bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary analysis of pyrotinib and dalpiciclib-based therapy in HER2-positive advanced breast cancer (ABC).
Authors: Wang Yongsheng , Yuan Peng , Yang Hua , Liu Yanbing , Yue Jian , Yang Yang , Li Huajun , Yu Jinming
Published: June 2023

e13027

Background: The efficacy of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) and HER2 target agents combined with endocrine treatment (ET) has been demonstrated in hormone receptor (HR)-positive and HER2+ ABC, while little was known about the role of CDK4/6i in HR-/HER2+ ABC. In this prospective, multi-center, multi-cohort, phase 2 study (NCT04095390), we assessed the efficacy and safety of pyrotinib (P) and a CDK4/6i, dalpiciclib (D)-based therapy in HER2+ ABC with disparate HR statuses. Methods: HER2+ ABC females with known HR status were eligible if previously treated with trastuzumab (T). No more than one prior systemic regimen in advanced setting was allowed. Cohort A: HR+ pts received P (320 mg QD) and D (125 mg QD, 21 days on and 7 days off) combined with letrozole (2.5 mg QD). Cohort B or C: HR- pts were randomized to receive P and D combined with or without capecitabine (500 mg TID). Pts were treated until progression or unaccepted toxicity. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: As of Jan. 16, 2023, 33 pts were enrolled. We describe pts' distribution and characteristics. 26 pts had at least one efficacy assessment, and 17 (65.4%) achieved confirmed objective responses. ORR was 66.7% (10/15), 80% (4/5), and 50% (3/6) in cohort A, B, and C, respectively. Among the ITT population, the estimated median PFS was 24.9 mo. (24.9 mo., NR, and 20.2 mo. in cohort A, B, and C, respectively). 32 (97.0%) pts experienced treatment-related adverse events (TRAEs). Grade (G) 3-4 TRAEs occurred in 81.8% of pts, and the most frequent (≥ 10%) ones were neutropenia (72.7%), leukopenia (57.6%), diarrhea (21.2%), and mucositis (12.1%). Safety profiles were similar among cohorts, except more G3-4 mucositis, hand-foot syndrome and thrombocytopenia in cohort B. Two in cohort B discontinued due to toxicity (1 rash, and 1 neutropenia). One death was reported after withdrawal and unrelated to the study. Median OS was not reached. Conclusions: Our study shows P and D combined with ET is effective in HR+/HER2+ ABC, providing a chemo-free option to these pts. In HR-/HER2+ ABC, we preliminarily observed that the addition of chemotherapy could improve effectiveness of P and D, but also increase toxicities. Due to the limited sample, the findings need further confirmation. Clinical trial information: NCT04095390 . [Table: see text]
Incidence of interstitial lung disease and cardiotoxicity with trastuzumab-deruxtecan in patients with breast cancer: A systematic review and single-arm meta-analysis.
Authors: Soares Leonardo Ribeiro , Rosa Victor Domingos Lisita , Vilbert Maysa , Oliveira Jessica Lopes , Deus Mariana Moreira , Freitas-Junior Ruffo
Published: June 2023

e13033

Background: The new antibody-drug conjugated directed to HER2, Trastuzumab-Deruxtecan (T-DXd), has shown the benefit of progression-free survival and overall survival in metastatic breast cancer (mBC) patients after progression to ≥1 HER2 targeted therapies. Interstitial lung disease (ILD) and cardiotoxicity are the most significant and concerning toxicities related to T-DXd. We performed a systematic review and meta-analysis to assess the incidence and severity of those adverse events (AE) in mBC patients treated with T-DXd. Methods: We comprehensively searched Pubmed, Cochrane, and Scopus databases for randomized clinical trials (RCT) and observational cohort studies, including mBC patients with HER2-low or -positive expression who have received at least one dose of T-DXd. The DESTINY-Breast02 study was also included after its presentation at the SABCS 2022. The statistical analysis was performed using R software, and the results are presented as pooled analysis in forest plots. Results: We included nine studies: three phase III RCTs, three phase II and two phase I non-RCTs, and one retrospective cohort comprising 1,443 patients with a mean follow-up of 14.9 months. The median age of our population ranged from 53 to 59 years. Most were non-Asian (40.5%) and presented with hormone-receptor positive mBC (66.8%). In a pooled analysis, the incidence of ILD was 13.0% (179 patients; 95%CI 11.0 to 13.0). Patients enrolled in phase III clinical trials had an ILD rate of 12.0%, while the observational cohort reported a numerically higher rate of 18.0%. Most ILD cases, 84.9% (152 patients), were mild (grade 1 or 2). Grade 3 or 4 AE were reported in 13 patients (7,3%), and grade 5 in 14 patients (7,8%). Decreased left ventricular ejection fraction (LVEF) was seen in 3.6% (95%CI 3.0 – 5.0%), and most patients were asymptomatic. Eleven patients developed prolonged QT interval, and four had left ventricular dysfunction and cardiac failure. Conclusions: Our meta-analysis reinforces the importance of close vigilance for pulmonary and cardiac toxicities in mBC patients on treatment with T-DXd. Early detection and management by a multidisciplinary team following the most recent guidelines may improve the patient outcomes. [Table: see text]
Safety and efficacy study of oral metronomic capecitabine in combination with pyrotinib for HER2-positive metastatic breast cancer: A phase II trial.
Authors: Li Qiao , He Maiyue , Liu Jiaxuan , Wang Zijing
Published: June 2023

e13038

Background: A single-arm prospective phase II trial to was conducted evaluate the efficacy and safety of oral metronomic capecitabine combined with pyrotinib in human epidermal growth factor receptor 2-positive (HER2 positive) metastatic breast cancer (MBC) patients. Methods: HER2-positive patients received oral metronomic capecitabine 500 mg three times daily and pyrotinib 400 mg. The primary endpoint was progression-free survival (PFS). Other endpoints included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety. Results: 50 patients with HER2-positive MBC were enrolled, and one was excluded due to medication irregularities. The median PFS and OS were 11.9 months (95%CI 8.8-14.6) and 29.3 months (95%CI 24.4-34.8) respectively. ORR was 34.7%, and CBR was 81.6% with 2 CR (4.1%), 15 PR (30.6%) and 23 SD (46.9%). The mPFS in first- or second-line treatment was 12.2 months. The most frequent treatment-related adverse complications included hand-foot syndrome, diarrhea, vomiting and nausea. Grade 3 adverse events occurred in 15 (30.6%) patients and included hand-foot syndrome (12.2%), diarrhea (12.2%), vomiting (4.1%), and nausea (2.0%). Grade 4 adverse event of diarrhea (2.0%) was observed in one case. Conclusions: The combination of metronomic capecitabine and pyrotinib is a promising regimen with competitive efficacy and improved tolerability in HER2-positive metastatic breast cancer patients. Clinical trial information: NCT03923166 .
Use of PARPi among patients with HER2+ve MBC: Results from a real world dataset.
Authors: Dawood Shaheenah S. , Brzozowski Kaylen
Published: June 2023

e13044

Background: Among individuals with germline mutations in BRCA1/ BRCA2 genes, life-time risk of developing breast cancer is approximately 50%. The majority of these cancers are HER2-ve with a low frequency of HER2+ve breast cancer (2.1%-10% in pts with BRCA1 mutations and 6.8%-13% of pts with BRCA2 mutations) with co-occurrence of BRCA mutation and HER2+ve status being a poor prognostic factor. PARPi have been shown in phase III trials to be effective in HER2-ve BRCA mutation MBC. The objective of this retrospective analysis was to look at the prognostic outcome associated with use of PARPi among pts with HER2 +ve BRCA mutated MBC in the real-world setting. Methods: We utilized a federated network of de-identified health data representing approximately 107 million pt lives available through the TriNetX Research Network. We identified patients with MBC who were treated with PARPi, and pts were assumed to have BRCA mutated MBC if they were recorded with a PARPi. Overall survival (OS) was computed using the Kaplan Meier product limit method. Pts with MBC were defined as having HER2+ve status if they received an anti-HER2 therapy after metastasis, HR+ve if they received endocrine therapy after metatstasis, and triple negative (TNBC) if they did not receive anti-HER2 therapy or endocrine therapy. Results: 1369pts with MBC were treated with PARPi, of whom 77.9%received olaparib. Mean age of pts was 57ys. 546(39.9%), 521(38.1%) and 73(5.3%) pts had TNBC, HR+ve/HER2-ve, and HER2+ve MBC, respectively. Among pts with HER2+ve disease, 35.2% and 74.0% had HR-ve and HR+ve MBC, respectively. Median time to use of PARPi was 7.1m, 15.1m, and 24.0m among pts with TNBC, HR+ve/HER2-ve, and HER2 +ve MBC respectively. Median OS was 44.4m, 47.0m, and 46.7m among pts with TNBC, HR+ve/HER2-ve and HER2+ve MBC respectively. Among pts with HER2+ve disease, median OS was 74.5m and 31.5m among pts with HR+ve and HER-ve disease, respectively (HR=0.27, p=0.0001). 321(23.4%) pts had brain metastases of whom 36.8%, 36.4% and 8.1% had TNBC, HR+ve/HER2-ve and HER2+ve MBC respectively. Among pts with HER2+ve MBC,38.3% received anti HER2 therapy before PARPi, 24.7% received anti HER2 therapy after PARPi and 37.0% received PARPi and anti HER2 therapy concurrently. Among pts with HER2+ve disease, median OS was 44.4m among those who received anti -HER2 therapy on or before PARPi and 93.8m among those who received anti-HER2 therapy after PARPi (HR 0.83, p=0.64).Among pts with brain metastases, median OS was 23.9m, 40.0m and 40.2m among pts with TNBC, HR+ve/HER-ve and HER2+ve MBC respectively. Conclusions: To our knowledge this is the first real world data set to report on the prognostic outcome of pts with HER2+ve BRCA mutated MBC. When PARPi inhibitors are given median OS is similar among the three subtypes of breast cancer. Although not significant, there appears to be a trend towards improved OS with earlier use of PARPi among patients with HER2+ve BRCA mutated MBC.
De novo metastatic Her2+ breast cancer in a diverse population of women under age 40.
Authors: Chung Victoria , Sheen Melanie Anne , Henry Marcia , Alberti Matthew , Peeples James , Yuan Helen , Saxena Raina , Olet Susan , Taylor Caitlin , Cattie Rabia
Published: June 2023

e13045

Background: Breast cancer (BC) is the most common malignancy among women. Her2 mutation has historically been associated with more aggressive disease and worse prognosis, however this paradigm is changing with Her2-directed therapies. Her2 positive BC presents with de novo metastatic disease more often than other subtypes. Young women are more likely to be diagnosed with Her2 positive BC, however previous studies have not had adequate representation of Black/African American women. We evaluated a diverse group of young women under the age of 40 to determine if Her2+ disease was more likely to present with de novo metastatic disease. Methods: We performed a retrospective chart review and collected data on 746 women diagnosed with BC under the age of 40 from 2012 to 2022. We collected age at diagnosis, Her2 receptor status, self-identified race, and stage at diagnosis. 187 of these patients were Her2 positive, and 276 patients were Black. We stratified patients as Black versus White, and as stage IV at diagnosis versus stages I to III at diagnosis. We performed Fisher's exact test to determine if Her2 positive BC was more or less likely to present as de novo metastatic disease compared to Her2 negative BC. Results: In our population of 746 young women under the age of 40 presenting to our health system in a 10-year period, 48 (6.4%) presented with de novo metastatic BC, and 19 (39.6%) of these were Her2 positive. 36% of our study population was Black, which is representative of the demographics of our region. We performed Fisher's exact test, and found that Her2 positive BC was more likely to present as de novo metastatic disease compared to Her2 negative BC. This was statistically significant (p = 0.024). When divided for race, this was not statistically significant for White patients alone (p = 0.052) or Black patients alone (p = 0.234). Conclusions: Our data shows that Her2 positive BC in women under the age of 40 is statistically more likely to present with de novo metastatic disease. Previous research in this area has not been inclusive of Black patients. Current guidelines only recommend staging imaging among patients with systemic symptoms. Based on this data, consideration should be made for staging scans for young women presenting with new HER2+ breast cancer diagnoses. There is limited data available for breast cancer subtype incidence and prognosis among Black patients, and this study underscores the need for more inclusive study populations.[Table: see text]
Impact of use of CDK4/6i and neratinib among patients with HER2 +ve MBC: Results from a real world dataset.
Authors: Dawood Shaheenah S. , Brzozowski Kaylen
Published: June 2023

e13046

Background: The introduction of anti-HER2 therapy has improved the prognostic outcome of pts with HER2+ve MBC. A phase II trial revealed that among pts with HR+ve/HER2+ve MBC the use of CDK4/6i with anti-HER2 and endocrine therapy was associated with a survival advantage compared to anti-HER2 therapy and chemotherapy. A phase III trial showed that neratinib + capecitabine improved OS compared to lapatinib and capecitabine. With a plethora of new and efficacious anti-HER2 therapy now available the true clinical utility of CDK4/6i and neratinib are undetermined. The objective of this retrospective analysis was to look at the prognostic outcome associated with use of CDK4/6i and neratinib among pts with HER2+ve MBC in the real-world setting. Methods: We utilized a federated network of de-identified health data representing approximately 107 million pt lives available through the TriNetX Research Network. We identified pts with 6511pts with HER2+ve MBC diagnosed since 2015 who were treated with ant-HER2 therapy including trastuzumab, pertuzumab, neratinib, lapatinib, TDM-1 and margetuximab. OS was computed using the Kaplan Meier product limit method. HR+ve status was defined by treatment with endocrine therapy after metastasis, and triple negative (TNBC) status was identified if they did not receive anti-HER2 therapy or endocrine therapy. Results: Mean age was 57.0 yrs. 3679(57.2%) and 2832(42.8%) pts had HR+ve and HR-ve disease, respectively. 2-year OS among pts diagnosed prior to 2015 and during or after 2015 was 79.7% and 82.8%, respectively (p=0.0041). 2-year OS among pts with HR+ve and HR-ve MBC was 87.0% and 75.4%, respectively (p<0.0001). Among pts with HR+ve MBC, 592(16.1%) received a CDK4/6i. Median time to use of CDK4/6i was 4.7m. 2-year OS among pts who did and did not receive a CDK4/6i was 85.1% and 87.5%, respectively (p=0.1844). Median OS among pts who received CDK4/6i within the first year of MBC diagnosis compared to those who received it after the first year of diagnosis was 71.0m and 69.4m, respectively (p=0.0679). No difference in OS was observed among pts with HR+ve disease who had brain mets who did and did not receive CDK4/6i(49.5m vs 54.5m p=0.7335). 327(5.0%) pts received neratinib, of whom 63.9% had HR+ve MBC. 2-year OS among pts who did and did not receive neratinib was 85.1% and 82.6%, respectively(p=0.2366). No difference in 2-year OS was observed among pts who did and did not receive neratinib stratified by HR status and presence of brain metastasis. Conclusions: OS among pts with HER2+ve MBC has significantly improved over time. The use of CDK4/6i among pts with HR+ve/HER2+ve MBC and use of neratinib among pts with HER2+ve MBC did not impact OS.
BPI-16350, a novel promising CDK4/6 inhibitor for HR+/HER2- metastatic breast cancer (MBC): Results from a phase I study.
Authors: Zhang Jian , Liu Rujiao , Gao Shuiping , Chen Wenyan , Han Xinghua , Ma Yanjie , Ding Lieming , Wang Jiabing , Lan Hong , Hu Xichun
Published: June 2023

e13051

Background: BPI-16350 is a highly potent CDK4/6 inhibitor, and has a similar structure to abemaciclib but with less inhibition of CDK9 in pre-clinical experiments. This is an open-label, dose-escalation and -expansion phase I study to evaluate the safety, pharmacokinetics, and preliminary antitumor activity of BPI-16350 as monotherapy (Part A) and combined treatment with fulvestrant (FUL) in pts with HR+/HER2- MBC (Part B). Methods: In Part A, patients (pts) who had failed standard therapies were eligible to receive BPI-16350 in a standard 3+3 pattern at doses ranging from 50−500 mg QD. In Part B, BPI-16350 (300 mg or 400 mg QD) plus intramuscular FUL was administered in pts who had experienced secondary endocrine resistance. Pts in this part should have received no more than one line of chemotherapy for metastatic disease and no prior therapies with other CDK4/6 inhibitors, FUL or everolimus. Results: As of 13 November 2022, 24 pts were enrolled in Part A (50 mg, n=4; 100 mg, n=4; 200 mg, n=3; 300 mg, n=3; 400 mg, n=4; 500 mg, n=6), including 23 pts with MBC and one pt with abdominal liposarcoma. 66.7% (16/24) of pts had received ≥ 2 lines of chemotherapies and 70.8% (17/24) had received ≥ 2 lines of endocrine therapies. Only one dose-limiting toxicity event (i.e. Grade 3 blood creatinine increased) was observed at 500 mg dose, and the maximum tolerated dose was not reached. Grade ≥ 3 AEs occurred in 45.8% (11/24) of pts, with the most common being diarrhea (4/24), anemia (3/24), and neutropenia (2/24). The median time to peak concentration for BPI-16350 was 2.0-17.0 hours, and the mean half-life was 35.6-51.0 hours, supporting once-daily dosing. After a single oral dose of 50–500 mg of BPI-16350, the drug exposure was dose-proportional. With a QD dosing regimen, accumulation was 2.1–3.3 fold. The disease control rate (DCR) was 70.8% (17/24, 95% CI: 48.9%-87.4%). One pt (4.2%) achieved a partial response at 500 mg dose. In Part B, 46 pts with HR+/HER2- MBC were enrolled (300 mg, n=9; 400 mg, n=37), and 63.0% (29/46) of pts were still on treatment. Grade ≥ 3 AEs occurred in 42.5% (20/46) of pts, with the most common being anemia (8/46), leukopenia (6/46), hypokalemia (6/46), and neutropenia (5/46). Among the 46 pts, 43 pts were evaluable for efficacy. The DCR was 97.7% (42/43, 95% CI: 87.7%-99.9%). The confirmed overall response rate was as high as 60.5% (26/43, 95% CI: 44.4%-75%). The median progression-free survival has not been reached (95% CI: 11.1 months–not reached). Conclusions: To our knowledge, BPI-16350 plus FUL demonstrated numerically highest antitumor activity compared with the already approved CDK4/6 inhibitors and less Grade ≥ 3 diarrhea than abemaciclib. A phase III study (NCT05433480) comparing BPI-16350 plus FUL versus placebo plus FUL in pts with MBC is ongoing. Clinical trial information: NCT03791112 .
Outcome of second-line treatment after CDK4/6 inhibitors in hormonal-positive HER-2 negative metastatic breast cancer: Single institution experience.
Authors: Alghanmi Hosam , Elsamany Shereef Ahmed , Elnaghi Khaled
Published: June 2023

e13053

Background: In patients with metastatic hormonal receptors (HR)-positive, HER2-negative breast cancer, CDK 4/6 inhibitors with hormonal therapy is the current standard first line therapy in patients without visceral crisis. Limited data is available about the outcome of second line therapy after CDK 4/6 inhibitors. In this study, we reported the survival outcome of second line systemic therapy after CDK 4/6 inhibitors in a single institute in Saudi Arabia. Methods: We retrospectively checked patients with metastatic HR-positive, HER2-negative breast cancer who received first line therapy with palbociclib in addition to an aromatase inhibitor in King Abdullah Medical City, Saudi Arabia. Patients who received second line systemic therapy were recruited. Different clinicopathological data were checked in addition to type of second line therapy, dates of starting 1st and second lines therapy and dates of progression. We check progression-free survival (PFS) with second line therapy in relation to the type of second line therapy, duration of 1st line therapy and other potential prognostic factors. Results: We recruited 59 eligible patients. Median PFS of the study group was 4 months (95% CI 2.9-5.1). No significant difference in PFS according to type of second line systemic therapy (chemotherapy: 4 months, everolimus with hormonal therapy: 6 months, hormonal monotherapy: 3 months, p=0.17). In addition, there was no significance difference in second line therapy PFS according to duration of 1st line palbociclib-hormonal therapy (≤ 12 months: 4 months vs. >12 months: 5 months, HR 0.97, 95% CI: 0.55-1.7, p=0.92). Similarly, taking 6 months as a cutoff, no significant difference in PFS (≤ 6 months: 4 months, >6 months: 6 months, HR 0.73, 95% CI: 0.43-1.24, p=0.25). Similarly, no difference in second line PFS according to menopausal status, age at diagnosis (≤ 50 vs >50) or ER-Allred score (≤ 6 vs >6). Conclusions: Outcome of 2nd line systemic therapy following first line palbociclib with hormonal therapy was poor in the study cohort. No significant difference in PFS according to type of systemic therapy, duration of first line therapy, or other clinicopathological factors.
Comparative effectiveness of palbociclib plus aromatase inhibitor versus fulvestrant alone as initial endocrine therapy for HR+/HER2- advanced breast cancer in Chinese clinical practice: A real-world study.
Authors: Yue Jian , Yuan Peng , Wang Xue , Ju Jie , Gao Song-lin , Yang Zixuan , Kang Yikun , Lei Zixuan , Shuai You , Wei Tong
Published: June 2023

e13057

Background: In the real world, there are still a large number of HR+/HER2- advanced breast cancer patients receiving initial endocrine therapy with fulvestrant monotherapy in China, especially patients with bone metastases only. It is due to lack of data comparing the effective between Palbociclib combined with AI and fulvestrant monotherapy as initial endocrine therapy. On the other hand, there are economic factors and access issues. According to the National Cancer Center's previous clinical experience, Palbociclib combined with AI is superior to fulvestrant monotherapy in HR+/HER2- advanced breast cancer patients receiving initial endocrine therapy. Therefore, we collected and summarized the previous clinical data in our center to compare the effective of Palbociclib combined with AI and fulvestrant monotherapy for HR+/ HER2-advanced breast cancer patients receiving initial endocrine therapy in China. Methods: This is a retrospective real-world experience aimed at verifying the effective of Palbociclib combined with AI and fulvestrant monotherapy for HR+/ HER2-advanced breast cancer patients receiving initial endocrine therapy in China. The primary aim was rwPFS; secondary aims were overall survival, and objective response rate. Patients received Palbociclib combined with AI or fulvsetrant monotherapy. Results: In total, 346 patients were enrolled, 193 to Palbociclib plus AI and 153 to fulvestrant monotherapy. Median age was 55 years (range 28-88); 191 had visceral involvement (116 in Palbociclib plus AI group and 75 in fulvestrant group). At a median follow up of 38 months (range 4-78). The median PFS was 20.0 months (95% CI 17.3–22.7) in the Palbociclib plus AI group and 12 months (95% CI 9.6–14.3) in the fulvestrant group (hazard ratio 0.593, 95% CI 0.470–0.749, p<0·0001). The 6-month progression-free rate was 83.9% in the Palbociclib plus AI group and 75.8% in fulvestrant group. The 6-month progression-free rate was 83.9% in the Palbociclib plus AI group and 75.8% in fulvestrant group. The 12-month progression-free rate was 65.8% in the Palbociclib plus AI group and 46.4% in fulvestrant monotherapy group. The over survival was not reached in the Palbociclib plus AI group and it was 65 months (95% CI 55.6–75.4) in the fulvestrant group. Grade 3-4 adverse events occurred in Palbociclib plus AI group. The most common grade 3 or 4 adverse events were neutropenia (47.7%) and leucopenia (27.5%) in the Palbociclib plus AI group. Conclusions: The efficacy of palbociclib plus AI is worthy of recognition and the toxicity was acceptable. Compared with fulvestrant monotherapy in HR+/HER2- advanced breast cancer patients receiving initial endocrine therapy, Palbociclib plus AI might have a better survival. Clinical trial information: NCT05000736 .
Clinicopathological characteristics, evolution, treatment patterns and outcomes of hormone-receptor-positive/HER2-low-positive metastatic breast cancer: A retrospective analysis.
Authors: Wang Biyun , You Shuhui , Zhao Yannan
Published: June 2023

e13058

Background: HER2-low positivity is more prevalent in breast cancers with positive hormone receptor (HR). Patients with HR-positive and low HER2 expression may have different prognosis and characteristics. Nevertheless, research focusing on HR-positive/HER2-low-positive breast cancer remains scarce. Methods: This study included 458 patients with HR-positive/HER2-negative metastatic breast cancer (HR+/HER2- MBC) who received first- or second-line endocrine therapy at the Fudan University Shanghai Cancer Center (FUSCC) between July 2010 and October 2022. Results: Clinicopathological characteristics, HER2 expression in primary and metastatic lesions, treatment patterns, and clinical outcomes of various therapies were compared between the HER2-low-positive and HER2-zero groups. 54.37% (249/458) of the HR+/HER2- MBC patients were HER2-low-positive. Comparable clinicopathological characteristics were observed in the HER2-low-positive and HER2-zero groups. PFS of first- and second-line endocrine treatment was comparable for HER2-low-positive and HER2-zero patients. When taking chemotherapy, the HER2-low-positive group had a shorter PFS than the HER2-zero group (median PFS: 8.64 vs. 9.03 months, p = 0.03). 41.79% (28/67) of HER2-zero primary tumors increased their HER2 score on biopsy, while 41.67% (35/84) of HER2-low-positive tumors became HER2-zero. Patients with an elevated HER2 IHC score from the primary tumor to the metastatic tumor had a longer PFS than those with constant HER2-low-positive status (median PFS: 11.99 months vs. 8.84 months, p = 0.02). Conclusions: HR-positive MBC patients with HER2-low and HER2-zero expression responded similarly to endocrine therapy. But HER2-low-positivity in HR-positive MBC may reduce chemotherapeutic effectiveness and HER2 heterogeneity should be taken into consideration.
The association between baseline patient characteristics and alpelisib-induced hyperglycaemia in patients with HR+, HER2-, PIK3CA-mutated metastatic breast cancer.
Authors: Godina Eva , Borstnar Simona
Published: June 2023

e13059

Background: Alpelisib (A) is a PI3Kα-selective inhibitor and degrader which, in combination with fulvestrant, has been approved for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC). Hyperglycemia is the most commonly observed adverse event of A. A pooled analysis of X2101 AND SOLAR-1 trials showed the association between five baseline patient characteristics (age, fasting plasma glucose (FPG), glycated haemoglobin, body mass index (BMI) and blood monocyte count (BMC)) and the development of A-induced hyperglycaemia (HG). We examined the association between baseline factors and the A-induced HG grade (G) ≥2 in a real-world setting. Methods: We performed the retrospective observational study and included patients (pts) with HR+, HER2-, PIK3CA-mutated metastatic breast cancer who received A + fulvestrant between Oct 18, 2019, and Oct 13, 2022, at the Institute of Oncology Ljubljana. Electronic records were reviewed. Baseline age, FPG, glycated haemoglobin, BMI and BMC before the start of A therapy and glucose levels during treatment with A were collected. Random plasma glucose values (RPG) were used for HG grading according to CTCAE V. The chi-square test was used to determine the association between the baseline characteristics and A-induced HG G ≥2. Results: Thirty-one female pts were included in the analysis. The median follow-up was 21 months, and the median duration of A treatment was 5.4 months. The baseline pts characteristics were as follows: median age 58 years (range 33–80), median FPG 5.6 mmol/L (range 3.10–8.6), median BMI 21.7 kg/m² (range 18.7–30.4), and median BMC was 10.3% (range 5.3–16.6). Baseline glycated haemoglobin values were only known for 58.1% of patients, so we did not further analyse them. The highest HG grades during treatment with A were as follows: G0 in 14 pts (45.2%), G1 in 5 pts (16.1%), G2 in 6 pts (19.4%), G3 in 6 pts (19.4 %). The calculated cut-off values associated with A-induced HG ≥2 were: age above 65 years, FPG above 5.9 mmol/L and BMC more than 11.5. None of the BMI cut-off values was associated with HG G≥2. Association between the baseline age, FPG and BMC and A-induced HG G≥2. Conclusions: Age over 65 years, FPG more than 5.9 mmol/L and BMC more than 11.5% have a statistically significant higher probability for A-induced HG G≥2. Therefore, these patients need more frequent blood glucose measurements, lifestyle adjustments and early treatment with metformin and/or other oral glucose-lowering agents. [Table: see text]
Treatment patterns and clinical outcomes following endocrine resistance among with HER2-low metastatic breast cancer: Retrospective observational study.
Authors: Mehta Sandhya , Savill Kristin M. Zimmerman , Wang Peng , Pathak Prathamesh , Lam Clara , Kwong Jackie , Feinberg Bruce A.
Published: June 2023

e13069

Background: Endocrine therapy (ET) ± CDK 4/6 inhibitors is a common initial treatment for HR+/HER2-low (IHC 1+ or IHC2+/ISH-) metastatic breast cancer (mBC). However, many patients eventually progress on ET-based regimen and receive subsequent chemotherapy (CT). This study aimed to describe treatment patterns and outcomes following endocrine resistance among HR+/HER2-low mBC patients in U.S community oncology practices. Methods: Participating oncologists from Cardinal Health’s Oncology Provider Extended Network (OPEN) provided data from the medical charts of adult patients with HR+/HER2-low mBC who received at least two lines (2L) of systemic therapy, with first line (1L) initiated between Feb 19, 2016, and Dec 31, 2018. Analysis was performed among patients who received a subsequent chemotherapy (CT) after progression on their last observed line of ET-based regimen. Patient characteristics and treatment history were summarized descriptively. Kaplan-Meier analyses of treatment outcomes, including physician-reported real-world progression free survival (rwPFS), time to treatment response (TTR) and time to treatment discontinuation (TTD) were performed. Results: 150 HR+/HER2-low mBC patients who received subsequent chemotherapy after ET resistance were included [mean age: 61±11 years, 57.3% were white and 32.7% were black]. The proportion of patients who stopped ET after 1L, 2L and ≥3L of ET were 23.3% (n=35), 70.7% (n=106) and 6.0% (n=9), respectively. The mean duration of ET-based regimens was 29.7 (SD: 13.12) months. Among patients who stopped ET after 1L (n=35), most patients received fulvestrant + palbociclib (48.6%) in 1L prior to switching to CT. Among those who stopped ET after 2 or more lines (n=115), most patients received letrozole + palbociclib (57.4%) in 1L and fulvestrant (46.1%) in 2L. The most common CT regimen utilized was capecitabine (47.0%) followed by paclitaxel (28.0%). The median rwPFS on CT was 8.12 months (95% CI 7.36-9.24), with slightly shorter median rwPFS among those who stopped ET after 1L (7.82 months, 95% CI 7.07-9.53) vs. 2L+ (8.19 months, 95% CI 6.97-9.99). The median TTD of CT was 7.82 months (95% CI 7.07-8.61) and TTR was 4.96 months (95% CI 4.24-5.72), with similar estimates observed between patients who stopped ET after 1L and 2L+. Conclusions: In this small sample of HR+/HER2-low mBC patients, most patients switched to CT after receiving two lines of ET based regimens. Following ET resistance, durability of response with subsequent CT was short and similar irrespective of number of prior lines of ET based regimens. This preliminary chart review study highlights the unmet need for a more effective therapeutic alternative to CT after ET for HR+/HER2-low mBC patients. Further research using larger sample and more robust clinical data is warranted to confirm the study findings.
A quality improvement initiative on the utility of the Oncotype DX breast cancer assay in a community hospital.
Authors: Iqbal Sabah , Desai Krishna , Baralo Bohdan , Jain Akhil , Pereira Kristal , Renzu Mahvish , Mehta Vidhi , Singh Vartika , Ramesh Nithya , Deshpande Sohiel , Edlukudige Keshava Vinay , Thirumaran Rajesh
Published: June 2023

e13072

Background: Since the advent of Oncotype DX (ODX) breast recurrence score (RS) assay, the use of adjuvant chemotherapy (CT) in the treatment of breast cancer has significantly reduced. This test not only estimates the benefit of CT, but also determines the risk of distant recurrence in patients with early-stage breast cancer with hormone-receptor (ER/PR) positive, human epidermal growth factor receptor (HER) 2-negative, and axillary lymph node negative or positive (1-3 positive nodes) disease. All patients are categorized based on their scores ranging from 0-100 as follows: low (RS≤10), intermediate (RS11-25) and high risk (RS≥26). Further studies proved that adjuvant CT is beneficial in pre-menopausal women with RS 0-25, however offered no benefit to post-menopausal women in the same category. The aim of our study was to assess the implementation of these guidelines in a community hospital in an underserved area. Methods: At Mercy Catholic Medical Center, we performed a retrospective analysis on 303 female patients with newly diagnosed breast cancer, identified between January 2017 – October 2022. We included patients with ER/PR+, HER2-, lymph node negative or positive, who had undergone surgery and were to receive endocrine therapy with or without adjuvant CT. Patients who were lost to follow-up or did not undergo the genetic testing were excluded from the study. We then analyzed the treatment strategies based on RS categories. All patients who did not receive CT was either because it was not indicated (old age, post-menopausal) or patients refused. Results: 81 patients underwent ODX testing among whom, 60.5%, 35.8%, and 3.7% patients were Black, White and Hispanic/Asian, respectively. 1.2%, 9.8%, 18.51%, 34.56%, 35.08% were aged ≤40, 41-50, 51-60, 61-70 and ≥71 years, respectively. Based on the RS, we identified 29.62% in low risk, 56.79% in intermediate risk, and 13.5% in high-risk categories. 100% patients in the high-risk category were prescribed CT and only 7.4% patients with RS 0-25 received CT. 12 patients were found to be lymph node positive, among whom, 3 had RS≥26 and 2 were pre-menopausal, all of whom were prescribed CT. Out of these, 7 were post-menopausal with RS 0-25 and only 1 received CT. Conclusions: Our hospital data suggests that implementation of ODX and adherence to its guidelines has significantly helped avoid CT and its related side effects in the low and intermediate risk categories. Implementation of this cost-effective test has consistently increased in the last two decades and is now an imperative tool in clinical decision-making specially in community hospitals serving underprivileged populations. [Table: see text]
Is HER2 expression related to CDKi efficacy in HER2-negative luminal metastatic breast cancer?
Authors: Garcés María Yeray Rodríguez , Fernández Madrigal Laura , Morales Pancorbo David , Bayo Juan L.
Published: June 2023

e13073

Background: Cyclin kinase inhibitors (CDKi) are the standard of care in the first line of luminal (Lum) metastatic breast cancer (MBC). HER2 overexpression is a classic risk factor in BC, however, the use of targeted therapy has changed the prognosis of this disease, even with anti-HER2 efficacy data in cases of low HER2 expression. We wonder if the level of HER2 expression can be a predictor of efficacy in treatment with CDKi. Methods: Descriptive, observational, retrospective and analytical study of patients with MBC treated with CDKi, in the period 2018-2022. Descriptive and analytical statistical analysis (IBM SPSS Statistics 22) using logistic regression and Kaplan-Meier with long-rank test to analyze the relationship between CKi efficacy and HER2 expression (negative = 0+; HER2 low = 1+ and 2 + with SISH negative). Results: We analyzed 152 patients (p) with Lum MBC under treatment with CDKi (median 58 years), in first and successive lines. HER2 expression: 31% 46p (0+), 54% 81p (1+) and 14% 21p (2+ and SISH negative). 41% were treated with palbociclib, 34% with ribociclib, and 26% with abemaciclib. Radiological response (RR) to CDKi was achieved by 34.1% (CRR 2.4%, PRR 31.7), and the rest stable disease (SD) or progressive disease (PD): SD 42% and PD 22%. In the overall OR, there was no evidence of a risk association between the response to CDKi and the level of HER2 expression. We obtained similar results in the analysis stratified by type of CDKi. In the multivariate study, for the variables CDKi type and HER2 expression, the logistic regression model was not statistically significant either. Regarding the Kaplan-Meier analysis, we compared the median PFS and OS using the Long-rank test, based on the expression of HER2. In the complete series we did not find statistically significant differences between the curves. In the palbociclib subgroup the curves split in favor of HER2 0+ vs. HER2 low: 44 months 95%CI (7.6-80) vs 16 months 95%CI (7.9-24); p = 0.01. Regarding OS, we found no significant differences. With ribociclib, the curves separate in favor of HER2 low versus HER2 0+: 33 months 95%CI (7.2-18) vs. 13 months 95%CI (23-42); p = 0.03. In OS we did not find significant differences either. In the subgroup with abemaciclib, we observed a trend towards greater survival in HER2 0+ patients, but with no significant difference between the PFS or OS curves. Conclusions: Based on our study, the expression of HER2 could be considered a predictor of efficacy depending on the CDKi used. We assume greater survival with palbociclib in HER2 negative patients (0+) and with ribociclib in HER2 low patients. We consider it essential to develop studies with a larger sample size and clinical trials that allow us to demonstrate the hypothesis of our work with scientific evidence.
Inhibition of FASN as a potential treatment of advanced endocrine therapy-resistant breast cancer.
Authors: Gunuganti Avani , Balinda Henriette , Brenner Andrew J.
Published: June 2023

e13077

Background: The past decade has seen significant advancement in increasing survival estrogen receptor alpha (ERα) positive breast cancer. The use of selective estrogen receptor down-regulators and modulators (SERMs) and cyclin-dependent kinase inhibitors aided to extend overall survival of breast cancer patients. However, resistance to endocrine therapy is a common occurrence and patients will eventually succumb to their disease. Fatty acid synthase (FASN), a key enzyme in lipid biosynthesis, is overexpressed in more aggressive and therapy-resistant tumors, including breast cancers. FASN inhibitor, TVB-2640, has been evaluated in multiple tumor cell lines and in a phase 1 clinical study, and showed partial responses in 5 patients and multiple patients with prolonged stable disease (≥16 weeks). Methods: We generated therapy-resistant cells by long term exposure to tamoxifen (MCF7/TamR cells), and fulvestrant (MCF7/FR cells). Palbociclib-resistant (MCF7/RB1Crispr and ZR75/RB1Crispr) cells were generated through CRISPR/Cas9 knockout of the retinoblastoma (RB) gene. We assessed the impact of TVB-3166 inhibitor in these cells on proliferation, viability, cell cycle, apoptosis, ERα expression in patient derived explants, and tumor growth in xenografts. RNA sequencing of tamoxifen- and fulvestrant-resistant cells was performed to investigate gene expression. Subcellular localization of ERα was assessed using subcellular fractionations. Palmitoylation and ubiquitination of ERα were assessed by immunoprecipitation. ERα and p-eIF2α protein levels were analyzed by western blot after treatment with TVB with or without the addition of palmitate or BAPTA. Results: TVB treatment leads to a marked inhibition of proliferation in tamoxifen-, fulvestrant- and palbociclib-resistant cells compared to the parental cells. RNA sequencing of explants of patients with ERα positive disease showed down regulation of ESR1 related genes and genes involved in invasiveness. RNA sequencing of fulvestrant-resistant cells showed that treatment with TVB results in down regulation of EMT and E2F target genes, cholesterol homeostasis genes and mTORC1 signaling. Additionally, TVB significantly inhibited tumor growth in mice and decreased proliferation of primary tumor explants compared to untreated controls. FASN inhibition significantly reduced ERα levels most prominently in endocrine resistant cells and altered its subcellular localization. Furthermore, we showed that the reduction of ERα expression upon TVB treatment is mediated through the induction of endoplasmic reticulum stress. Conclusions: Our preclinical data provide evidence that FASN inhibition presents a promising therapeutic strategy for treatment of endocrine-resistant breast cancer. Further clinical development of FASN inhibitors for endocrine resistant breast cancer should be considered.
Clinical characteristics and outcome of PIK3CA mutated hormone receptor positive (HR+), human epidermal growth factor 2 negative (HER2-), advanced breast cancer (BC) treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i): Real world data.
Authors: Dedic Plavetic Natalija , Čular Katarina , Križić Marija , Popovic Marina , Plestina Stjepko , Silovski Tajana
Published: June 2023

e13078

Background: BC is the most common malignant disease and leading cancer-related cause of death in women. Despite significant achievements in the treatment, advanced BC (aBC) is still an incurable disease. HR+/HER2- subtype accounts for 70% of all BC. One of the most common mutations in BC is the PIK3CA gene mutation which can induce endocrine and chemo- resistance. In early BC, patients (pts) with PIK3CA mutations mostly have better, but in aBC worse prognosis. Standard first-line treatment for HR+/HER2- aBC is a combination of CDK4/6i and endocrine therapy. PIK3CA status is most often assessed in this group of pts and combination of alpelisib - PIK3CA inhibitor and fulvestrant is second-line treatment option in PIK3CA mutated pts. Methods: Medical records of HR+/HER2- aBC pts who started CDK4/6i therapy between 01.08.2018. and 01.10.2020. were analyzed with prior University Hospital Center Zagreb Ethics Committee approval. Demographics, tumor characteristics, clinical presentation and therapy information were collected. Molecular analysis of PIK3CA mutations was performed on tumor tissue samples. Time to treatment failure (TTF) was analyzed using the Kaplan-Meier method and the data cut-off was 31.12.2022. Results: Of the 103 pts with determined PIK3CA status, 45 (43.7%) had a detectable mutation. Median follow-up was 35 months. CDK4/6i were first line therapy in 31 (68.9%) pts with and 29 (50%) pts without PIK3CA mutation. Endocrine resistance, de novo metastatic disease and bone marrow infiltration were more common in PIK3CA mutated subgroup. The incidence of visceral metastases was similar in both groups, whereas liver metastases were more common in the unmutated group. Disease progression was observed in 69 (67%) pts, 28 (40.6%) of whom were PIK3CA mutated. Median TTF in mutated subgroup was 24 months (95% CI 21-33) and 25 months in unmutated subgroup (95% CI 19-36). During the follow-up period, 35 (34%) pts died, 14 (40%) of whom were PIK3CA mutated. Odds ratios in pts with a PIK3CA mutation. Conclusions: There was no relevant difference in TTF between two groups. However, PIK3CA mutated subgroup had more aggressive clinical features - more often presented with bone marrow infiltration and de novo aBC, statistically relevant OR 5.158 and 2.323 respectively, which is related to lower quality of life and highlights the importance of treatment improvement for this subgroup of pts. [Table: see text]
Commercial next generation sequencing in a real-world cohort of patients with metastatic breast cancer.
Authors: Taneja Kamil , Cohen Jules A.
Published: June 2023

e13082

Background: Clinicians increasingly order next generation sequencing (NGS) of tissue or liquid (ctDNA) biopsies from patients with metastatic breast cancer. Although some genetic information is clinically actionable, some, particularly non-ERBB2 gene amplifications, is not. We reviewed NGS data from a real-world cohort of metastatic breast cancer patients to evaluate the prevalence of somatic abnormalities using commercial NGS technology. Methods: We evaluated Foundation One NGS data from 44 tissue and 17 liquid biopsies from patients seen in a medical oncology practice between 2016 and 2022. We used KM Plotter to measure overall survival in early-stage patients by relative gene expression. Results: 76% of patients had ductal and 24% had lobular carcinomas. 59% of patients had luminal (ER-positive) and 32% of patients had basal breast cancer (ER-negative). Only 9% of patients had HER2-positive disease. 48% of the tumors had a p53 abnormality, either a point (59%) or frameshift mutation (36%). 50% tumors had a somatic mutation in a tumor suppressor gene such as PTEN, RB or APC. One patient had a germline BRCA1 mutation and 5 patients had germline BRCA2 mutations. 39% of patients carried a somatic mutation in PIK3CA, predominantly H1047R (45%) in the kinase domain or E545X (20%) in the helicase domain. KM plotter showed worse OS in early-stage patients with low p53 gene expression or high PIK3CA expression. 10/11 patients with lobular carcinoma had somatic mutations in CDH1, 70% of which were frameshift mutations. 8/27 patients with luminal cancer had an ESR1 mutation, predominantly Y537 or D538. 9 patients, predominantly luminal, had amplifications of the 11q13 (CCND1). 7 patients had amplifications of 8q24 (MYC). 20q13 (AURKA) amplifications were only seen in luminal cancers. 12p13 (CCND2) amplifications were only seen in basal cancers. 27% of lobular cancers (vs. 6-17% of ductal cancers) demonstrated amplification of the 11q13, 8q24 and/or 8p11 amplicons. 20q13 and 12p13 amplifications were only seen in ductal cancers. Liquid biopsies were more likely to detect point mutations than tissue biopsies. p53 mutations were seen in 65% of liquid vs. 48% of tissue biopsies. 47% of liquid biopsies showed two p53 mutations. PIK3CA mutations were seen in 71% of liquid vs. 39% of tissue biopsies. 18% of liquid biopsies showed two PIK3CA mutations. 93% of basal cancers had at least one p53 mutation. 44% of luminal cancers had a PIK3CA mutation. ESR1, GATA3 and AKT1 mutations were only seen in luminal cancers. While ESR1 mutations were seen in ductal and lobular cancers, GATA3 and AKT1 mutations were only seen in ductal cancers. Conclusions: Commercial NGS testing of a real-world cohort yields actionable mutations that can impact clinical management and outcome of metastatic breast cancer patients. NGS testing demonstrates the range of gene amplifications and corresponds closely with what has been reported in the published literature.