bluuebunny/crossref_metadata_2025 huggingface dataset:
Overall survival in patients with HER2-low breast cancer at a reference hospital in Mexico.
Authors: Rubio-Anguiano Brenda Lorena , Valencia-Cedillo Raquel , Grajales Rocio
Published: June 2024

e12578

Background: Breast cancer is the most diagnosed cancer in women. The 5-year overall survival (OS) rate in early-stage disease is 97% while in advanced disease is 36%. HER2 is a growth receptor involved in cell survival and proliferation. An overexpression of this protein leads to a more aggressive behavior; however, with targeted therapies, OS has improved. Recently, a new classification has been developed for tumors previously known as HER2-negative: HER2-low; which are those with IHC 1+ or 2+/ISH negative. It is believed that in these types of tumors, the signaling pathways of the HER2-positive subtype are also activated. There are conflicting studies on the prognostic impact of this subgroup. Currently, there is availability of anti-HER2 treatment for patients in advanced stages, as described in the DESTINY-Breast04 study, which changes the treatment paradigm for this pathology. Methods: The aim of this study is to determine overall survival in patients with HER2-low breast cancer. A retrospective, analytical, observational cohort was performed. Patients diagnosed with HER2-negative/low breast cancer, treated at the UMAE Oncology Hospital of the CMN Siglo XXI, from January 2018 to December 2022, were included. OS and disease-free survival (DFS) were calculated using Kaplan-Meier curves, and the impact of HER2-low expression on OS and DFS was assessed using log-rank analysis. The prognostic analysis of the complete model was performed using a Cox proportional hazards model. Results: We included 213 patients. The median age was 57 years. Ninety-five patients were HER2-low (44.6%), and 118 were HER2-negative (55.4%). Seventy-six percent had positive hormone receptor (HR) status. Patients with HR+/HER2-negative were 84 (52.2%), and HR+/HER2-low were 77 (47.8%). Among HR-negative status, the majority were HER2-negative (65.4%). When comparing HER2-negative and HER2-low, no statistically significant differences were found, with a 48-month overall survival of 70% for HER2-negative compared to 87.1% for HER2-low (p= 0.5700). OS analysis in the HER2-low group, comparing HR+ vs. HR-, a statistically significant difference at 48 months of 98.31% vs. 49.17% (p <0.0001), respectively, was found. Regarding DFS, a comparison between HR+ against HR-, it was 79.53% vs. 37.14%, respectively (p= 0.0002). The DFS analysis revealed that, among the variables studied, lymphovascular invasion (LVI) and HR+ status showed a statistically significant association with time to recurrence. Particularly, the presence of HR positivity was associated with a significant 82.6% reduction in the risk of recurrence. Conclusions: HER2 status alone (negative or low) did not offer a clear distinction in terms of OS or DFS. Nevertheless, it was observed a difference in OS and DFS outcomes favoring the HR-positive group when examining HR status among individuals with HER2-low, though this finding requires validation in a larger population.
Retrospective observational study of patients with luminal breast cancer in early stages: 10-year follow-up—Which luminal breast cancer relapse?
Authors: Puertas Andrea , Herruzo Cabrera Ismael , Ríos Pozo Maria Belén
Published: June 2024

e12586

Background: Luminal BC is a heterogeneous group of breast cancer (1), with molecular signatures of better prognoses and others of worse prognoses being found. Prosigna test provide the molecular BC subtype, an individualized prognostic score called “ROR score”. Our main objective is to analyze in 10 years which Luminal early BC patients have local and distant relapses. See if there is a correlation between ROR and relapse. As second objective is select this group of patients who relapse and analyze the presence of CAF S1 for a future study. Methods: We performed a retrospective observational study from the two main hospitals in Málaga (Spain) We included 415 women 43-79 years with EBC defined as T1 or T2 primary breast cancer <30 mm in the largest dimension) node negative. Molecular BC subtype analyzed by IHC and genomic platform Prosigna) The patients were treated with breast-conserving surgery with clear excision margins hypofractionated radiotherapy and adjuvant endocrine therapy. We followed them from 2014 to the present. Results: 415 patients. We made genetic platform Prosigna to all of them luminal A 55%, Luminal B 37%, Basal like 4.8% and Her2 3.6%. The median follow-up was 9.1 years. The cumulative incidence of recurrence in Luminal BC was 2.29% (44.4% locoregional 55.55% distant recurrence). In 55.55% of the patients that relapsed had a Prosigna test with high ROR score, in 11.11% of the patients that relapsed had a Prosigna test with an intermediate ROR score and in 33.33 of the patients that relapsed had a Prosigna test with a low ROR score. Conclusions: In our study the cumulative incidence of recurrence in Luminal BC was 2.29 % and the ROR score provided a good estimate of the risk of relapse. Currently we use genomic platforms as Prosigna to estimate the ROR and adapt treatments to the risk. However, until now there is no biological or translational study focusing on T1N0 luminal BC. Subsequently, there exists a real need for new strategies to determine the long-term prognosis of these patients. We selected a group of patients to analyze the presence of CAF S1 fibroblast for a future study. Distant recurrence in T1N0 Luminal BC is strongly associated with the presence of CAF-S1 fibroblast The determination of CAF-S1 could more accurately predict recurrence in this subgroup of patients and could be a target for future treatments.
Axillary lymph nodes pCR (apCR) versus breast pCR (bpCR): A meta-analysis involving 10,723 patients.
Authors: pu shengyu , Chen Heyan , Zhang Huimin , He Jianjun , Hao Na
Published: June 2024

e12630

Background: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) may improve the long-term survival of patients with breast cancer, as scored by disease-free survival (DFS) and overall survival (OS). Axillary lymph node pCR (apCR) is an important prognostic factor and may influence surgical de-escalation strategies; however, there is insufficient evidence to confirm that apCR produces a better prognosis than breast pCR (bpCR). The study aimed to perform a meta-analysis to assess the effect of apCR on survival compared with bpCR. Methods: We searched Cochrane Library, Web of Science, PubMed, Embase, and Clinical Trials.gov for breast cancer clinical trials with NAC. For included studies, we extracted the following data for analysis: study details, characteristics of participants, and survival data. Outcome data were reported as hazard ratios (HRs) and 95% confidence interval (CI) to measure the association between pCR and DFS, and OS. An I² test and subgroup analyses were performed to assess statistical heterogeneity in the included studies. Egger’s test and Begg’s funnel plot were used to determine potential publication bias. Results: We obtained data from 12 studies with 10,723 patients. Those patients with apCR had significantly better DFS than those with bpCR (HR=0.67, 95% CI, 0.60-0.76, P<0.00001), and no significant heterogeneity was observed between studies (I2=0%). As for OS, the HR significantly supported apCR (HR=0.72, 95% CI, 0.60-0.86, P=0.0002). There was no significant heterogeneity between studies (I2=35%). Subgroup analyses of each variable did not alter the results. Egger's test and Begg’s funnel plots indicated no significant publication bias in this analysis. Conclusions: This meta-analysis demonstrated that apCR is strongly associated with better DFS and OS than bpCR. This finding suggests that apCR has the potential to be an early surrogate endpoint for long-term prognosis.
Efficacy and safety of recombinant humanized anti-HER2 antibody-MMAE conjugate (RC48) in neoadjuvant for HER2-positive breast cancer: A single-arm phase II study.
Authors: Yang Jixin , Yang Yuqing , Wen Xinxin , Wu Jiang , Yu Jing , Wang Lei , Hu Wenyu , Xu Dongdong , Luo Jialing , Ma Wen , Li Nanlin ,   Xijing Hospital
Published: June 2024

e12636

Background: Breast cancer patients who achieve pCR after neoadjuvant therapy have a relatively good prognosis. Whether antibody‐drug conjugates (ADCs) can replace traditional chemotherapy combined with dual-target therapy in neoadjuvant therapy still needs to be explored. RC48 is a novel recombinant human anti-HER2 monoclonal antibody conjugated with a microtubule inhibitor (MMAE) via a cleavable linker, which can effectively kill HER2-positive tumors as well as tumors with low or heterogeneous HER2 expression through the bystander effect. The purpose of this study was to evaluate the efficacy and safety of RC48 in neoadjuvant treatment of HER2-positive breast cancer. Methods: Patients with HER2-positive breast cancer (size>20mm) or confirmed axillary lymph node metastasis were eligible and received RC48 at a dose of 2.5mg/kg alone every 2 weeks for 6 cycles followed by surgery. EC was administered postoperatively every 21 days for 4 cycles. Trastuzumab combined with pertuzumab was administered for 1 year in the adjuvant setting. The primary endpoints were ORR and pCR rates. Results: 23 patients had been enrolled, and all of them had completed surgical treatment. The median age was 45(38-70) years. The current results showed that 13.0% (3/23) achieved pCR, 78.3% (18/23) achieved PR, and 8.7% (2/23) experienced PD. The ORR was 91.3%. 42% (5/12) of patients with initially positive axillary lymph nodes turned negative after surgery. 11.8% (2/17) HR-/HER2+ patients achieved pCR. According to the proportion of target lesion reduction, patients were divided into mild response (0-50%) and moderate-to-severe response (51%-100%). In the HR-/HER2+ subtype group, 23.5% (4/17) had a mild response, and 76.5% (13/17) had a moderate-to-severe response. 6 patients with HR+ have been enrolled, and 16.7% (1/6) of them achieved pCR. All of HR+ subtypes had a moderate-to-severe response. No relevant serious (grade 3/4) toxicity has been reported. Conclusions: The present data showed an acceptable pCR rate with RC48 in HER2-positive breast cancer. Although the pCR rate was lower than the traditional chemotherapy combined with targeted therapy, the effect of rapid reduction of tumor volume was better (the moderate-severe remission rate was 82.6%). For HR+/HER2+ breast cancer, the ORR in this study reached 100%, indicating that the novel ADC had a significant inhibitory effect on the crosstalk between ER and HER2. And it was expected that the Destiny Breast 11 study would show similar results. This scheme had a good negative conversion rate for patients with positive axillary lymph nodes. Finally, RC48 provided a neoadjuvant treatment option with low toxicity and high patient compliance for HER2-positive breast cancer. Clinical trial information: NCT05134519 .
Trends over time in liquid biopsy testing in patients with metastatic breast cancer (MBC) across the Mayo Clinic enterprise.
Authors: Yadav Sumeet Kumar , Rajput Sanjna , Samineni Thoshik , Thompson Kevin , Tang Xiaojia , Leon-Ferre Roberto Antonio , O'Sullivan Ciara Catherine , Peethambaram Prema P. , Advani Pooja Prem , Sideras Kostandinos , Chumsri Saranya , Gill Paula , Ticku Jonathan , Anderson Karen S. , Ernst Brenda , Northfelt Donald W. , Haddad Tufia C. , Goetz Matthew P. , Kalari Krishna Rani , Giridhar Karthik
Published: June 2024

e13036

Background: In January 2023, the FDA approved elacestrant for ESR1-mutated, ER+/HER2- MBC based on a companion diagnostic cell free (cf)DNA test (Guardant Health). In this study, we analyze the trends of liquid biopsy utilization at Mayo Clinic (MC) over a 3 year period to understand the impact of this drug approval on testing patterns and identify emergent alterations in patients (pts) with MBC. Methods: We extracted clinically performed Guardant 360 and Guardant 360 CDx ordered at MC sites in Rochester (MN), Florida (FL), Arizona (AZ), and across 9 additional Mayo Clinic Health System (MCHS) sites. Pts with MBC were identified using the EMR and analyzing visit diagnosis codes and staging information. Shifts in testing patterns were analyzed over a 3 year period from January 1, 2021 - December 31, 2023. Data was collected on the number of tests, serial testing, frequency of pathogenic mutations, and emergent mutations in ESR1 and PIK3CA. Chi-square test was used to compare the categorical values. Results: Between 2021-2023, 2,741 pts with MBC were seen across all sites. A total of 408 cfDNA tests were performed in 370 unique patients with MBC. Most pts (90%) had 1 test performed. The proportion of pts with MBC tested was 85/1350 (6.3%) in 2021, 77/1495 (5.2%) in 2022, and 208/1558 (13.4%) in 2023. The increased proportion of pts tested in 2023 was statistically significant compared to prior years (p<0.0001), while no difference was observed between 2021 and 2022 (p 0.19). Testing patterns varied by site, with FL ordering the highest number of tests, followed by MN and AZ. Of the 34 providers practicing during the entire period seeing more than 10 MBC pts, the number of providers ordering Guardant testing increased from 15/34 (2021) and 14/34 (2022) to 20/34 (2023), though not statistically significant (p 0.15). Of the 41% with EMR-documented staging available, testing was highest in the ER+/HER2- (81.3%) subtype, followed by TNBC (13.6%) and then HER2+ (5.2%). The most commonly identified mutations identified in the first testing were PIK3CA (41.1%), TP53 (40.5%), ESR1 (30.5%), and ATM (13.2%). D538G (8.0%), Y537N (4.4%), and Y537S (3.5%) were frequent emergent mutations seen in ESR1. Conclusions: We observed an increase in cfDNA testing at the start of 2023 which aligns with the FDA approval of elacestrant. We observed variation by site and individual providers that warrants further exploration to improve cfDNA testing in MBC pts at Mayo Clinic.
PIK3CA testing and treatment patterns among patients with metastatic breast cancer in US community clinical practice.
Authors: Kim Eunice , Dhillon Preet Kaur , Lambert Peter , Cheng Anna , Basho Reva K.
Published: June 2024

e13059

Background: PIK3CA mutations are present in ~35-40% of HR+/HER2- breast cancer patients. Targeted treatments are approved and in development for patients with advanced disease, and clinical guidelines recommend biomarker testing. This retrospective cohort study characterized PIK3CA mutation testing and treatment patterns among HR+/HER2- metastatic breast cancer (mBC) patients in United States (US) community clinical practices. Methods: We used the nationwide Flatiron Health electronic health record-derived de-identified database to select patients diagnosed with HR+/HER2- mBC from January 2011 to May 2023. We described baseline characteristics of patients tested and not tested for PIK3CA mutation. We captured rates of PIK3CA mutation testing (anytime and ≤1 year) prior to starting first-line (1L), second-line (2L), and third-line (3L) treatment; test and sample types; secular trends over time; and test turnaround time (TAT). Treatment patterns for patients with a PIK3CA-mutated tumor were also described from 2019 onwards. Results: Among 14,246 HR+/HER2- mBC patients treated at community sites, 4,537 had a PIK3CA mutation test result during the study period. 25% of patients had more than one PIK3CA mutation test. Test rates increased from 2011 to 2023 for all patients starting 1L, 2L, or 3L during the study period (Table). In 2023, the percentage of patients tested anytime prior to 1L, 2L, and 3L start dates were 11% (37 of 324 patients), 52% (140 of 271 patients), and 65% (133 of 204 patients), respectively. Among tested patients, those who were tested between 1L and 2L increased from 32% in 2018 to 45% in 2023. Median time from mBC diagnosis date to first test was variable across years: 8, 10, and 3 months in 2018, 2020, and 2022, respectively. During the study period, most PIK3CA mutation tests were next-generation sequencing (NGS) (88%) and used tumor tissue (72%). Median TAT decreased from 12 days in 2018 to 7 days in 2023. Among patients with a PIK3CA-mutated tumor in 2019 and onwards who received treatment, 36% of patients received alpelisib-containing regimens. Conclusions: PIK3CA mutation testing in HR+/HER2- mBC patients has increased over time in community clinical practice, and timing has shifted to earlier lines of therapy among tested patients. However, overall testing and subsequent treatment with pathway-directed therapy are still low despite clinical guidelines, which may reflect potential gaps in access to PIK3CA mutation testing and the continued unmet need regarding available targeted agents within the current treatment landscape. [Table: see text]
Use of Oncotype vs. Breast Cancer Index (BCI) for extended endocrine therapy decisions: A single center analysis in stage IA hormone receptor positive breast cancer.
Authors: Kovalenko Iuliia , Seltun Faith , He Alice , Garg Chandi , Azhar Maha , Proskuriakova Ekaterina , Wert Yijin , Lu Kit Yu
Published: June 2024

e13083

Background: Extended Endocrine Therapy (EET) for hormone receptor positive HER-2 negative early-stage breast cancer reduces late recurrence risks but raises concerns about toxicity. Biomarker tests like the Breast Cancer Index (BCI) are vital for identifying patients who could benefit from continued ET, reassuring others against unnecessary extension. This study evaluates prognostic implications for both Oncotype Dx (Recurrence score, RS) and BCI amidst concerns about added testing costs in patients with early stage, estrogen receptor (ER) positive breast cancer. Methods: This is a single institution retrospective review of Stage IA ER positive HER-2 negative breast cancer patients who underwent both Oncotype Dx and BCI testing from January 2021 to December 2023. Pearson's correlation coefficient (r) was used to assess the linear relationship between the assays (p<0.05 for significance), analysis was performed with SAS software, version 9.4. Results: Fifty-eight patients with Stage IA ER positive HER-2 negative breast cancer who had both Oncotype and BCI results were identified (100% female; mean age 72.2 years [54-87]). After a median followed up of 72 months (63-75), no systemic or locoregional recurrences were reported. A low positive correlation between Oncotype and BCI was observed across the entire cohort (r=0.4058; p=0.0016). However, subgroup analysis showed no significant correlations: Oncotype <11 (n=17; r=0.2415; p=0.3504), Oncotype ≤18 (n=43; r=0.0914; p=0.5600), Oncotype <26 (n=51; r=0.2530; p=0.0733); Oncotype ≥26 (n=7; r=-0.5634; p=0.1878). Correlation was also not found in patients with Grade 1 tumor (n=16; r=0.3138; p=0.2365). Thirty-nine patients (67.24%) had their treatment recommendation changed based on BCI results. Side effects from ET affected 15 patients (25.86%) and included arthralgias (60%, n=9), hot flashes (26.67%, n=4), depression (13.33%, n=2), insomnia (6.67%, n=1), and others (53.3%, n=8). Twenty-two patients (37.93%) developed new osteopenia, and 6 (10.34%) new osteoporosis while on EET. Eight patients (13.79%) had ET interruption during their treatment course. Conclusions: Despite inclination towards cost-saving measures, Oncotype DX may be more useful to give prognosis in the early adjuvant period whereas BCI is more useful to evaluate late recurrence risk. Low or high Oncotype scores and tumor grade may not align with BCI findings. Considering the importance of managing toxicity against the risk of late recurrence, incorporating BCI testing can enhance EET recommendations, even for Stage I, node-negative, ER positive patients.
A phase II trial combining SHR-1316, bevacizumab, and cisplatin/carboplatin in patients with TNBC with active brain metastases.
Authors: Li Ting , Zhao Mingchuan , Cao Jun , Wang Jianfei , Tao Zhonghua , Wang Biyun , Hu Xichun , Zhang Jian
Published: June 2024

e13133

Background: Triple-negative breast cancer (TNBC) has a high risk of brain metastases (BM), leading to poor survival. Treatment options for BMs are limited, and the combination of chemotherapy and immune checkpoint inhibitor is the standard-of-care for PD-L1 positive metastatic TNBC. Platinum-based systematic therapy is the mainstay of TNBC treatment and the addition of bevacizumab has shown improvement in the progression-free survival (PFS) of patients with BM. Therefore, this study aims to investigate the efficacy and safety of SHR-1316 (anti-PD-L1) in combination with bevacizumab and cisplatin/carboplatin in TNBC patients with BMs. Methods: In this single-center phase II trial, TNBC patients with active BM received SHR-1316, bevacizumab, and cisplatin/carboplatin. Prior treatment with bevacizumab or anti-PD-1/PD-L1 were not allowed. Prior platinum was allowed only in cases of previous platinum-sensitive response. The primary endpoint was objective response rate (ORR) of central nervous system (CNS), as assessed according to the response assessment in neuro-oncology brain metastases. The secondary endpoint included clinical benefit rate (CBR) of CNS, PFS, overall survival (OS), first progression site and safety. Results: As of January 12th, 2024, a total of 23 female patients with ECOG PS≥1(100%) were enrolled. The median number of previous lines of therapy for metastatic disease was 1 (0-3). All patients had active BM, of which 87% (20/23) were BM treatment-naïve and 13% (3/23) had BM progression after previous local therapy, 26.1% (6/23) had received a prior platinum agent. Of the 23 evaluable patients, the confirmed CNS ORR was 65.2% (95%CI: 42.7%-83.6%), with 3 complete response (CR), 12 partial response (PR), 7 stable disease (SD), and 1 progressive disease (PD). The median CNS-PFS was 11.2 months (95%CI, 5.8 to not reached), median PFS was 7.6 months (95%CI, 5.7-11.9), and median OS was 13.2 months (95%CI, 9.5 to not reached). Treatment-related adverse events (TRAEs) were reported in all 23 patients, and the most common TRAEs were neutrophil count decreased (69.6%, 16/23), anemia (65.2%, 15/23), asthenia (60.9%, 14/23), Hypomagnesaemia (56.5%, 13/23), leukopenia (52.2%, 12/23) and electrocardiogram T wave abnormal (52.2%, 12/23). The incidence of grade ≥3 TRAEs was 43.5% (10/23), including neutropenia (13%, 3/23), platelet count decreased (8.7%, 2/23), and hypertension (8.7%, 2/23). Only one patient had a grade 4 TRAE (lymphocytopenia), and SHR-1316 related serious adverse event (facial nerve disorder) occurred in only one patient. No grade 5 AEs were noted. Conclusions: SHR-1316 plus bevacizumab and cisplatin/carboplatin achieves a significant improvement in CNS ORR and brings PFS and OS benefits in TNBC patients with active BMs. As an effective and safe treatment, this triple-combination warrants further investigation. Clinical trial information: NCT04303988 .
Prevalence of “HER2 ultra-low” among patients with advanced breast cancer with historical IHC0 status.
Authors: Mehta Sandhya , Iyengar Anushree , Barman Hannah , Rangarajan Nivedita , Woo Michele Sue-Ann , Sredni Simone T. , Di Donato Rosemarie , Simsek Safak , Downs Erinn P. , Nassar Aziza , Wilson Darren M. , Krieser Katherine , Patzke Elise Bieri , Kyek Natalie , Hipp Jason , Wagner Tyler
Published: June 2024

e13156

Background: Breast Cancer (BC) patients are classified as HER2-positive (IHC3+ or IHC2+/ISH+) or HER2-negative (IHC0, IHC1+ and 2+/ISH-). Within the HER2-negative category, patients who meet HER2-low (IHC1+ or IHC2+/ISH-) criteria can benefit from HER2 targeted therapy like trastuzumab deruxtecan. Patients who meet IHC0 criteria with incomplete and faint membrane staining in >0 but ≤10% of tumor cells — defined as “HER2 Ultra-low”, may also benefit from HER2 targeted therapy. This study aimed to assess the prevalence of “HER2 Ultra-Low” expression based on re-scored HER2 IHC biopsy slides. Methods: This study utilized EHR data from all three US Mayo Clinic campuses. A total of 300 patients with advanced BC (stages III-IV), and clinically documented HER2 IHC0 status between Jan 2017 and Jan 2023, were identified. One biopsy slide per patient (IHC assay: VENTANA Pathway anti-HER2/neu (4B5) rabbit monoclonal primary antibody) was digitized and scanned at 40x magnification. Two Mayo Clinic pathologists independently scored and reported HER2 status according to 2023 ASCO-CAP guidelines and included tumor stain percentage for each slide. Patients were considered “HER2 Ultra-Low” if their slide was scored as IHC0 with >0% but ≤10% staining. Cohen’s κ was used to quantify agreement between pathologists. Results: The re-scored patients (n=300) had a mean age of 57.8 years (SD=13.5), with ~97% having IHC0 documentation within 30 days of the reviewed biopsy slide. A total of 285 (95%) patients remained classified as IHC0 by at least one pathologist. Of these, 60% (n=171) were determined as “HER2 Ultra-low” by at least one pathologist. The rate of “HER2 Ultra-Low” per pathologist ranged from 43% (n=121) to 45% (n=104). The overall inter-pathologist concordance was 57%; patients with no observable HER2 IHC staining accounted for majority of the concordant patients (Table). Conclusions: About 3 in 5 advanced BC patients originally classified as HER2 IHC0 met the “HER2 Ultra-Low” criteria by at least one pathologist, implying that significant number of additional patients may benefit from HER2 targeted therapy. The relatively low concordance between HER2 expert pathologists in identifying lower levels of HER2 expression suggests the need for increased precision enabled by digital tools, leveraging AI, training for community practice pathologists, and continuing to follow best practice recommendations in determining HER2 IHC status. [Table: see text]
Mutations and mortality in very young patients with breast cancer.
Authors: Saxena Raina , Chung Victoria , Peeples James , Yang Yanming , Song William , Olet Susan , Sheen Melanie Anne
Published: June 2024

e13157

Background: Breast cancer diagnoses in young women have increased over the last 10 years. Despite decreasing mortality rates for breast cancer, disparities continue to exist for specific populations including Black women and premenopausal women. Recent studies observe a 41% increased death rate in Black women compared to White women, and a two-fold increased mortality in women younger than 50 years. Many biological and societal factors can affect breast cancer mortality. We sought to evaluate the relationship between germline mutations (GM), breast cancer subtype, and mortality based on race in a unique, young breast cancer patient population. Methods: We assembled a 10-year retrospective chart review (2012 to 2022) of 773 women diagnosed with breast cancer under the age of 40 in a regional health network. Data was collected from electronic medical records. Associations were assessed using the chi-square test using SAS version 9.4. Results: Out of the 773 patient information collected, 60% of patients were White, 36% Black, and 3% Other. A total of 675 patients had genetic results and 124 patients with documented GM. Of patients with GM, 48 were Black and 74 were White. 13 patients with germline mutations had documented deaths. There was no statistical link between germline mutations and mortality. Of the 13 patients, 4 (30%) were Black and 9 (70%) were White. There was no statistical difference amongst area deprivation index (ADI) quintiles for mortality in patients with GM. Of the 675 patients with genetics data, 72 patients without GM died which includes 31 Black patients, 38 White patients, 3 Other. Based on our data, there is a higher prevalence of germline mutations (60%) in White patients over Black patients and a descriptive predominance of mortality despite absence of statistical significance. More patients who resided in areas of higher ADI (2-4) with GM died than in areas of lower ADI. Conclusions: Our data demonstrates a descriptive prevalence in mortality among young White patients compared to young Black patients. Across the USA, the Black population is 13% and in Louisiana, that population is 33%. Given that our cohort population was 36% Black, it is noteworthy that we were unable to demonstrate a statistical mortality predominance among these young patients. [Table: see text]
A phase Ia/b trial of ARX788 combined with toripalimab for HER2-low advanced breast cancer (ABC) and other HER2-expressing solid tumors.
Authors: Shao Xiying , Kuang Ming , Chen Zhanhong , Zheng Yabing , Li Guangliang , Shen Xia-Bo , Huang Ping , Cao Wenming , Xu Lixia , Wang Xiaojia
Published: June 2024

e13159

Background: ARX788 has been proved with superior PFS compared with a combination of capecitabine and lapatinib in the randomized phase Ⅱ/Ⅲ study for HER2-positive ABC (Ambrx, 2023). Here we report the preliminary safety and efficacy of ARX788 plus toripalimab in HER2-low ABC and other HER2-expressing solid tumors. Methods: This was a phase Ⅰ study conducted in China. Eligible patients were HER2-low (IHC2+ and FISH- or IHC1+) ABC or HER2-expressing (IHC 2+ or 3+) solid tumors. Dose exploration with ARX788 is 1.3, 1.5mg/kg, IV, Q3W plus toripalimab 240mg, IV, Q3W. Primary endpoint was safety and RP2D of Ⅰa and efficacy of Ⅰb. Results: Totally, 12 patients were enrolled in phase Ⅰa, 10 patients were diagnosed with ABC, 1 was diagnosed with BTC and 1 was CRC. 6 patients each were treated with 1.3 and 1.5mg/kg. No DLTs were observed. 12 patients (100%) experienced ≥1 ADRs. The most common (≥20%) ADRs were AST increased (75%), platelet count decreased (75%), alopecia (41.67%), white blood cell count decreased (25%), ALT increased (25%), dry eye (25%), interstitial lung disease (25%) and neutrophil count decreased (25%). 1.5mg/kg dose level showed a slightly higher incidence in hematologic toxicities, interstitial lung disease and alopecia. Grade 3 ADRs occurred in 8 patients (66.67%) with equal incidence of the 2 dose levels, those were ocular events (41.7%, 2 of each level), interstitial lung disease (8.3%, 1 of 1.5mg/kg), platelet count decreased (8.3%, 1 of 1.5mg/kg), jaundice (8.3%, 1 of 1.3mg/kg) and immune-mediated myocarditis (8.3%, 1 of 1.3mg/kg). No grade 4 or 5 ADRs occurred. All ADRs were manageable and have recovered. ORR was 41.7% in 12 patients, with 33.3% and 50% in 1.3 and 1.5mg/kg dose level. In 10 patients with ABC, ORR was 50%, with 40% and 60% in each level. DCR was 83.33% and 100%, respectively. Thus, 1.5mg/kg was determined as RP2D and phase Ⅰb is ongoing with HER2-low ABC patients. Conclusions: ARX788 with 1.5mg/kg combined with toripalimab was shown acceptable safety profile with promising efficacy, no significant increase in adverse reactions or serious unexpected immune-related adverse reactions compared with ARX788 monotherapy, which supports further evaluation for HER2-low ABC in a larger sample in Ⅰb trial. Clinical trial information: CTR20222247.
Frequency of HER2-Low in breast cancer biopsies in Chile.
Authors: Vidal Martín , Rivera Alvaro , Schuler Constanza , Garnham Nicolas , Alcalde Elisa , Ahumada Pablo Pinto , Renner Alex
Published: June 2024

e13163

Background: In breast cancer (BC), human epidermal growth factor receptor 2 (HER2) is a prognostic and predictive biomarker. Traditionally, the use of HER2-targeted therapies is reserved for BC that overexpress HER2, defined as immunohistochemical (IHC) expression of 3+ or 2+ with amplification of the gene encoding HER2, detected by in situ hybridization (ISH). Recently, the term HER2-Low, defined as the IHC expression of 1+ or 2+ with negative ISH, has gained relevance as a new predictive biomarker for the use of trastuzumab-deruxtecan. The frequency of HER2-Low BC in the Chilean population is unknown. The objective of this study is to show the frequency of HER2-Low BC in a Chilean center. Methods: Descriptive cross-sectional analysis of clinical records and biopsies of localized or metastatic invasive breast carcinoma performed at Clínica Santa María between January 2020 and December 2023. The IHC expression of the estrogen receptor (ER), progesterone receptor (PR), Ki-67, HER2, histological grade (G) and HER2 in situ hybridization (ISH) when appropriate. The frequency and characteristics of HER2-Low cases are described and compared with the surrogate clinicopathological subtypes luminal A, luminal B (HER2-Positive and Negative), HER2-Positive and Triple Negative (TN), according to the St Gallen Consensus Conference 2013. Results: Between January 2020 and December 2023, a total of 339 biopsies with invasive BC were identified, from which 104 (36.0%) met the definition of HER2-Low. The frequency of luminal B and luminal A that met the definition of HER2-Low was 54 (51.9%) and 40 (38.5%), respectively. Of the 253 biopsies classified as luminal, 94 (37.2%) met the definition of HER2-Low, while of the 36 biopsies classified as TN, 10 (27.8%) did. Luminal B HER2-Negative and TN surrogate subtypes that met the definition of HER2-Low had a higher frequency of G3 than their non-HER2-Low counterpart. Conclusions: In the population analyzed, a considerable percentage of cases meet the definition of HER2-Low. This has relevant therapeutic implications. Distribution of biopsies that meet HER2-Low criteria according to surrogate clinicopathological subtype of breast cancer. [Table: see text]
The role of epithelial-mesenchymal transition markers in invasive breast cancer among patients of Arab descent.
Authors: Salleh Mais , Alkaram Waed , Zaiem Fadi , Kheil Mira , Jain Deepti , Wahidi Marya , Boerner Julie , Jang Hyejeong , Kim Seongho , Morris Robert , Bandyopadhyay Sudeshna , Ali-Fehmi Rouba
Published: June 2024

e13166

Background: Epithelial-mesenchymal transition (EMT) is the process wherein polarized and cohesive epithelial cells lose their epithelial characteristics and acquire a mesenchymal phenotype and proceed to the invasive form of the tumor. Numerous regulators play a role in the complex signaling pathways that mediate the EMT process. This study aims to investigate the immunohistochemical (IHC) expression of several EMT-related markers and their implications on the diagnosis and prognosis of breast cancer in a cohort of Arab descent women. Methods: Patients of Arab descent treated surgically for invasive and in-situ breast cancer between 2017-2020 were included in the study. Expressions of Ki-67, Transforming growth factor- β (TGF-β), NF-kappaB (NF-kB), Snail, Vimentin, E-cadherin (E-Cad), and B-catenin (B-Cat) were evaluated by IHC in tissue microarray slides, as per guidelines in the literature. We examined the association between the tumor markers and other clinicopathological variables and prognosis. Fisher's exact tests were utilized to compare categorical variables between groups. Results: One hundred eleven patients were included, 65.8% had invasive ductal carcinoma (IDC); 19.8% had invasive lobular carcinoma (ILC); 13.5% had both ductal and lobular features, and 0.9% had ductal carcinoma in situ. 91 (54.1%) were grade 2 and 303 (41.4%) were grade 3 tumors. Most tumors were ER positive (81.8%), PR positive (75.7%), and HER-2 negative (77.5%). The median age at diagnosis was 52 years. High TGF- β expression was associated with higher frequency of grade 3 tumors (p=0.036), AJCC stage III (p=0.042), and larger tumor size (p=0.036) compared to those with low TGF-B expression. Patients with positive B-Cat expression had a higher risk of death compared to those with negative B-Cat expression (HR, 3.90; 95% CI, 1.19 to 15.93; p=0.024). IDC had a statistically significant increased expression of TGF-B (69.9% vs.45.5%, p=0.045), E-Cad (76.7% vs. 13.6%, p<0.001), and B-Cat (P 39.7% vs. 0%, p<0.001) when compared to ILC. The overall survival at 1 and 5 years were 96.3% (95% CI, 92.7-99.9) and 81.7% (95% CI, 73.8-90.3), respectively. Conclusions: Tumors with high expression for TGF- β and B-Cat exhibit more aggressive clinical behavior, suggesting the potential prognostic and therapeutic value of these markers. Due to the limited research focused on Arab descent women, findings from this study may provide the foundation for more extensive molecular and clinical studies to assess the validity and clinical utility of these biomarkers in breast cancer patients from diverse ethnic backgrounds.
Closing classification gaps in luminal breast cancer with single-cell RNA-seq insights from normal breast lineages.
Authors: Baranov Oleg , Turova Polina , Kushnarev Vladimir , Balabanian Linda , Kotlov Nikita , Chernyshov Konstantin , Fowler Nathan Hale , Lennerz Jochen K.
Published: June 2024

e13168

Background: Almost two decades ago, invasive breast cancer was classified into five subgroups based on expression patterns, each with distinct biological and prognostic characteristics. Advances in single-cell RNA sequencing offers insights into the expression profiles of normal luminal epithelial cells. Here, we investigate the connection between breast cancer (BC) classification and luminal expression profiles. Methods: We applied single-cell data from recent studies (Table) to compile gene signatures corresponding to expression profiles of luminal epithelial cell clusters in normal breast tissue. Normalized enrichment scores (ESs) of these signatures were calculated for bulk RNA-seq gene expression data from open source cohorts (TCGA-BRCA, SCAN-B, METABRIC). The BC molecular subtype of each tumor sample was predicted based on a modified PAM50 classification using gene expression profiling (1); LumA and LumB subtypes were combined into Luminal. ESs of signatures were compared between the BC subtypes (Table). Results: The ESs of all signatures differed significantly across BC subtypes (p < 0.001, Kruskal-Wallis test, Table 1). The ESs of signatures for LumSec-major and Luminal progenitor clusters are the highest in subtypes HER2-low and Basal-like (p < 0.001, Dwass-Steel-Critchlow-Fligner test [DSCF]). Basal-like also had the highest enrichment of the ductal signature (p < 0.001, DSCF). Luminal subtype showed the highest ESs of signatures corresponding to HR+ clusters of mature luminal cells and of the TDLU signature (p < 0.001, DSCF). HER2-low subtype showed the highest ES of the LumSec-lac signature (p < 0.001, DSCF). Conclusions: Our analyses challenge traditional classifications by showing that luminal breast cancers are less similar to most luminal epithelial clusters in normal breast tissue than other breast cancer subtypes. These findings suggest traditional expression classification may not fully capture the complexity of this largest subset of luminal-type breast cancers. 1. Turova et al., SABCS, 2023. [Table: see text]
Effect of cancer immunotherapy with CD39/PD-L1 bispecific antibody OriA631-b.
Authors: Li Xiaopei , Zhang Yuchen , Yang Ze , Deng Qi , Wang Huajing , Zhu Haiyan , Lu Ligong , Li Xian-Yang , Qu Ryan , He Xiaowen
Published: June 2024

e14508

Background: Despite significant advancements in cancer immunotherapy through the use of immune checkpoint inhibitors, there remains a need for more robust strategies to enhance anti-tumor immune responses. This study introduces and characterizes OriA631-B, an innovative CD39/PD-L1 bispecific antibody. By simultaneously targeting the metabolic checkpoint CD39 and the immune checkpoint PD-L1, this novel antibody has the potential to significantly augment anti-tumor efficacy, particularly in cold tumors characterized by a scarcity of infiltrating immune cells. The development of OriA631-B marks a breakthrough in concurrently addressing two crucial immunosuppressive pathways. Methods: The creation of OriA631-B involved cutting-edge antibody engineering methodologies to guarantee optimal binding affinity and specificity for its target antigens, CD39 and PD-L1. With meticulous design and refinement, OriA631-B was developed to exhibit robust binding capabilities to both CD39 and PD-L1, enabling simultaneous and precise recognition. Leveraging advanced antibody engineering techniques was instrumental in crafting OriA631-B as a potent tool with heightened binding properties, broadening its potential applications across diverse therapeutic contexts. Results: In vitro investigations revealed the efficacy of OriA631-B, derived from the foundation of a clinically validated in-house generated PD-L1 antibody (YN035). This innovative antibody effectively thwarted CD39-mediated adenosine production, resulting in heightened effector T cell function and proliferation. In vivo efficacy assessments conducted on syngeneic hot tumor models MC38 and Hepa1-6 underscored the remarkable effectiveness of OriA631, the CD39 monoclonal antibody (mAb), in controlling tumor growth. Notably, OriA631-B, the CD39/PD-L1 bispecific antibody, exhibited even more profound impacts, significantly restraining tumor growth beyond the effects observed with single-target treatments in the hot tumor model or combination therapies in both the hot tumor model MC38 and the cold tumor model CT26. These findings underscore the potent therapeutic potential of OriA631-B and its capacity to exert robust anti-tumor activity by concurrently targeting CD39 and PD-L1. Additionally, safety profiling revealed an acceptable toxicity profile for OriA631-B, with no significant adverse events observed during the study. Conclusions: In summary, OriA631-B demonstrates potential as an innovative immunotherapeutic strategy for cancer treatment by concurrently targeting CD39-mediated immune suppression and PD-L1-mediated T cell exhaustion. Further exploration, including clinical trials, is imperative to fully uncover the therapeutic capabilities of this groundbreaking bispecific antibody in cancer immunotherapy.
Single-cell transcriptome sequencing to explore the infiltration and disappearance of NK cells in liver cancer.
Authors: Cang Hongyu , Qin Yingchun , Shi Yuting , Liu Tianliang , Cheng Shaochen , Li Yingxiang , Liang Run
Published: June 2024

e14520

Background: The emergence of tumor immunotherapy such as immune checkpoint blocking has greatly promoted the development of Hepatocellular carcinoma (HCC) treatment. However, the response rate of HCC patients to immunotherapy is not high, and the probability of adverse reactions is high. Natural killer (NK) cells play a crucial role in inhibiting the proliferation and metastasis of tumor cells and are expected to become a new hope for tumor therapy. Methods: The HCC single-cell transcriptome atlas was constructed by using the tumor tissues, adjacent tissues, peripheral blood of HCC patients. To emulate the hypoxic state within the tumor, NK cells were treated with rotenone, and the post-rotenone treatment changes of NK cells in transcriptome levels were evaluated using qPCR. The proliferation, apoptosis, and cytotoxicity of NK cells were assessed via flow cytometry. The study also investigated the role of c-Jun N-terminal protein kinase (JNK) in NK cell function by applying the JNK inhibitor tanzisertib (CC-930) in vitro. The impact of JNK inhibition on the tumor-killing potential of NK cells was examined in vivo using tumor-bearing mice NCG (NOD/ShiLtJ-Prkdcem26Cd52Il2rgem26Cd22/Gpt). Results: Analysis of the source of NK cell subsets found that the specific NK cells in tumor tissues were tissue-resident NK cells (trNK). Both RNA velocity analysis and pseudo-time sequence analysis suggested that trNK cells differentiated from PBMC-1 NK cells. Upon treatment of PBMC-1 NK cells with Tanzisertib, we observed inhibition of NK cell apoptosis. Through the subcutaneous tumor formation experiment of NCG mice, Tanzisertib-treated NK cells were transferred into tumor-bearing mice. Notably, we observed a significant reduction in tumor weight (Before treatment: 0.19g, 0.19g, 0.22g, 0.24g, 0.26g, 0.27g; After treatment: 0.16g, 0.17g, 0.17g, 0.19g, 0.21g, 0.23g; P value = 0.049). TUNEL assay confirmed a significant increase number of apoptotic cells within the tumor and an increased number of infiltrated NK cells. Conclusions: The NK cells in HCC tumors are likely derived from the infiltration of NK cells in peripheral blood. Importantly, the inhibition of JNK function can significantly inhibit the apoptosis of NK cells and enhance the killing ability of NK cells against tumor cells in vivo.
Novel specific TCRs targeting KRASG12V-related cancers.
Authors: Xie Xingwang , J Dong , Wang Jianghua , Zhai Jiahui , Yan Baoqi , Bi Jinglei , Shi Yunqiang , Li Yonghong , Zhu Yaping
Published: June 2024

e14528

Background: KRAS mutations act as oncogenic drivers in a variety of tumors, such as pancreatic, colorectal and lung cancer. Among these, the KRASG12V mutation, being one of the most common mutations, is associated with adverse outcomes in patients. KRAS has been regarded as an “undruggable” target, and no clinical trials targeting tumors carrying shared KRASG12V mutation have been initiated. Notably, KRASG12D specific TCR-T has shown high effectiveness, including the regression of metastases in patients with pancreatic cancer. Therefore, TCR-engineered T cells could be a promising strategy for the treatment of solid tumors harboring G12V mutation. Methods: We have developed an innovative approach to rapidly and sensitively identify natural TCRs from single T cell derived from patients using CorreGene’s Single T cell TCR Cloning platform, thus obviating the requirement for NGS sequencing and TCR gene synthesis. Additionally, natural TCRs can be refined with SMART-TCR system, utilizing T cell reporter cell lines to construct a high-throughput T-cell Display Platform for functional screening of TCRs. This system is meticulously designed to enrich TCRs with superior potency and specificity from a natural TCR mutation library. We performed a thorough assessment of each TCR identified, evaluating them across both in vitro and in vivo settings. Results: In the present study, we identified three natural TCRs from patients' TILs, designated as KVA11-N01, KVA11-N02 and KVA11-N04 respectively, that specifically recognized the HLA-A*11:01-restricted KRAS G12V epitope. KVA11-N01 exhibited lower affinity and potency, prompting us to develop an affinity-optimized variant, KVA11-M01-231, using the SMART-TCR system. For comparison, we used the murine TCR TRAV3-301/BV401, identified by NCI from HLA-A11:01 transgenic mice immunized with KRAS G12V7-16, as a benchmark. Three of our TCRs, including KVA11-N02, KVA11-N04 and the engineered KVA11-M01-231, outperformed TRAV3-301/BV401 in both in vitro and in vivo assays. These three TCRs exhibited excellent expression intensity and stability on T cells, and notably, their IFN-γ release potency surpassed that of TRAV3-3*01/BV4*01. Furthermore, in vivo experiments confirmed the significant tumor suppression efficacy of our TCRs in a tumor-bearing mouse model, showing enhanced tumor growth inhibition compared to TRAV3-301/BV401. TCRs from Corregene’s platform exhibited exceptional specificity, with no allo-reactivity, no reaction to KRASG12V-negative cell lines, and no off-target effects. Additionally, all our TCRs demonstrates favorable tolerance in mice during in vivo studies. Conclusions: TCRs via Corregene’s Single T cell TCR Cloning platform and SMART-TCR system showed significantly excellent anti-tumor activities with great specificity and offers a promising solution for the treatment of KRASG12V-related cancers.