Growth Factor Receptor 2-positive Breast Research Articles

Abstract P3-02-05: Interim Analysis Results from a European Disease Registry Study Aimed to Prospectively Observe Treatment Patterns and Outcomes in Patients with HER2+ Unresectable Locally Advanced or Metastatic Breast Cancer

Abstract BACKGROUND: Metastatic breast cancer (MBC) is incurable, with the primary goal of treatment being to extend survival while preserving quality of life. Treatment options available to patients (pts) with human epidermal growth factor receptor-2 positive breast cancer (HER2+ BC) may vary between countries, in terms of both the drugs used and the sequence in which they are used. There is limited data available on the clinical characteristics and outcomes in pts with unresectable locally advanced (LA) BC. This study aimed to capture real-world data on treatment patterns and clinical outcomes in HER2+ unresectable LABC and MBC. METHODS: SAMANTHA (NCT02913456) is an ongoing, prospective, multicentre non-interventional study designed to observe pts with HER2+ unresectable LABC or MBC for a period of up to 8 years on study. The primary objectives are progression-free survival (PFS), assessed according to standard medical practice, and the treatment received. Secondary objectives included overall survival (OS), duration of response and safety. This pre-planned interim analysis reports baseline characteristics, treatment regimens received, first-line (1L) PFS by advanced BC status and the incidence of adverse events (AEs). RESULTS: The study enrolled 647 pts from five European (EU) countries (Nov 2016-Nov 2019); 629 received 1L treatment and were included in data analysis. At data cut-off date (16 Nov 2021), median follow-up on study was 30.4 months (mo; range: 0.1; 60.0); 342 (54%) pts discontinued 1L treatments, of whom 170 (50%) pts received 2L treatments, 74 pts died, 49 pts were lost to follow-up, 35 pts withdrew consent and 14 pts withdrew due to physician decision. The full analysis set (FAS) included 222 (35%) LABC pts and 407 (65%) MBC pts [Table]. Pertuzumab/trastuzumab based regimens were given as 1L in the majority of pts [462 (73 %)]. The FAS Median (m) PFS in 1L was 41.3 mo (95% CI: 36.1, 54.1) for LABC and 23.5 mo (95% CI: 20.6, 27.6) for MBC. Median OS was not reached. In the FAS, any AEs were reported in 352 (56%) pts; of these 212 (34%) had a grade 3 or higher AE. Serious (S) AEs were reported in 135 (22%) pts; of whom, 36 (6%) pts had treatment related SAEs. CONCLUSIONS: This interim analysis of SAMANTHA provides a snapshot of LABC/MBC treatment practices in five EU countries, where pertuzumab/trastuzumab based regimens appear to be the most used 1L treatment options, which aligns with the recommended standard of care. The mPFS is consistent with previous literature although higher than what was reported in the pivotal clinical trial CLEOPATRA. Given the good outcome observed in 1L and the current follow-up period of 30.4 mo, the data are not yet mature enough to provide complete insights into the treatment sequencing patterns and the clinical outcomes associated with these treatments. Acknowledgments: The study is sponsored by F. Hoffmann-La Roche Ltd. Table: Demographics and baseline disease characteristics of patients by status of advanced BC Citation Format: Marija Balic, Luis Costa, Joseline Ojaimi, Cristina Marinela Oprean, José L. Passos Coelho, Isabel Pazos, Fabio Puglisi, Thibaut Sanglier, Giuseppa Scandurra, Michael Schenker, Laurentia A. Wahyudi, Georgi Zhbantov, Constanta Timcheva. Interim Analysis Results from a European Disease Registry Study Aimed to Prospectively Observe Treatment Patterns and Outcomes in Patients with HER2+ Unresectable Locally Advanced or Metastatic Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-02-05.

Abstract P4-03-34: Treatment Patterns and Associated Outcomes Among Patients with HER2+ Metastatic Breast Cancer in the United States

Abstract Background Historically, standard-of-care treatments for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC) have been pertuzumab and trastuzumab combined with a chemotherapeutic agent in first line (1L), and trastuzumab emtansine (T-DM1) in the second line (2L). However, two new treatments have recently been approved for patients who previously received HER2-targeted therapy; fam-trastuzumab deruxtecan-nxki [Enhertu®] and tucatinib [Tukysa] (in triplet combination) in 2019 and 2020, respectively. The goal of this study was to characterize treatment patterns of patients with HER2+ mBC from receipt of first line therapy and subsequent treatments received in real world community oncology practices. Methods Adults diagnosed with HER2+ mBC from January 2013 – January 2021 were selected from the Flatiron Health electronic health record–derived database; a US-wide database curated from community clinics that comprises de-identified patient-level structured and unstructured data. Patients were followed from index date (start of 1L therapy) to death or last activity date. Descriptive statistics reported baseline patient characteristics and treatment patterns. Time to treatment discontinuation (TTD), real-world progression-free survival (rwPFS), and real-world overall survival (rwOS) were estimated using the Kaplan-Meier method. Results A total of 2,074 mBC HER2+ patients with at least 1 line of therapy were included during the study time period. Median follow-up time was 26.0 months (Interquartile range [IQR]: 12.6-44.7). Patients were mostly white (62.7%), median age 61 years (IQR:24-84), 43.0% were stage IV at initial breast cancer diagnosis, and 62.8% had positive hormone receptor (HR) status. Of the 2,074 patients in our study population, 1,159 (55.8%) received 2L therapy, and 584 (28.2%) received a 3L therapy. In terms of 1L therapy, 1,607 (77.5%) received a trastuzumab-based (T-based) regimen, 205 (9.9%) received chemotherapy only, and 153 (7.4%) received a T-DM1 based therapy. The most common regimens across 1L included pertuzumab+trastuzumab+taxane (THP) (38.9%), THP + a platinum agent (7.5%), and T-DM1 (6.1%). From start of 1L, overall median TTD was 10.8 months (95% confidence interval [CI]: 10.1-11.5), median rwPFS was 11.5 months (95% CI: 10.8-12.3), and median rwOS was 40.3 months (95% CI: 37.8-43.4). Among the 1,607 patients who received any T-based regimen in 1L, 496 (30.9%) received T-DM1, 175 (10.9%) received a T-based regimen again, 78 (4.9%) received any other HER2-based regimen, 59 (3.7%) received hormonal therapy alone and 33 (2.1%) received chemotherapy. The most common regimens across 2L (n=1,159) were T-DM1 monotherapy (35.7%), THP (11.2%), and T-DM1+hormone therapy (8.0%). From start of 2L, overall median TTD was 8.3 months (95% CI: 7.6-9.0), median rwPFS was 7.4 months (95% CI: 6.8-8.1), and median rwOS was 27 months (95% CI: 25.9-30.0). Conclusions Variability, which may impact outcomes, is observed in treatment approaches for HER2+ mBC. Additionally, more than half the patients on 1L treatment progressed within a year of initiating treatment, highlighting a remaining need for effective therapies that limit progression and maintain clinical benefit in 1L. Citation Format: Clara Lam, Della Varghese, Beth L. Nordstrom, Brian Murphy, Jenna Collins, Sandhya Mehta. Treatment Patterns and Associated Outcomes Among Patients with HER2+ Metastatic Breast Cancer in the United States [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-34.

Abstract PD18-11: Dose-Expansion Study of Trastuzumab Deruxtecan as Monotherapy or Combined With Pertuzumab in Patients With Metastatic Human Epidermal Growth Factor Receptor 2-Positive (HER2+) Breast Cancer in DESTINY-Breast07 (DB-07)

Abstract Background: In trials of HER2+ metastatic breast cancer (mBC), trastuzumab deruxtecan (T-DXd) monotherapy showed durable efficacy (DESTINY-Breast01) and significantly prolonged progression-free survival vs trastuzumab emtansine (DESTINY-Breast03). T-DXd is approved in the US for patients with HER2+ unresectable/mBC who received ≥1 prior anti-HER2–based treatment (tx) in the metastatic or neo-/adjuvant setting and recommended for approval in the EU as 2nd-line tx. Preclinical data suggest that T-DXd used in combination with other anticancer tx may lead to improved efficacy. The purpose of DB-07 is to assess the safety and efficacy of T-DXd alone or with other anticancer tx for patients with HER2+ mBC. Here we report preliminary data from the DB-07 dose-expansion phase for T-DXd monotherapy and T-DXd + pertuzumab (P) as 1st-line (1L) tx in mBC. Methods: DB-07 (NCT04538742) is an ongoing, phase 1b/2, 2-part (part 1: dose finding; part 2: dose expansion), modular, open-label trial of T-DXd alone or with other anticancer tx in patients with HER2+ mBC. In part 2, patients in module (mod) 0 received T-DXd 5.4 mg/kg every 3 weeks (Q3W) and in mod 2, T-DXd 5.4 mg/kg + P 420 mg Q3W (loading dose: 840 mg), the recommended phase 2 dose. Patients in these mods must be mBC tx naive. For part 2, the primary objective is to assess safety and tolerability. A secondary objective is to assess the objective response rate (ORR) per local investigators by Response Evaluation Criteria In Solid Tumors v1.1. We report results for patients randomized before Oct 13, 2021 to mods 0 and 2 of part 2 (data cutoff [DCO]: Mar 4, 2022); recruitment is ongoing. Based on the distinct mechanism of action of T-DXd and P, we conducted preclinical studies with the drugs in HER2-overexpressing cell lines to elucidate their potential synergies. To assess the effects on T-DXd internalization, live cell imaging was performed using pH-dependent fluorescently labeled T-DXd. To assess the effects on HER2 signaling, total and p-HER2 levels and downstream substrates were evaluated by immunoblot. Results: 23 patients were enrolled in the T-DXd monotherapy mod; 20 (87.0%) were receiving tx and 3 (13.0%) discontinued tx (withdrawal by patient, n=2; adverse event [AE], n=1) by DCO. 22 patients were enrolled in the T-DXd + P mod; 20 (90.9%) were receiving tx and 2 (9.1%) discontinued tx (AE, n=1; disease progression, n=1) by DCO. All patients experienced AEs (Table); 1 patient in each mod died. The unconfirmed ORR (80% CI) with T-DXd monotherapy and T-DXd + P was 82.6% (68.2%-92.2%) and 77.3% (61.9%-88.5%), respectively; updated data will be presented. Preclinical studies showed that T-DXd was more rapidly and effectively internalized in combination with P than when administered alone. Immunoblotting of cell lysates showed a greater reduction in total HER2 and HER2 signaling in response to combination tx than with T-DXd or P alone. Discussion: In summary, 1L T-DXd monotherapy and T-DXd + P safety profiles and antitumor activity were consistent with those previously reported for T-DXd. Mature data in these mods are awaited, and other T-DXd combinations are being investigated in additional mods. Preclinical studies showed the potential for P to induce greater internalization of T-DXd and inhibition of HER2-driven signaling. These results support investigation of T-DXd in larger ongoing trials (eg, NCT04784715). Table 1: Summary of treatment duration and safety data Citation Format: Erika Hamilton, Komal Jhaveri, Sherene Loi, Carey Anders, Peter Schmid, Konstantin Penkov, Elena Artamonova, Lyudmila Zhukova, Daniil L. Stroyakovsky, Dinesh Chandra Doval, Rafael Villanueva, Flavia Michelini, Sarat Chandarlapaty, Matt Wilson, Sarice R. Boston, Adam Konpa, Shoubhik Mondal, Fabrice Andre. Dose-Expansion Study of Trastuzumab Deruxtecan as Monotherapy or Combined With Pertuzumab in Patients With Metastatic Human Epidermal Growth Factor Receptor 2-Positive (HER2+) Breast Cancer in DESTINY-Breast07 (DB-07) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-11.

Abstract OT2-16-03: Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress)

Abstract Background: The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients (pts) progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in pts with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in pts with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods: HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 pts will be enrolled. Eligible pts will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, ECOG Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Pts will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Pts with HR+ disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, with additional sites planned. Citation Format: Erika Hamilton, Junji Tsurutani, Giuseppe Curigliano, Miguel Martín, Ciara C. O’Sullivan, Joo Hyuk Sohn, Konstantinos Tryfonidis, Libero Santarpia, Shan Yang, Véronique Diéras. Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-16-03.

A Real-World Data Retrospective Cohort Study of HER2-positive, Early-Stage Breast Cancer in Patients 70 Years of Age or Older: Natural History, Treatment Patterns, and Outcomes

PurposeEarly-stage human epidermal growth factor receptor 2-positive (HER2-positive) breast cancers (BCs) are routinely treated with intense perioperative chemotherapy combined with HER2-targeted agents. There is thus an unmet need for knowledge about treatment patterns and outcomes among patients 70 years of age or older, as this is an under-represented subset of patients in large clinical trials. MethodsWe used a deidentified cohort derived from a nationwide electronic health record database to conduct a retrospective cohort study of patients with HER2-positive BCs. Descriptive statistics were used to evaluate tumor characteristics, treatment patterns across age groups, and pathologic complete response rates. We used Kaplan–Meier survival curves to estimate recurrence-free and overall survivals; Cox proportional methods were used for adjustments with covariates of interest, including age as a categorical variable. ResultsWe included 395 patients with HER2-positive stage I to III BCs who were 70 years of age or older. Most patients had tumors with high nuclear-grade T2 tumors, and received surgical treatment first. Most patients (61.7%) who received HER2 therapies underwent treatment in the adjuvant setting; paclitaxel and trastuzumab combination was the most commonly used adjuvant regimen. Older age was associated with increased hazard of recurrence or death. We did not detect significant evidence of decline in performance status, but there was modest weight drop after perioperative HER2 treatments. ConclusionFindings suggest that patients in this older-age cohort were treated with de-escalated perioperative strategies and had poorer outcomes; our findings should be validated in future studies.

High-throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with HER2-targeting drugs in breast cancer.

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is an aggressive subtype of this disease. Targeted treatment has improved outcome, but there is still a need for new therapeutic strategies as some patients respond poorly to treatment. Our aim was to identify compounds that substantially affect viability in HER2+ breast cancer cells in response to combinatorial treatment. We performed a high-throughput drug screen of 278 compounds in combination with trastuzumab and lapatinib using two HER2+ breast cancer cell lines (KPL4 and SUM190PT). The most promising drugs were validated in vitro and in vivo, and downstream molecular changes of the treatments were analyzed. The screen revealed multiple drugs that could be used in combination with lapatinib and/or trastuzumab. The Src-inhibitor dasatinib showed the largest combinatorial effect together with lapatinib in the KPL4 cell line compared to treatment with dasatinib alone (p < 0.01). In vivo, only lapatinib significantly reduced tumor growth (p < 0.05), whereas dasatinib alone, or in combination with lapatinib, did not show significant effects. Protein analyses of the treated xenografts showed significant alterations in protein levels compared to untreated controls, suggesting that all drugs reached the tumor and exerted a measurable effect. In silico analyses suggested activation of apoptosis and reduced activity of survival pathways by all treatments, but the opposite pattern was observed for the combinatorial treatment compared to lapatinib alone.

Absolute Lymphocyte Count Changes During Neoadjuvant Chemotherapy are Associated With Prognosis of Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Patients

ntroduction/BackgroundSome reports have shown that absolute lymphocyte count (ALC) is associated with prognosis in breast cancer; however, the impact of ALC changes remains unclear. This study aimed to investigate the relationship between ALC changes during neoadjuvant chemotherapy for human epidermal growth factor receptor-2 (HER2)-positive breast cancer patients and disease prognosis. Patients and MethodsThis retrospective cohort study January 2010 to September 2020) included patients diagnosed with HER2-positive breast cancer and treated with trastuzumab-based neoadjuvant chemotherapy. The ALC ratio was defined as the ALC value after administration of the anti-HER2 drug divided by the ALC value before administration. The optimal ALC ratio cut-off value was identified using the receiver operating characteristic curve analysis and Youden's index. The relationship between the ALC ratio and disease-free survival was assessed using the Kaplan–Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model. ResultsData from a total of 100 HER2-positive breast cancer patients were analyzed. The cut-off value of the ALC ratio was set as 1.142. The median follow-up period was 52.0 (range: 5.1-123.7) months. The 5-year disease-free survival rates were 88.4% and 60.9% in the high-and low-ALC ratio groups, respectively, and were significantly higher in the high-ALC ratio group (p = .0031). The ALC ratio was an independent prognostic factor in multivariate Cox proportional hazards analysis (p = .0032). ConclusionHER2-positive breast cancer patients with a higher ALC ratio during trastuzumab-based neoadjuvant chemotherapy may have a better prognosis than their counterparts.

CMTM6 overexpression confers trastuzumab resistance in HER2-positive breast cancer

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is characterized by invasive growth, rapid metastasis and chemoresistance. Trastuzumab is an effective treatment for HER2+ breast cancer; however, trastuzumab resistance leads to cancer relapse and metastasis. CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) has been considered as a new immune checkpoint for tumor-induced immunosuppression. The role of CMTM6 in trastuzumab resistance remains unknown. Here, we uncover a role of CMTM6 in trastuzumab-resistant HER2+ breast cancer. CMTM6 expression was upregulated in trastuzumab-resistant HER2+ breast cancer cell. Patients with high CMTM6 expressing HER2+ breast cancer had worse overall and progression-free survival than those with low CMTM6 expression. In vitro, CMTM6 knockdown inhibited the proliferation and migration of HER2+ breast cancer cells, and promoted their apoptosis, while CMTM6 overexpression reversed these effects. CMTM6 and HER2 proteins were co-localized on the surface of breast cancer cells, and CMTM6 silencing reduced HER2 protein levels in breast cancer cells. Co-immunoprecipitation revealed that CMTM6 directly interacted with HER2 in HER2+ breast cancer cells, and CMTM6 overexpression inhibited HER2 ubiquitination. Collectively, these findings highlight that CMTM6 stabilizes HER2 protein, contributing to trastuzumab resistance and implicate CMTM6 as a potential prognostic marker and therapeutic target for overcoming trastuzumab resistance in HER2+ breast cancer.

Overview on Current Trends and Emerging Therapies in the Chemotherapy of Patients with Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

Over the past few decades, significant progress has been made in the management of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) due to the development of targeted therapies. However, HER2-positive BC is an aggressive subtype, posing significant challenges, including treatment resistance and disease recurrence. Current standard treatment options for HER2-positive BC include combinations of chemotherapy drugs, targeted therapies such as trastuzumab and pertuzumab, and hormone therapies. However, some important limitations of these treatments, such as resistance and adverse effects, are reported. Also, we showed emerging therapeutic options, such as novel chemotherapy agents, antibody-drug conjugates, and immune checkpoint inhibitors, and discussed their mechanisms of action, potential benefits, and potential future directions in the field.

ΔNp63 is regulated by insulin/IGF-1 signaling in normal basal/progenitor mammary cells and in luminal-type breast cancer cells.

Breast cancers are a heterogeneous group of tumors classified according to their histological growth patterns and receptor expression characteristics. Intratumor heterogeneity also exists, with subpopulations of cells with different phenotypes found in individual cancers, including cells with stem or progenitor cell properties. At least two types of breast cancer stem cells (CSCs) exist, the epithelial and the basal/mesenchymal subtypes, although how these phenotypes are controlled is unknown. ΔNp63 is a basal cell marker and regulator of stem/progenitor cell activities in the normal mammary gland and is expressed in the basal-like CSC subpopulation in some estrogen receptor-positive (ER+) and/or human epidermal growth factor receptor 2-positive (HER2+) breast adenocarcinomas. Whilst p63 is known to directly impart CSC properties in luminal breast cancer cells, how p63 is regulated and induced in these cells is unknown. We initially confirmed the existence of a small subpopulation of ΔNp63+ cells in lymph node metastases of ER+ human ductal adenocarcinomas, indicating together with previous reports that ΔNp63+ tumor cells are present in approximately 40% of these metastases. Notably, ΔNp63+ cells show a preferential location at the edge of tumor areas, suggesting possible regulation of ΔNp63 by the tumor microenvironment. Subsequently, we showed that the high levels of ΔNp63 in basal non-transformed MCF-10A mammary epithelial cells rely on insulin in their culture medium, whilst ΔNp63 levels are increased in MCF-7 ER+ luminal-type breast cancer cells treated with insulin or insulin-like growth factor 1 (IGF-1). Mechanistically, small molecule inhibitors and siRNA gene knockdown demonstrated that induction of ΔNp63 by IGF-1 requires PI3K, ERK1/2, and p38 MAPK activation, and acts through FOXO transcriptional inactivation. We also show that metformin inhibits ΔNp63 induction. These data reveal an IGF-mediated mechanism to control basal-type breast CSCs, with therapeutic implications to modify intratumor breast cancer cell heterogeneity and plasticity.

Clinical Verification on the Predictors for Febrile Neutropenia in Breast Cancer Patients Treated With Neoadjuvant Chemotherapy.

Febrile neutropenia (FN) is a potentially life-threatening complication of chemotherapy. In this study, we evaluated the predictors for FN according to neoadjuvant chemotherapy (NAC) in all breast cancer subtypes. We examined 327 patients with breast cancer treated with NAC. The correlation between the development of FN and clinicopathological features, including systemic inflammatory markers, and prognosis was evaluated retrospectively. There were no significant differences between patients with and without FN in terms of disease-free survival or overall survival (p=0.562, p=0.149, log-rank, respectively). Low body mass index (BMI) (p<0.001), white blood cells (WBC) at baseline (p=0.008), and NAC regimen (p=0.026) significantly related with FN in all patients with breast cancer. Moreover, among patients with hormone receptor-positive/human epidermal growth factor receptor 2-positive breast cancer, low WBC (p=0.007) and low absolute lymphocyte counts (ALC) at baseline (p=0.039) were significantly associated with FN, and overall survival was significantly worse in patients with FN development (p=0.039, log-rank). Poor immune activity-related factors, low ALC or BMI, may be useful to predict the development of FN in patients with breast cancer.

Treatment strategies for hormone receptor-positive, human epidermal growth factor receptor 2-positive (HR+/HER2+) metastatic breast cancer: A review.

Hormone receptor-positive HER2-positive (HR+/HER2+) metastatic breast cancer (MBC) is a unique subtype of breast cancer. Most current guidelines recommend that combination regimens based on anti-HER2 therapy should be used as first-line treatment for HER2+ MBC, irrespective of HR status. Endocrine therapy can be applied as maintenance therapy for patients who are intolerant to chemotherapy or post-chemotherapy. Increasing evidence suggests that complex molecular crosstalk between HR and HER2 pathways may affect the sensitivity to both HER2-targeted and endocrine therapy in patients with HR+/HER2+ breast cancer. Recent research and clinical trials have revealed that a combination of endocrine therapy and anti-HER2 approaches without chemotherapy provides along-term disease control for some patients, but the challenge lies in how to accurately identify the subsets of patients who can benefit from such a de-chemotherapy treatment strategy. In this review, we aim to summarize the results of preclinical and clinical studies in HR+/HER2+ MBC and discuss the possibility of sparing chemotherapy in this subgroup of patients.

Oncologic necessity for the complete removal of residual microcalcifications after neoadjuvant chemotherapy for breast cancer

The surgical range of breast cancer that shows pathologic complete response (pCR) without change in microcalcifications after neoadjuvant chemotherapy (NAC) is controversial. This study examined whole breast specimens to evaluate the necessity of mastectomy in those cases. The viability of cancer cells around the residual microcalcification was assessed using prospectively collected breast samples to confirm the presence or absence of cancer cells. A total of 144 patients with breast cancer and diffuse microcalcifications were classified into the reduced mass with no change in residual microcalcification (RESMIN, n = 49) and non-RESMIN (n = 95) groups. Five specimens were prospectively evaluated to assess the presence of viable cancer cells around the microcalcification. Tumor responses to NAC were significantly better with high pCR rates in the RESMIN group (p = 0.005 and p = 0.002). The incidence of human epidermal growth factor receptor 2-positive and triple-negative breast cancers was significantly high in the RESMIN group (p = 0.007). Although five (10.2%) patients had locoregional recurrence in the RESMIN group, no local recurrence in the breast was reported. Although pCR was highly estimated, residual cancers, including ductal carcinoma in situ, remained in 80% cases. Therefore, given the weak scientific evidence available currently, complete removal of residual microcalcifications should be considered for oncologic safety.

Tumor-Infiltrating Lymphocytes and Immune Response in HER2-Positive Breast Cancer.

Human epidermal growth factor receptor 2-positive (HER2-positive) breast cancer accounts for 15 to 25% of breast cancer cases. Although therapies based on the use of monoclonal anti-HER2 antibodies present clinical benefit for a subtype of patients with HER2-positive breast cancer, more than 50% of them are unresponsive to targeted therapies or they eventually relapse. In recent years, reactivation of the adaptive immune system in patients with solid tumors has emerged as a therapeutic option with great potential for clinical benefit. Since the approval of the first treatment directed against HER2 as a therapeutic target, the range of clinical options has expanded greatly, and, in this sense, cellular immunotherapy with T cells relies on the cytotoxicity generated by these cells, which ultimately leads to antitumor activity. Lymphocytic infiltration of tumors encompasses a heterogeneous population of immune cells within the tumor microenvironment that exhibits distinct patterns of immune activation and exhaustion. The prevalence and prognostic value of tumor-infiltrating lymphocyte (TIL) counts are associated with a favorable prognosis in HER2-positive breast cancers. This review discusses emerging findings that contribute to a better understanding of the role of immune infiltrates in HER2-positive breast cancer. In addition, it summarizes the most recent results in HER2-positive breast cancer immunotherapy and anticipates which therapeutic strategies could be applied in the immediate future.

Resistance to antibody-drug conjugates in breast cancer: mechanisms and solutions.

Antibody-drug conjugates (ADCs) are a rapidly developing therapeutic approach in cancer treatment that has shown remarkable activity in breast cancer. Currently, there are two ADCs approved for the treatment of human epidermal growth factor receptor 2-positive breast cancer, one for triple-negative breast cancer, and multiple investigational ADCs in clinical trials. However, drug resistance has been noticed in clinical use, especially in trastuzumab emtansine. Here, the mechanisms of ADC resistance are summarized into four categories: antibody-mediated resistance, impaired drug trafficking, disrupted lysosomal function, and payload-related resistance. To overcome or prevent resistance to ADCs, innovative development strategies and combination therapy options are being investigated. Analyzing predictive biomarkers for optimal therapy selection may also help to prevent drug resistance.

Pyrotinib combined with trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer: a single-arm exploratory phase II trial

PurposeA substantial need for effective and safe treatment options is still unmet for patients with heavily pre-treated human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Herein, we assessed the efficacy and safety of pyrotinib plus trastuzumab and chemotherapy in patients with heavily treated HER2-positive MBC.MethodsIn this single-arm exploratory phase II trial, patients with HER2-positive MBC previously treated with trastuzumab plus lapatinib or pertuzumab, received pyrotinib plus trastuzumab and chemotherapy. The primary end point was progression-free survival (PFS) in the total population (TP). Secondary end points included PFS in the subgroup with brain metastases (Sub-BrM), confirmed objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), exploration of predictive factors of PFS, and safety.ResultsBetween November 1, 2018, and March 31, 2021, 40 patients were eligible for this study. The median PFS reached 7.5 months (95% confidence interval [CI] 4.7 to 9.9 months) and 9.4 months (95% CI 6.6 to 12.1 months) in the TP and Sub-BrM, respectively. ORR was 50.5% (20/40). CBR was 75.5% (30/40) and DCR reached 97.5% (39/40). Cox univariate and multivariate analyses demonstrated that liver or/and lung metastases was the significant adverse prognostic factor for PFS (p = 0.018; p = 0.026; respectively). The most frequent grade 3 or 4 treatment-related adverse events were diarrhea, neutropenia and leukopenia. No new safety signals were observed.ConclusionPyrotinib plus trastuzumab and chemotherapy offered a promising option with manageable safety profile for heavily pre-treated HER2-positive MBC, especially for those without liver or/and lung metastases.

Trastuzumab deruxtecan versus trastuzumab emtansine for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: A cost-effectiveness analysis

BackgroundDESTINY-Breast03 (NCT03529110) was the first global phase III study to assess the antitumor activity of trastuzumab deruxtecan (T-DXd) compared to trastuzumab emtansine (T-DM1) in 2022. However, the balance between efficacy and cost of T-DXd remains unclear. As a result, the present study's goal is to investigate the cost-effectiveness of T-DXd vs T-DM1 as a second-line treatment for patients with HER2-positive MBC from the US and Chinese payer's perspectives. MethodsA Markov model with a 20-year time horizon was developed to evaluate the overall cost of patient treatment, incremental cost-effectiveness ratio (ICER), quality-adjusted life-years (QALYs), and life-years (LYs) in the US and China at WTP levels of 150,000/QALY and 37,653/QALY, respectively (3 times GDP per capita in 2021). Key data were gathered from the US government's official website, the Xiangya Hospital of Central South University, and published literature. To determine the model's stability, a sensitivity analysis was performed. A subgroup analysis was also implemented. ResultsCompared with T-DM1, treatment with T-DXd generated an additional 1.672 QALYs (2.796 LYs), resulting in an ICER of $13,342/QALY (US) and $186,017/QALY (China). The cost of drugs is the most influential factor in the American and Chinese models. Subgroup analysis revealed that the T-DXd and T-DM1 regimens were more cost-effective at reducing the risk of death in the US and Chinese HER2-positive MBC patients. ConclusionT-DXd as second-line treatment could gain more health benefits for HER2-positive MBC patients in comparison with T-DM1, which is considered to be cost-effective in the US but not in China.

Strategies for the treatment of HER2+ advanced breast cancer based on clinical practice in Chinese patients: a roundtable discussion.

Human epithelial growth factor receptor 2-positive (HER2+) breast cancer is easy to relapse and metastasize in the early stage, and usually has more aggressive clinical behavior and worse patient survival outcomes as compared with estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer. The HER2+ breast cancer has been significantly enhanced by trastuzumab and other multiple novel HER2 anti-tumor drugs. The dual combination regimen of trastuzumab + pertuzumab has been established as the standard first-line therapy for advanced HER2+ patients, and pyrotinib with capecitabine is the preferred second-line treatment in Chinese patients. However, no third- or later-line regimens are currently recommended, and thus, the treatment needs of these patients remain unmet. Margetuximab is a human/mouse chimeric anti-HER2 immunoglobulin G1 (IgG1) monoclonal antibody (mAb) based on the murine precursor of trastuzumab, has shown greater efficacy than trastuzumab in terms of its natural killer (NK) cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) effect and may become the preferred solution for HER2+ metastatic breast cancer (mBC) following progression on second-line therapy with small molecule tyrosine kinase inhibitors (TKIs). This paper explores discussion of therapeutic strategies of anti-HER2 drugs based on Chinese clinical practice, and summarizes the consensus and controversy in the post-anti-HER2 TKIs guideline recommendations, so as to provide certain guidance to HER2+ mBC patients pretreated with TKIs in the third or later lines.

46P The impact of antibiotics and proton pump inhibitors in neoadjuvant treatment of HER2+ breast cancer

Anti-HER2 monoclonal antibodies improved the pathologic complete response (pCR) and prognostic of human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC). Antibiotics (ATB) and proton pump inhibitors (PPI) may affect the efficacy of cancer therapies, by modulating gut microbiota and consequently disturb the immune response. Here we aimed to evaluate the impact of ATB and PPI in HER2+ BC neoadjuvant treatment response.

Survival and clinicopathological significance of blood vessel invasion in operable breast cancer: a systematic review and meta-analysis.

Lymphovascular invasion, including lymphatic-vessel invasion and blood-vessel invasion, plays an important role in distant metastases. The metastatic pattern of blood-vessel invasion may differ from that of lymphatic-vessel invasion. However, its prognostic significance in breast cancer remains controversial. We evaluated the role of blood-vessel invasion in the prognosis of operable breast-cancer patients and its association with clinicopathological characteristics. We systematically searched EMBASE, PubMed, the Cochrane Library and Web of Science for studies in English through December 2020. Disease-free survival, overall survival and cancer-specific survival were the primary outcomes. Pooled hazard ratios and 95% confidence intervals were assessed using a random-effects model. Twenty-seven studies involving 7954 patients were included. Blood-vessel invasion occurred in 20.4% of tumor samples. Pooled results showed significant associations of blood-vessel invasion with worse disease-free survival (hazard ratio=1.82; 95% confidence interval=1.43-2.31) and overall survival (hazard ratio=1.86; 95% confidence interval=1.16-2.99) in multivariate analyses. The results of the univariate analyses were similar. Among the clinicopathological factors, blood-vessel invasion was associated with larger tumor size, lymph-node metastasis, nonspecific invasive type, higher histological grade, estrogen receptor-negative breast cancer, human epidermal growth factor receptor 2-positive breast cancer and lymphatic-vessel invasion. In the lymph-node-negative subgroup analyses, the presence of blood-vessel invasion led to poorer disease-free survival (hazard ratio=2.46; 95%confidence interval=1.64-3.70) and overall survival (hazard ratio=2.94; 95%confidence interval=1.80-4.80). We concluded that blood-vessel invasion is an independent predictor of poor prognosis in operable breast cancer and is associated with aggressive clinicopathological features. Breast-cancer patients with blood-vessel invasion require more aggressive treatments after surgery.