toxicity rates with trastuzumab,80 with 15–40% of patients requiring early discontinuation, particularly patients who are age 80 years or older and have multimorbidities. Methods: Open-label, exploratory, phase 2 study done at one center in Venezuela. Patients were eligible if they had previously untreated, histologically confirmed, unilateral, invasive, cN0, HER2-positive, ER-positive breast cancer and older >70y. Patients were treated every 3 weeks with intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and intravenous pertuzumab (840 mg loading dose in the first cycle and then at 420 mg) and intramuscular fulvestrant (500 mg) every 4 weeks for four cycles. The coprimary endpoints were change from baseline in Ki67 expression at surgery and pathological complete response. Results: Between January, 2020, and June, 2023, we enrolled 12 patients. At baseline, geometric mean Ki67 expression was 42·9 and 12·1 at time of surgery (n=8; p=0·013). A clinical objective response immediately before surgery was achieved by 10 of 12 patients. At surgery, eight patients had a pathological complete response in breast and axillary nodes. The most frequent grade 3 adverse events was diarrhea (n=4), and stomatitis. No grade 4 or serious adverse events were recorded in the study and there were no deaths. Conclusions: The combination of fulvestrant, trastuzumab, and pertuzumab had a effect on the expression of Ki67 and pCR at surgery. Triple targeting of ER, HER2, could be an effective chemotherapy-free treatment strategy for older patiens. Further clinical testing and additional molecular characterisation is necessary.

Trastuzumab Deruxtecan in Human Epidermal Growth Factor Receptor 2-Expressing Biliary Tract Cancer (HERB; NCCH1805): A Multicenter, Single-Arm, Phase II Trial.

Treatment options for patients with unresectable or recurrent biliary tract cancer (BTC) who progress on a gemcitabine-containing regimen are limited. In addition, the significance of anti-human epidermal growth factor receptor 2 (HER2) therapy in HER2-expressing BTC has not been sufficiently investigated. In this phase II trial, participants from five institutions in Japan were enrolled. Eligible patients had pathologically confirmed unresectable or recurrent BTC with centrally confirmed HER2-positive (immunohistochemistry [IHC]3+ or IHC2+ and in situ hybridization [ISH]+) or HER2-low (IHC2+ and ISH-, IHC1+, and IHC0 and ISH+) and were refractory or intolerant to a gemcitabine-containing regimen. The patients received 5.4 mg/kg trastuzumab deruxtecan (T-DXd) once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was the confirmed objective response rate (ORR) in HER2-positive BTC by an independent central review (threshold ORR, 15%; expected ORR, 40%). A total of 32 patients were enrolled and treated. Among these patients, 22 with HER2-positive disease comprised the primary efficacy population and had a confirmed ORR of 36.4% (90% CI, 19.6 to 56.1; P = .01), meeting the primary end point. Eight with HER2-low disease comprised the exploratory population and had a confirmed ORR of 12.5%. The most common ≥grade 3 treatment-related adverse events were anemia (53.1%) and neutropenia (31.3%). Eight patients (25.0%) had interstitial lung disease (ILD), including two grade 5 events. T-DXd showed promising activity in patients with HER2-positive BTC and a signal of efficacy in patients with HER2-low BTC. Although the safety profile was generally manageable, ILD requires careful monitoring and early intervention.

Exploring sexual health in premenopausal patients with hormone positive early breast cancer: Comparison between LHRH and oophorectomy.

e23172 Background: Ovarian function suppression (OFS) is recommended for premenopausal patients with hormone (HR) positive early breast cancer at higher risk of recurrence. This is achieved with the use of the luteinizing hormone–releasing hormone agonist (LHRH) or oophorectomy. Sexual health is an important aspect for women with breast cancer, although unfortunately this issue is often not addressed. The aim of this study was to explore sexual health issues in premenopausal HR-positive patients with LHRH vs. Oophorectomy. Methods: A prospective observational study was conducted during the period of June 2023 and December 2023, enrolling premenopausal patients with Early stage HR positive (HER2 positive or negative) breast cancer diagnosed between 2017 and 2023, who were treated with OFS and remained free of disease. Involved patients were divided in two groups: Group A – received LHRH and Groups B - underwent oophorectomy. All patients were surveyed with EORTC QLQ-BR-45 questionnaire during their follow-up or scheduled LHRH injection visits at clinic. The questionnaire included Functional (F) and Symptom (S) scales evaluating sexual functioning, sexual enjoyment, endocrine therapy symptoms, endocrine sexual symptoms. Results: It was planned to enroll 100 patients in the study, but only 34 patients (24 in Group A, 10 in Group B) consented to participate, the majority of patients did not want to share their sexual life issues, even anonymously. Of those enrolled, median age was similar (42 in group A, 43 in group B), all had stage I-II breast cancer, and all were in continued remission at the time of enrollment. A similar proportion had HER2 positive disease (25% and 20%, respectively). Far more people in Group A were treated with breast conserving surgery (67% vs 30%, respectively) with 20% of participants in in Group B undergoing bilateral mastectomy. More volunteers received chemotherapy in Group A (88% vs 60% in group B). Among those in Group B, 6 of 10 were previously treated with LHRH before oophorectomy and the procedure was done due to endometrial hyperplasia (n = 3), known BRCA mutation (n = 1), persistent estrogen levels despite LHRH (n = 1), and patient preference (n = 5). More patients had a partner at enrollment in group B (90% vs 67% in Group A); only one person identified as a lesbian (enrolled in group B). F score S > 60 was noted in more Group A vs Group B participants (50% vs 30%). More people in Group A had S score S < 40, indicating higher quality of life (79% vs 50%, respectively). Conclusions: The study suggests that sexuality after cancer is a difficult area to study in Georgia, likely due to cultural issues. While we could not account for the contribution of known variables that impact sexuality in this population (e.g. surgery type, chemotherapy) due to small numbers, our data suggest that LHRH antagonist use may have a lesser risk to sexual function compared to oophorectomy.

Evaluating the efficacy of neoadjuvant endocrine therapy in HER2 low vs. HER2 negative breast cancer: An NCBD analysis.

599 Background: Neoadjuvant endocrine therapy (NET) is an important treatment option for hormone receptor (HR)-positive breast cancer (BC). Innovative ADCs targeting HER2 low tumors has sparked debate regarding the distinct nature of HER2 low tumors and whether it merits a unique treatment approach. With favorable outcomes in metastatic disease, there is interest in adopting similar strategies for early-stage treatment approaches. Methods: We examined the National Cancer Database for stage I-III ER-positive BC in women who underwent neoadjuvant endocrine therapy (NET) from 2010 to 2017, for at least 90 days to a maximum of 270 days. Patients with prior neoadjuvant chemotherapy, other malignancies, HER2-positive disease by either IHC or FISH, metastatic disease, or unknown stage were excluded. HER2 status was grouped as negative or low per 2023 ASCO-CAP guidelines. Patients’ response to therapy included pathologic complete response (CR), partial pathologic response (PR), stable pathologic response, or progression in primary tumor at time of resection. We employed multivariable binomial logistic regression to examine how clinicopathologic factors influence the probability of any response (combining CR and PR) to neoadjuvant hormonal therapy. Results: 3,808 patients met the inclusion criteria. 1,055 (27.8%) patients had HER2 negative disease, and 2,753 (72.2%) patients were HER2-low. 48 (1.2%) patients had primary tumor CR, and 1,484 (39%) had PR. Among HER2-low patients, 37 (1.3%) had pathologic CR, and 1,134 (41.1%) had PR. Among HER2-negative patients, 11 (1.0%) had pathologic CR, and 350 (33.1%) had PR. Multivariable logistic models revealed that age, duration of NET, and HER2 status were significant predictors of any response to NET. HER2-low tumors were more likely to have any response compared to HER2-negative (aOR=1.16, 95% CI 1.01 - 1.34, p=0.04). Patients who received >150 days of hormonal therapy were more likely to respond (aOR=1.33, 95% CI 1.16 - 1.52, p=<0.001); patients >50 years old were more likely to have any response (aOR=1.41, 95% CI 1.07 - 1.90, p=0.02). Clinical node positivity and tumor grade did not have significant effect on response to NET at time of resection. Conclusions: Our study offers a real-world estimate of outcomes associated with NET in localized BC. HER2 low tumors had greater significant clinical responses to NET when compared to HER2 negative, suggesting that HER2 low tumors may benefit from tailored treatment in the neoadjuvant setting. [Table: see text]

Clinical utility of molecular imaging in newly diagnosed metastatic breast cancer.

1019 Background: Optimizing patient outcome prediction in metastatic breast cancer (MBC) can potentially reduce patients’ and healthcare burden. Molecular imaging to visualize early metabolic change, baseline whole-body human epidermal growth factor receptor-2 (HER2) and estrogen receptor (ER) expression might achieve this. In the prospective multicenter IMPACT study, we evaluated the clinical utility of molecular imaging to improve standard diagnostics in patients with newly diagnosed MBC of all subtypes. Methods: Patients underwent extensive workup, including baseline metastasis biopsy, [18F]FDG-PET, [89Zr]trastuzumab-PET (HER2-PET), [18F]FES-PET, and early [18F]FDG-PET after 2 weeks. Treatment was based on HER2 or ER subtype determined in biopsy (immunohistochemistry, IHC; standard-of-care) or PET findings (HER2- and [18F]FES-PET; investigational) in case of negative biopsy but positive HER2 and/or [18F]FES-PET scan. Clinical utility of molecular imaging was defined as the capacity to identify poor patient outcome, measured as progressive disease (PD) on CT at 8 weeks, progression-free survival (PFS), and overall survival (OS). Results: Two hundred patients were included. Progression on early [18F]FDG-PET was related to poor outcome in all subtypes (median PFS 4.1 versus 19.4 months, OS 19.4 versus 45.0 months). Early [18F]FDG-PET correctly predicted non-PD on 8 week CT (specificity 90.5%, negative predictive value 94.1%), but sensitivity and positive predictive value for PD was low (50 and 37.5%, respectively). However, early [18F]FDG-PET related better to long-term outcome than CT: patients with non-PD on 8 week CT, but with progression on early [18F]FDG-PET, had a median PFS and OS of 9.5 and 22.3 months respectively, compared to 19.4 and 50.1 months without [18F]FDG-PET progression (PFS HR 1.76 (95%CI 1.0 – 2.9), OS HR 1.93 (1.0 – 3.5)). HER2 or ER subtype was discrepant between biopsy and PET in 52 out of 200 (26%) patients, yielding investigational PET-based treatment options in 41 (21%) patients. In patients with HER2-positive biopsy IHC disease who received standard HER2-targeting treatment, median PFS with positive- versus negative HER2-PET was 23.2 and 4.5 months, respectively. In patients with biopsy IHC HER2-negative disease but positive HER2-PET, median PFS was with investigational HER2-targeted treatment 11.4 months, without 7.4 months. The pattern was similar in ER-positive disease, although less pronounced for biopsy- and PET-based subtypes. Conclusions: This study supports the clinical utility of molecular imaging with [18F]FDG-PET, HER2-PET, and [18F]FES-PET, to improve standard diagnostics for outcome and subtype assessment in patients with newly diagnosed MBC. Clinical trial information: NCT01957332 .

Phase II clinical trial of docetaxel and trastuzumab for HER2-positive advanced extramammary Paget's disease (EMPD-HER2DOC).

No consensus has been reached regarding the optimal chemotherapy for metastatic extramammary Paget's disease (EMPD), a rare cutaneous adenocarcinoma, because of the lack of solid evidence from prospective trials. However, the immunohistochemical profile of EMPD reportedly resembles that of breast cancer, particularly in terms of human epidermal growth factor receptor 2 (HER2) expression, suggesting that HER2 is a promising therapeutic target for advanced HER2-positive EMPD. In this phase II single-arm trial, 13 Japanese patients received intravenous trastuzumab (loading dose of 8 mg/kg and maintenance dose of 6 mg/kg) and docetaxel (75 mg/m2) every 3 weeks for up to 2 years. The docetaxel dose was reduced or discontinued according to its toxicity. The primary trial endpoints were objective response rate (ORR) after 3 cycles of treatment and safety throughout the study period. All 13 patients completed 3 cycles of combination therapy. The median follow-up was 27.9 months. The ORR was 76.9% (n = 10/13; 90% CI, 50.5-93.4). Frequently observed adverse events were neutropenia (100%), hypoalbuminemia (84.6%), and mucocutaneous infection (84.6%), all of which were well tolerated. The combination of docetaxel and trastuzumab demonstrated a favorable clinical effect and acceptable tolerability, which makes it a good treatment option for HER2-positive metastatic EMPD (ClinicalTrials.gov Identifier: UMIN000021311, jRCTs031180073).

A randomized, multicenter, open-label, phase 2 study of TRK-950 in combination with ramucirumab and paclitaxel as second-line therapy in patients with Caprin-1 positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.

TPS4181 Background: Caprin-1 is strongly expressed on the cell membrane of many cancer types including G/GEJ and on cancer stem cells. High expression is associated with enhanced in vitro colony-forming activity and in vivo tumorigenicity. TRK-950 is a first in class humanized antibody targeting CAPRIN-11). In the phase I study (NCT02990481), TRK-950 was well tolerated as monotherapy with no DLTs and MTD not reached at doses of 3-30mg/kg IV weekly. Subsequently the Phase 1b study demonstrated that TRK-950 was well tolerated with a high potential for synergistic anti-tumor activity when used in combination with standard of care treatment(s) in selected advanced solid tumors (NCT03872947). Specifically, Regimen D which evaluated TRK-950 in combination with Ramucirumab and Paclitaxel in G/GEJ showed a DCR of 100% in all nine patients receiving 10 mg/kg and partial responses were seen in 5/9 (55%) patients. Caprin-1 strong expression was observed in 4/9 patients and an ORR of 100% was seen in those patients2). A Phase II clinical trial in gastric/GEJ cancer patients with strong Caprin-1 expressions is now enrolling patients. Methods: The phase II study is a multi-national, open-label, randomized, multicenter study evaluating the efficacy of TRK-950 in combination with ramucirumab (Ram) + paclitaxel (PTX ) as compared with Ram + PTX treatment alone in patients with previously treated metastatic G/GEJ adenocarcinoma (NCT06038578). Patients enrolled across 10 sites in Japan, South Korea and the United States are randomized 1:1:1 by the permuted block method to (arm A) TRK-950 5mg/kg plus Ram + PTX, (arm B) TRK-950 10mg/kg plus Ram + PTX or (arm C) Ram + PTX alone. Inclusion criteria include patients with Caprin-1 positive (cutoff; 30% at ≥ 2+ staining) advanced/metastatic G/GEJ adenocarcinoma who have received first line therapy. Key exclusion criteria include HER2 positive disease. The primary endpoint is progression free survival (PFS) based on Independent Central Review (ICR) assessment per RECIST v1.1. Key secondary and exploratory endpoints include overall survival (OS), ORR, DoR, and biomarker evaluation. An interim analysis will be performed after 105 patients are randomized in stage 1 to determine the optimal dose of TRK-950 (5mg/kg or 10mg/kg) that will be evaluated in arm stage 2. In total 146 patients will be enrolled (40 patients in one arm and each 53 patients in two arms). This study opened in September 2023. 1. Okano F, et al. Cancer Res Commun. 2023 Apr 18;3(4):640-658. 2. Cassier P, et al. J Clin Oncol. 2023 Vol. 41, No. 4, suppl. Clinical trial information: NCT06038578 .

Incidence and survival of primary metastatic breast cancer in Denmark; implication of breast cancer screening, classification, and staging practice.

Primary metastatic breast cancer (pMBC) accounts for 5-10% of annual breast cancers with a median survival of 3-4 years, varying among subtypes. In Denmark, the incidence of breast cancer increased until 2010, followed by a stabilisation. Several factors influencing pMBC incidence and survival, including screening prevalence, staging methods, and classification standards, remain pivotal but inadequately documented. This retrospective observational study involving pMBC patients diagnosed between 2000 and 2020 encompassed all Danish oncology departments. Data from the Danish Breast Cancer Group database and the National Patient Register included diagnosis specifics, demographics, treatment, and follow-up. Between 2000 and 2020, 3,272 patients were diagnosed with pMBC, a rise from 355 patients in 2000-2004 to 1,323 patients in 2015-2020. The increase was particularly observed in patients aged 70 years or older. Changes in tumour subtypes were observed, notably with a rise in human epidermal growth factor receptor 2 (HER2)-positive cases but a steady distribution of estrogen receptor (ER) status. Diagnostic practices changed over the two decades, with 6% evaluated with PET/CT (positron emission tomography-computed tomography) or CT (computed tomography) with a bone evaluation in 2000-2004 and 65% in 2015-2020. Overall survival (OS) improved from 23 months in 2000-2004 to 33 months in 2015-2020. In patients with ER-positive and HER2-positive disease, the multivariable model showed improved survival by year of diagnosis, and further, patients with ER-negative/HER2-negative disease fared worse the first 2 years after diagnosis. Our study delineates changes in the treatment and survival of pMBC over two decades. Stage migration, screening introduction, and changes in registration practice, however, prevent a valid assessment of a possible causal relationship.

Abstract PO3-20-07: Five years and counting: A case of a 47-year-old female with De Novo Metastatic HER2 positive disease on multiple lines of treatment

Abstract HER2-positive breast cancer refers to a specific subtype of breast cancer characterized by the overexpression or amplification of the human epidermal growth factor receptor 2 (HER2) protein on the surface of cancer cells. The overexpression of HER2 leads to increased signaling pathways that promote cell growth and division, making HER2-positive breast cancer inherently more aggressive compared to other subtypes. The aggressive behaviour of HER2-positive disease may be attributed to its rapid cell growth, high metastatic potential, and increased risk of recurrence. Fortunately, there are targeted therapies that specifically inhibit the HER2 protein. These targeted treatments help to block HER2 signaling, slow down tumor growth, and reduce the risk of recurrence. We report a case 47 year old premenoapausal Filipino female diagnosed with de-novo metastatic HER2-positive breast cancer with liver and lung metastasis in 2018. Advised Pertuzumab Trastuzumab and Taxane therapy but due to financial constraints was amenable only to Trastuzumab and Paclitaxel. During treatment noted symptomatic cardiac decline, hence shifted to Lapatinib & Capecitabine, tolerated well with stable disease for 1 year. Disease then progressed to the contralateral breast, given 6 cycles of Ado Trastuzumab Emtansine with partial response followed by modified radical mastectomy of the right and toilet total mastectomy of the left breast. She was lost to follow up. Her cancer recurred 1 year later as skin lesions on chest wall. She was given 6 cycles of Ado Trastuzumab Emtansine, however still with progression as skin lesions on the chest. Patient was then given 5 cycles of Trastuzumab with Eribulin. Despite treatment, there was progression with symptomatic brain metastasis and further increase in size and number of skin metastasis of the chest wall. Lesions were noted to be ulcerating and bleeding. Hence patient underwent 5 of 5 sessions of Fractionated stereotactic radiation therapy and 10 of 10 sessions of palliative radiotherapy to the chest wall. Patient was then given Pertuzumab & Trastuzumab with note of improvement of chest wall lesions. However, after 7 cycles of treatment, noted progression again as skin metastasis on the chest wall. Hence patient was shifted to Trastuzumab Deruxtecan. At the time of writing, the patient has had a good response with Fam-Trastuzumab Deruxtecan-nxki with partial resolution of her skin metastases on the chest with stable disease of lung and brain target lesions. No bleeding or ulcerations of the lesions and no recurrence of dizziness or imbalance reported. The patient will continue to receive Fam-Trastuzumab Deruxtecan-nxki until disease progression and/or unacceptable toxicity. Here we have a case of patient with extended survival after being fortunate to have received multiple lines of treatment for the disease. In this case we were able to apply the advances of research in HER2-positive breast cancer and see it in the clinical setting. Thus, ultimately translating to extended overall survival for the patient. We see the importance of continuous research on HER2-positive breast cancer disease and how these studies have helped us in overcoming treatment resistance, understanding disease progression, tailoring of therapies to individual patients, optimizing treatment outcomes, developing new therapies, and enhancing the quality of life for patient. Ongoing research continues to explore new therapeutic approaches and strategies to further improve outcomes for individuals with metastatic HER2-positive breast cancer. This is truly an exciting time for cancer research because what used to be a very deadly disease is now becoming something that we are able manage. Citation Format: Sofia Dominique Unson, Rubi Li. Five years and counting: A case of a 47-year-old female with De Novo Metastatic HER2 positive disease on multiple lines of treatment [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 PO3-20-07.

Abstract PO3-14-11: Association between BRCA alterations detected by circulating tumor DNA and germline mutations in breast cancer patients: a retrospective mono-institutional analysis

Abstract Background: PARP inhibitors (PARPi) are a standard of care for breast cancer (BC) patients (pts) with germline BRCA (gBRCA) mutation, with benefit demonstrated also in patients with somatic (s) BRCA1/2 mutations. The use of circulating tumor (ct) DNA testing allows to detect resistant and actionable alterations in BC, but it could be associated with the incidental identification of germinal mutations. The aim of this study was to describe the incidence of both, somatic and germinal BRCA1/2 alterations, and the impact on the therapeutic outcomes in a retrospective BC cohort with clinical ctDNA testing for their BC. Materials and methods: A retrospective cohort of 245 BC pts that underwent ctDNA analysis (Guardant 360) between August 2014 and May 2023 at Weill Cornell Medical College was identified. Pts with at least a BRCA1/2 alteration, including variant of uncertain significant (VUS) and synonymous, were enrolled in the study. A descriptive analysis was performed. Results: Among 35 patients included, 34 had metastatic disease, the median age was 61 years old (IQR 40-67), and 65.7% were post-menopausal at diagnosis. 57.1% of pts had hormone receptor positive/HER2 negative (HR+/HER2-) BC, 20% had HER2 positive disease and 22.9% were triple-negative (TN) BC. Ten (28.6%) and 20 (57.1%) pts had a sBRCA1 or a sBRCA2 alteration on ctDNA, respectively; 5 pts (14.3%) had a coexisting sBRCA1/2 mutation. The median variant allele frequency (VAF) was 1.2% for BRCA1 and 2.7% for BRCA2 alterations. Furthermore, 53.3% and 6.7% of sBRCA1 and 40% and 8% of sBRCA2 mutations were identified as VUS and synonymous, respectively. The most common associated genomic alterations included TP53 (62.9%), ESR1 (20%) and PI3KCA (52%) with a median number of 4 variants (IQR 2-7). Next generation sequencing (NGS) testing on tissue was available for 3 patients: two demonstrated concordance with BRCA alterations detected by ctDNA, whereas no alteration in BRCA1/2 genes was found for the third patient despite the tissue analysis was performed at the same time of the ctDNA. Germline testing was available for 24 (69%) pts; a corresponding gBRCA1 mutation was found for 3 pts (VAF 48.6%-84.3%), and a gBRCA2 for 8 pts (VAF 26.7%-49.5%). Due to the small sample size, a univocal VAF cut-off to detect gBRCA1/2 mutations could not be calculated. Twenty-nine pts had a sBRCA1/2 mutation detected by ctDNA test before starting a new therapy; of these 55.2% had HR+/HER2- disease, while 17.2% and 27.6% were HER2 positive and TN BC, respectively. The median progression free survival (mPFS) was 10.3 (3.2-17.4) months (ms) and the 1-year and 2-year overall survival (OS) rates were 82.3% and 70.5%, respectively. The mPFS was 10.3 ms (0-25.0) for patients (n=16) that underwent chemotherapy, 5.6 ms (0-15.1) for those who had received endocrine therapy (n=9), and not reached for patients treated with PARPi (n=4). Conclusions: ctDNA analysis allows the detection of sBRCA1/2 mutations that could be missed by tissue-based testing. The identification of BRCA alterations on ctDNA could guide the use of germline testing even when these are present at a lower VAF than expected, with relevant impact on the therapeutic choices and family screening. Further evaluation to establish the impact of sBRCA1/2 detected by ctDNA on the therapeutic algorithm decision are needed. Citation Format: Letizia Pontolillo, Eleonora Nicolò, Laura Munoz Arcos, Carolina Reduzzi, Mara Serena Serafini, Amanda Kaylan Strickland, Nadia Bayou, Jeannine Donahue, Elisabetta Molteni, Lorenzo Gerratana, Diana Giannarelli, Eleni Andreopoulou, Emilio Bria, Massimo Cristofanilli. Association between BRCA alterations detected by circulating tumor DNA and germline mutations in breast cancer patients: a retrospective mono-institutional 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 PO3-14-11.

Abstract PO4-14-10: Circulating Tumor DNA as a Biomarker for ADCs in Metastatic Breast Cancer

Abstract Background: Breast cancer is a complex disease characterized by heterogeneity, and the analysis of circulating tumor DNA (ctDNA) holds promise for capturing this heterogeneity. Recently, ctDNA testing has been employed in clinical practice to guide targeted therapies for metastatic breast cancer, particularly in cases of hormone receptor-positive disease with mutations in PIK3CA and ESR1. This approach becomes necessary when traditional tumor biopsies are inadequate for next-generation sequencing (NGS) testing or fail to capture the full extent of the cancer's heterogeneity. Moreover, the utilization of antibody-drug conjugates (ADC) in addressing tumor heterogeneity continues to expand. However, there has been no biomarker, outside of HER2 protein expression, to predict ADC response. In this project, we test the hypothesis that ctDNA can be utilized as a biomarker to predict response to novel therapies such as ADCs. Methods: We analyzed a subset of patients from the Dallas Metastatic Breast Cancer Study comprised of patients with metastatic breast cancer (n= 109) who underwent ctDNA testing using the Tempus xF liquid biopsy ctDNA sequencing panel. This panel detects 105-genes that are known oncogenic drivers and resistance mutations. The data was collected from a single academic medical center between the initial year of ctDNA collection in 2019 and 2023. Results: Among these patients, 85 (77.9%) had hormone receptor-positive disease, 13 (11.9%) had triple-negative breast cancer, and 11 (10.0%) had HER2-positive disease (including 3 (2.75%) patients with triple-positive disease). Only 22 of these patients had tissue biopsies that underwent NGS testing. Analysis of all patients revealed that the most common gene alteration was PIK3CA, which was identified in 70 patients. Specifically, the most frequently observed alteration was PIK3CA p.545K, found in 25 patients. Table 1 further details the frequency of each gene in this subset of patients. Among the patients, 34 out of 109 (31%) received an ADC, while only 8 out of 109 (7%) received immunotherapy. Patients with CDKN2A achieved the longest progression-free survival (PFS) on an ADC, with a median PFS of 7 months, whereas patients carrying mutations in TP53, PIK3R1, PIK3CA, PTEN, NF1, BRAF, RHOA, FGFR4, KRAS, TERT, GATA3, HNF1A, FB1, STOP had median PFSs of 2 months or less. Table 2 provides additional information on the response of patients with specific mutations to ADCs. Notably, only one patient received sequential ctDNA testing, and in that case, there was a gain of TP53 p.N239S following sacituzumab govitecan administration compared to the baseline ctDNA test, followed by a gain of PIK3CA p.P449_L455del after trastuzumab deruxtecan administration. Conclusions: As we observe changes in subtypes following treatment progression, researchers are actively seeking biomarkers to better characterize real-time changes in tumor biology that can predict response and resistance to treatments. Further studies are needed to identify additional genes present in ctDNA that can provide mechanistic insights into why certain patients respond favorably to ADCs while others do not. We are currently enrolling patients for a prospective study that aims to assess baseline ctDNA levels and monitor changes in variant allele frequency following treatment with ADCs and immunotherapy. Table 2 Median PFS on ADC by Gene Citation Format: Hannah Chang, Isabela Anawate, Alyssa Low, Shao-Po Huang, Julia Maues, Christine Hodgdon, Isaac Chan. Circulating Tumor DNA as a Biomarker for ADCs in Metastatic Breast Cancer [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 PO4-14-10.

Abstract PO3-16-09: Real-World Experience with Trastuzumab Deruxtecan at a Diverse NCI Comprehensive Cancer Center

Abstract Background: Trastuzumab Deruxtecan (T-DXd) is an antibody-drug conjugate originally approved for use in patients with HER2–positive metastatic breast cancer (MBC). In June 2022, data from the DESTINY-Breast04 trial revealed a near-doubling of progression-free survival (PFS) and significantly improved overall survival (OS) for patients with HER2-low MBC (immunohistochemistry [IHC] grade 1+ or IHC2+ in situ hybridization [ISH]-negative) treated with T-DXd versus standard-of-care chemotherapy. The data from this clinical trial led to the approval of T-DXd for use in patients with HER2-low MBC. However, the DESTINY-Breast studies completed to date have included < 5% black patients. This retrospective study of patients at a racially diverse NCI Comprehensive Cancer Center was designed to study whether T-DXd in a real-world population are comparable to published data. Methods: A retrospective chart review was conducted and identified 72 patients with HER2-low and HER2-positive MBC who received T-DXd between December 2019 and March 2023 at the Winship Cancer Institute at Emory University. Data collected for all patients included demographics, prior breast cancer history, T-DXd -specific and post-T-DXd treatment, and clinical outcomes where applicable. Results: Of the 103 patients who were dosed with T-DXd, 55 (53.4%) had HER2-positive disease, and 48 (46.7%) patients had HER2-low disease. 71 (68.9%) patients had hormone-receptor positive disease and 32 (31.1%) patients had hormone-receptor negative disease. The overall study population was 46% Caucasian; 38% African American; 13% Asian; 4% Unreported. The average number of cycles received was 11 (on treatment an average of 8 months). Pneumonitis occurred in 5 patients (4.9%). HER2-positive patients were typically on T-Dxd for a greater number of cycles than HER2-low patients (Table 1). Additionally, patients with brain metastases were, on average, treated with T-Dxd longer than patients without brain metastases, 14.5 versus 9 cycles. The number of cycles of T-Dxd received, the need for dose reduction, and incidence pneumonitis did not differ significantly between black and white patients. The data for this study is preliminary 48% of the patient population are still actively undergoing T-Dxd treatment. Conclusion: This study reviewed and analyzed T-Dxd treatment in a diverse population of both HER2-positive and HER2-low MBC patients, and in this study, outcomes of treatment did not differ by race. More attention to this topic is needed in future studies of larger populations, along with increased efforts to enroll diverse patient populations in clinical trials. Table 1. Citation Format: Jane Meisel, Maisey Ratcliffe. Real-World Experience with Trastuzumab Deruxtecan at a Diverse NCI Comprehensive Cancer Center [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 PO3-16-09.

Abstract PO2-04-06: Investigation of the genomic evolution of HER2-positive breast cancer following progression on dual HER2-targetted therapy with Trastuzumab and Tucatinib

Abstract Background: Advanced HER2-positive breast cancer remains an incurable and highly morbid condition. One of the key challenges has been treatment of central nervous system (CNS) metastases, commonly seen in those with HER2-positive disease. Tucatinib is a recently approved treatment HER2-targetting tyrosine kinase inhibitor with proven CNS activity. There has been little analysis of potential genomic mechanisms of drug resistance. Method: We retrospectively identified patients that were treated with tucatinib, capecitabine and trastuzumab. We collated baseline clinical data and treatment history and all tumour and plasma samples available were obtained for testing. DNA was extracted from plasma samples using the QIAamp DNA Mini Kit (Qiagen) on 4ml plasma samples. Targeted next generation sequencing (NGS) of serial tumour and plasma samples was performed using a custom hybrid capture assay that covered 180 genes known to be recurrently mutated in breast cancer focusing on the known genomic landscape of metastatic disease as well as the inclusion of specific actionable targets. Survival analyses was performed using Cox regression models. Results: We identified 11 patients at our institution. Plasma samples were available for all 11 patients with a total of 107 serial samples across multiple time points, with a median of 8 (range 2-19) samples per patient. All 11 patients had baseline and End of Treatment (EOT) samples. In addition, 6/11 (54%) patients had tumour sequenced on the same NGS platform prior to commencement of therapy, with 12 individual tumour samples tested. The median PFS of our cohort was 9.6 months (4.0 - NR) with a median OS of 36.2 months (10.4-NR). 7/11 (64%) patients had CNS disease at baseline with their median PFS being 13.5 months (3.9-24.4) and median OS of 36.2months (10.4-NR). Overall, we observed an average of 18.4 (4-35) mutations per patient in tumour, 5.1 (1-15) in baseline plasma and 5.8 (2-14) in EOT plasma. The most frequent mutations seen in baseline tumour samples were ERBB2 (92%), KMT2C (67%) and NCOR1 (58%) compared with KMT2C (64%), NOTCH4 (36%) and PIK3CA (27%) in baseline plasma. Patients with a lower number of ctDNA mutations at baseline showed a trend towards improved survival (PFS 14 months vs 7.5 months). In this small cohort of patients we identified a higher than expected rates of KMT2C mutations. A KMT2C mutation was identified in 67% of samples which is higher than previously described rates of 7-15% in TCGA and METABRIC cohorts respectively. The presence of a concordant ctDNA KMT2C mutation in baseline and progression samples was a poor prognostic indicator (mPFS 7.5 months) when compared with no KMT2C mutation (mPFS 15.5 months) p =0.14 suggesting a possible mechanism of resistance to tucatinib. Conclusions: In this retrospective analysis of patients treated with Tucatinib, Trastuzumab and Capecitabine we established the genomic landscape of heavily pre-treated, advanced HER2-positive disease is complex. We observed there may be a correlation with KMT2C mutations and poorer clinical outcomes, however given the very small number of patients this data remains hypothesis generating, requiring validation with larger datasets. Citation Format: Elizabeth Blackley, Courtney van Geelen, Yi-An Ko, Stephen Wong, Miriam Yeung, Stephen Luen, Sarah-Jane Dawson, Sherene Loi. Investigation of the genomic evolution of HER2-positive breast cancer following progression on dual HER2-targetted therapy with Trastuzumab and Tucatinib [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 PO2-04-06.

Abstract PO1-25-08: Evaluating the role of CDK4/6 inhibition on STAT3 activation in a transgenic mouse model of HER2-positive breast cancer

Abstract Background: The human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase overexpressed in approximately 20-25% of breast cancers with varying biological differences according to hormone receptor (HR) positive status. Combination of chemotherapy with dual HER2 blockade and endocrine therapy (adjuvant) or CDK4/6 inhibitor (CDK4/6i) therapy (metastatic) is standard of care for HER2-positive/HR-positive breast cancer. However, de-escalation of chemotherapy remains of significant interest given associated toxicities and, as a result, alternative therapeutic strategies are needed. One such strategy is targeting the signal transducer and activator of transcription 3 (STAT3) which is constitutively activated in the HER-2 positive setting. Moreover, there is preclinical evidence to suggest that phosphorylated STAT3 (pSTAT3) induces overexpression of cyclin D1 (CCND1), which along with CDK4 may mediate resistance to targeted therapy for HER2-positive breast cancer. However, it is unclear if pSTAT3 plays a significant role in tumorigenesis or the development of resistance to therapy in HER2-positive disease. We aim to evaluate the effect of CDK4/6i therapy with palbociclib on tumor growth in an inducible transgenic HER2-positive mouse model and the impact on pSTAT3 and cyclin D1 levels. Methods: Using an inducible transgenic mouse mammary tumor virus (MMTV) model of HER2-positive breast cancer, we evaluated STAT3 phosphorylation in tumors driven by HER2 expression in addition to the impact of CDK4/6 inhibition with palbociclib on tumorigenesis and pSTAT3 activation. To model tumor recurrence, doxycycline was withdrawn from tumor bearing mice and tumor regression was observed. Subsequently, the mice developed recurrent mammary tumors. Given recurrent tumors in this model are driven by a HER2-independent mechanism, we examined expression of cell cycle proteins together with STAT3 phosphorylation to determine association with recurrence. Result: In addition to expressing HER2, the primary tumors expressed estrogen receptor (ERα), Rb, cyclin D1, and CDK4/6 proteins. STAT3 phosphorylation was also observed. Treatment with palbociclib decreased Rb phosphorylation and decreased tumor growth compared to vehicle treated mice (%TGI 79.37% after 21 days). Furthermore, pSTAT3 levels were not altered with palbociclib therapy. When recurrent tumors were analyzed, they lacked HER2 expression but expressed cyclin D1 and CDK4/6 supporting that tumor growth is driven by cyclin D1/CDK4 pathway. Recurrent tumors also demonstrated pSTAT3 despite lack of HER2 expression suggesting that STAT3 phosphorylation in the recurrent tumors is mediated by an alternative mechanism, potentially the CDK4/6 pathway. Conclusion: We demonstrate STAT3 activation in a mouse model of HER2 driven breast cancer and show persistent activation in recurrent tumors lacking HER2 expression rendering them resistant to HER2-targeted therapy. We also demonstrate the anti-tumor effect of palbociclib in primary tumors with HER2-dependent proliferation. Taken together, our findings suggest that pSTAT3 is a viable therapeutic target and provides the rationale for combination therapy with CDK4/6 inhibition using palbociclib and STAT3 inhibition with a novel STAT3 inhibitor in HER2-positive breast cancer. This therapeutic approach may represent a potential chemotherapy de-escalation strategy. Citation Format: Taiwo Adesoye, Linjie Luo, Tuyen Bui, Serena Kim, Hannah Wingate, Debu Tripathy, Kelly Hunt, Khandan Keyomarsi. Evaluating the role of CDK4/6 inhibition on STAT3 activation in a transgenic mouse model of HER2-positive breast cancer [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 PO1-25-08.

Abstract Db1-01: Anthracyclines …to give or not to give? “For” argument

Abstract Anthracyclines have been one of the mainstays of early breast cancer treatment for decades. In a recent patient-level meta-analysis including data from over 18,000 patients, anthracycline-containing regimens were associated with improvements in disease-free survival and overall survival, regardless of estrogen receptor or nodal status. Importantly, trials specifically designed and powered to assess the safety of anthracyclines omission failed to demonstrate the non-inferiority of taxane-based anthracycline-free regimens and confirmed the benefit of these agents, particularly in patients with node-positive and hormone receptor-negative breast cancer. Several therapies incorporated into the management of early breast cancer were studied in populations largely treated with anthracycline-based chemotherapy backbones in both HER2-negative (i.e., perioperative pembrolizumab, post neoadjuvant olaparib and capecitabine) and HER2-positive disease (i.e., dual HER2 blockade, adjuvant T-DM1). It is uncertain whether the benefits demonstrated by these strategies would be maintained if anthracyclines were omitted. While anthracyclines are associated with some long-term toxicities, particularly with an increased risk of lymphoproliferative malignancies and dose-dependent cardiotoxicity, these adverse events are not associated with an increased risk of death (including deaths from cardiovascular causes) when compared to anthracycline-free regimens. The identification of risk factors for cardiotoxicity, combined with improvements in monitoring strategies, allows improvements in patient selection, early detection of myocardial damage and, possibly, implementation of cardioprotective interventions, leading to improved cardiovascular outcomes. Until high-quality evidence demonstrates the safety of omitting anthracyclines in high-risk populations, these agents should continue to be used in carefully selected patients after individual risk versus benefit assessment to be shared with the patient. Citation Format: Martine Piccart, Guilherme Nader-Marta. Anthracyclines …to give or not to give? “For” argument [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 Db1-01.

Abstract PO3-01-04: Neoadjuvant compared to adjuvant chemotherapy combined with trastuzumab in patients with HER2-positive breast cancer: a register-based cohort study

Abstract Introduction Neoadjuvant therapy (NAT) is considered the standard of care in patients with HER2-positive breast cancer mainly due to the possibility to adjust the post-neoadjuvant treatment based on the tumor response to NAT. However, there is no convincing evidence on a survival benefit with NAT compared to adjuvant therapy (AT) for HER2-positive breast cancer. The aim of the present study was to compare the two therapeutic strategies in a register-based cohort of Swedish patients with primary operable HER2-positive breast cancer. Method The research database BCBaSe 3.0, which is based on the Swedish National Quality breast cancer register, was used to identify patients with primary operable HER2-positive breast cancer that diagnosed between 2008 and 2020 and received either NAT or AT including chemotherapy and trastuzumab. To mitigate confounding by indication bias, propensity score matching (PSM) with 1:1 matching was applied. The effectiveness of the two therapeutic strategies was investigated through analyzing distant disease-free survival (DDFS), breast-cancer specific survival (BCSS), and overall survival (OS). Multivariate Cox regression analyses were performed for the outcomes of interest to provide Hazard Ratios (HR) and corresponding 95% Confidence Intervals (CI). Results In total, 7258 patients with primary operable HER2-positive breast cancer treated with either NAT or AT were identified, 1789 (24.6%) received NAT and 5469 (75.4%) AT. After 1:1 PSM, 1258 patients in each therapeutic strategy were available for comparisons. After a median follow-up of 63 months, no statistically significant differences between NAT and AT were observed in either outcome (HR for DDFS: 0.97; 95% CI: 0.72 – 1.30; HR for BCSS: 0.69; 95% CI: 0.45 – 1.07; HR for OS: 0.72; 95% CI: 0.50 – 1.05). In subgroup analyses, estrogen-receptor status did not impact the results that remained statistically non-significant between NAT and AT whereas in patients with clinically positive lymph node status, NAT resulted in better BCSS (HR: 0.44; 95% CI: 0.22 – 0.89) and OS (HR: 0.49; 95% CI: 0.29 – 0.90). The latter trend was not evident in patients with clinically negative lymph node status. Conclusion Our study results confirm the equivalence of NAT and AT in terms of prognosis for patients with operable HER2-positive disease and imply a potential benefit of NAT compared to AT in patients with clinically positive lymph node status. Considering the emerging treatment strategies in HER2-positive breast cancer patients treated with NAT (pertuzumab as a part of NAT, T-DM1 as post-neoadjuvant therapy) that have been shown to improve survival but are not reflected in the study cohort, NAT should be considered as the strategy with the higher possibility to improve long-term prognosis for patients with HER2-positive disease. Citation Format: Servah Hosseini-Mellner, Åsa Wickberg, Antonis Valachis, Andreas Karakatsanis. Neoadjuvant compared to adjuvant chemotherapy combined with trastuzumab in patients with HER2-positive breast cancer: a register-based cohort study [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 PO3-01-04.

Abstract PO3-20-06: TRUDI: A phase II study of neoadjuvant TRastuzumab derUxtecan and Durvalumab for stage III HER2-expressing Inflammatory breast cancer

Abstract Background: Despite being a rare presentation of breast cancer, inflammatory breast cancer (IBC) is responsible for up to 10% of all breast cancer-related deaths. Most IBCs express HER2, with up to 40% of all IBCs being HER2-positive and 40% being HER2-low. Additionally, IBC more often exhibits PD-L1 expression compared to non-IBC, suggesting a preeminent role for immune evasion in the development and progression of IBC. No systemic treatment approaches have been yet developed specifically for IBC, and standard treatments commonly lead to poor outcomes. Trastuzumab deruxtecan (T-DXd) is an anti-HER2 antibody-drug conjugate currently approved for patients with pretreated HER2-positive and HER2-low metastatic breast cancer. Early-phase data highlighted the safety and potential synergy of combining T-DXd with the immune checkpoint inhibitor durvalumab. The aim of TRUDI is to evaluate the clinical activity and safety of neoadjuvant T-DXd with durvalumab among patients with HER2-expressing IBC. Trial Design: TRUDI is an ongoing, open label, multicenter, two cohort investigator-initiated phase II neoadjuvant trial for patients with stage III HER2-expressing IBC. The trial was activated in May 2023, with enrollment ongoing. Eligible participants are women and men with previously untreated, stage III (T4d, any N) breast cancer, clinically determined to be IBC. Patients will be included in two cohorts, depending on the locally determined HER2 status (with any hormone receptor [HR] status): Cohort 1 (n=36) for patients with HER2-positive disease (HER2 IHC 3+ or 2+/ISH amplified); Cohort 2 (n=27) for patients with HER2-low disease (HER2 IHC 1+ or 2+/ISH not amplified). Patients will receive eight cycles of T-DXd (5.4 mg/kg IV every 21 days) combined with durvalumab (1125 mg IV every 21 days), followed by modified radical mastectomy and post-mastectomy radiation. Post-surgical systemic treatment will follow local standards. Tumor tissue will be collected at baseline, cycle 1 day 8, and at surgery; blood will be collected at baseline, cycle 4 day 1, cycle 7 day 1 and at surgery; stool will be collected at baseline, after 3-6 weeks of treatment and surgery. The primary endpoint is pathologic complete response (pCR; ypT0/Tis ypN0). Patients in each cohort will be enrolled based upon Simon two-stage designs: in Cohort 1, if ≥8/20 patients with HER2-positive IBC experience pCR then a total of 36 patients will be enrolled. In Cohort 2, if ≥1/18 patients with HER2-low IBC experience pCR then a total of 27 patients will be enrolled. Secondary endpoints include the residual cancer burden at surgery, event free survival, distant progression or distant disease-free survival, as well as safety of the regimen. Exploratory objectives will investigate biomarker analyses on tissue, blood, and microbiome to explore the association of HER2 expression, immune variables, and stool composition on the efficacy of T-DXd with durvalumab among patient with HER2-expressing IBC. To our knowledge, this is the first and only ongoing study testing the combination of an anti-HER2 antibody-drug conjugate with immunotherapy for the neoadjuvant treatment of patients with IBC. Clinical trial information: NCT05795101. Citation Format: Paolo Tarantino, Samuel Niman, Antonio Giordano, Faina Nakhlis, Jennifer Bellon, Wendy Woodward, Azadeh Nasrazadani, Sadia Saleem, Anthony Lucci, Michelle DeMeo, Naoto Ueno, Sara Tolaney, Vicente Valero, Meredith Regan, Rachel Layman, Filipa Lynce. TRUDI: A phase II study of neoadjuvant TRastuzumab derUxtecan and Durvalumab for stage III HER2-expressing Inflammatory breast cancer [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 PO3-20-06.

Abstract PO5-05-14: Survival in Young Women with De Novo or Recurrent Metastatic Breast Cancer

Abstract Background. Approximately 12,000 women aged 40 years or younger are diagnosed with breast cancer every year in the United States alone. Limited data exist regarding survival in young women with metastatic breast cancer (MBC), particularly when considering modern tumor subtyping and treatment, though previous studies have suggested that patients presenting with MBC at diagnosis (de novo stage IV) have better prognosis than those who develop recurrent MBC after initial diagnosis of stage 0-III disease. We sought to determine survival rates in young patients with MBC stratified by disease presentation (de novo versus recurrent) and subtype. Methods. The Young Women’s Breast Cancer Study (YWS) is a multicenter, prospective cohort which enrolled 1,302 women diagnosed with stage 0-IV breast cancer at age ≤40 from 13 North American academic and community-based sites from 2006-2016. The current median follow-up is 10.1 (range 0.4-16.3) years. Histopathology slides were centrally reviewed for 97% of the participants, and clinical tumor molecular subtypes have been detailed. In the recurrent group, receptors were obtained from the initial breast surgery. Descriptive analyses were used to characterize patients with de novo or recurrent MBC, including demographic and disease characteristics, and survival rates. Overall survival was estimated using the Kaplan-Meier method and compared by log-rank test between those who presented with de novo and relapsed disease overall and within tumor subtypes. Results. Among 246 patients included in this analysis, 74.0% (n=182) had recurrent MBC and 26.0% (n=64) had de novo MBC. Most patients were white (n=208, 84.6%), while 6.9% were Asian (n=17), 4.5% Black (n=11), 0.8% Native American (n=2), 0.8% multiracial (n=2) and 2.4% other/unknown (n=6). A total of 4.5% of patients were Hispanic (n=11). Median age at diagnosis of de novo MBC was 37 years and 40 years for diagnosis of metastasis in the recurrent group. Median disease-free interval was 3.23 (range 0.32 – 13.84) years for the recurrent MBC group. Among all patients with MBC, most (55.7%, n=137) had estrogen receptor (ER) and/or progesterone receptor (PR)-positive, human epidermal growth factor receptor 2 (HER2)-negative disease, whereas 17.9% (n=44) had ER and/or PR-positive HER2-positive, 7.3% (n=18) had ER/PR-negative HER2-positive, and 18.7% (n=46) had triple-negative tumors. A greater proportion of participants (43.8%, n=28) had HER2-positive disease in the de novo group than in the recurrent group (18.7%, n=34), P=< 0.0001. A total of 10.9% (n=7) of de novo patients had a germline BRCA mutation, compared to 13.7% (n=25) in the recurrent group. Median survival was 5.09 (95% CI: 3.74 – 6.38) years in the de novo group and 2.63 (95% CI: 1.98 – 3.21) years in the recurrent MBC group (P=0.0004). When stratifying by subtype, survival among patients with de novo ER and/or PR-positive HER2-positive disease was longer than among patients with recurrent disease (P=0.0149), whereas there were no statistically significant differences in survival between the de novo and recurrent disease groups in other disease subtypes (Table 1). Conclusion. Survival in young women with MBC is highly heterogeneous and varies substantially by tumor subtype and disease presentation. Those with de novo ER and/or PR-positive HER2-positive subtype appear to have better outcomes than those with recurrent MBC with the same subtype. These findings can inform patient care and potential future research to improve outcomes for young patients with MBC. Table 1: Median survival by disease presentation and subtype * 1 patient with recurrent MBC was not included because the initial diagnosis was DCIS MBC: metastatic breast cancer; OS: overall survival; CI: confidence interval; ER: estrogen receptor; PR: progesterone receptor; HER2: human epidermal growth factor receptor 2 Citation Format: Leticia Varella, Yue Zheng, Shoshana Rosenberg, Gregory Kirkner, Craig Snow, Kathryn Ruddy, Rulla Tamimi, Jeffrey Peppercorn, Lidia Schapira, Virginia Borges, Steven Come, Laura Collins, Ellen Warner, Kate Dibble, Eric Winer, Ann Partridge. Survival in Young Women with De Novo or Recurrent Metastatic Breast Cancer [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 PO5-05-14.