HER2-negative Metastatic Breast Cancer Patients Research Articles

Abstract PO5-04-13: Liquid Biopsy Testing in a Greek Cohort of ER-positive, HER2-negative metastatic breast cancer patients

Abstract AIM Endocrine therapy (ET) represents the first line treatment for patients with ER+, HER2- breast cancer, however disease progression is observed in many cases. PIK3CA and ESR1 are the most encountered mutated genes that have been associated with targeted molecular treatment, as well as with resistance to Endocrine Therapy. Liquid biopsy is a non-invasive procedure, that can provide “real-time” monitoring of disease progression and response to treatment. The aim of this study is to determine the mutation rate of ESR1 and PIK3CA genes in a selected cohort of 200 Greek breast cancer patients, using liquid biopsies and NGS technology. PATIENTS AND METHODS Liquid biopsies were collected from 200 ER-positive, HER2-negative metastatic breast cancer patients who have received at least one previous line of endocrine treatment. cfDNA was extracted using the QIAamp Circulating Nucleic Acid Kit (Qiagen). Library preparation was performed using Oncomine™ Breast cfDNA Research Assay (Thermofisher Scientific) and sequencing was carried out using Ion GeneStudio™ S5 System (Thermofisher Scientific). Ion Torrent Oncomine Knowledgebase Reporter was used in sequence analysis and interpretation of Copy number variations, SNPs, and indels. RESULTS Preliminary data of the first 49 examined samples demonstrated the prevalence of ESR1 and PIK3CA mutations in 20.4% (10/49) and 38.7% (19/49) of the cases respectively. The most frequently mutated codon in the ESR1 gene is the Y537, while in the PIK3CA gene, the H1047 codon is mainly altered. ESR1 and PIK3CA genes were co-mutated in 10.2% of the cases. Mutations in KRAS (6.1%) and TP53 (24%) were also detected. CONCLUSION More than 20% of the ER-positive, HER2-negative breast cancer patients with metastatic disease are eligible for targeted treatment with elacestrant. In addition, the high prevalence of mutations detected in our cohort indicates that liquid biopsy NGS panel testing can be used to monitor treatment response, track the development of resistance, and identify emerging genetic alterations that may guide treatment adjustments or the selection of alternative targeted therapies in breast cancer patients. REFERENCES Demir Cetinkaya B, Biray Avci C. Molecular perspective on targeted therapy in breast cancer: a review of current status. Med Oncol. 2022 Jul 14;39(10):149. doi: 10.1007/s12032-022-01749-1. PMID: 35834030; PMCID: PMC9281252. Liao H, Huang W, Pei W, Li H. Detection of ESR1 Mutations Based on Liquid Biopsy in Estrogen Receptor-Positive Metastatic Breast Cancer: Clinical Impacts and Prospects. Front Oncol. 2020 Dec 15;10:587671. doi: 10.3389/fonc.2020.587671. PMID: 33384956; PMCID: PMC7770162. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-elacestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast-cancer Citation Format: Nikolaos Tsoulos, Angeliki Meintani, Georgios Kapetsis, Chrysiis Chatzigiannidou-Florou, Aikaterini Tsantikidi, Stella Maxouri, Eleni Thanou, Kalliopi Aggelaina, Vasiliki Metaxa-Mariatou, Georgios Tsaousis, Ioannis Natsiopoulos, Vasileios Venizelos, Christos Markopoulos, Flora Zagouri, Eleftherios Kampletsas, Eirini Karyda, Dimitrios Tryfonopoulos, Konstantinos Papazisis, Dimitrios Ziogas, Ilias Athanasiadis, Eirini Papadopoulou, Georgios Nasioulas. Liquid Biopsy Testing in a Greek Cohort of ER-positive, HER2-negative metastatic breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-04-13.

Abstract PO3-16-02: Trastuzumab and taxane chemotherapy in the first-line in MBC patients with a HER2-negative primary tumor and HER2-positive circulating tumor cells: a phase II trial

Abstract Purpose: HER2 overexpressing circulating tumor cells (CTCs) are observed in up to 20% of HER2-negative metastatic breast cancer patients. Since targeted anti-HER2 therapy has drastically increased the outcome of patients with HER2 positive breast cancer, we hypothesized that patients with HER2 overexpressing CTCs might benefit from the addition of trastuzumab to chemotherapy. Methods: In this single-arm, phase II trial, HER2 negative patients with HER2-positive CTCs received trastuzumab as addition to first-line treatment with taxane chemotherapy (trastuzumab group). Patients with detectable CTCs but without HER2 overexpression and that received taxane chemotherapy only, were used as internal control group (taxane monotherapy group). The primary outcome measure was progression-free rate at 6 months (PFR6). The study was powered to reach a PFR6 of 80%; in this case this strategy was considered worth further investigation. In November 2022, the study was terminated early due to slow patient accrual. Results: 63 HER2 negative patients with metastatic disease were screened, of which 8 patients had HER2-positive CTCs and were treated in the first line with trastuzumab in addition a taxane. Patients receiving taxane monotherapy were used as a control group (n = 27). The median number of CTCs was 15 (range 1 – 131) in patients with HER2-positive CTCs, compared to median 5 (range 1-1047) in the control group. PFR6 was 50% in the trastuzumab group and 64% in the taxane monotherapy group, with no significant difference in median PFS (8 versus 9 months, p=0.51). Excluding the patients that had no measurable CTCs, there was a borderline significant difference between median CTC count in the patients that did and that did not have HER2 positive CTCs (p=0.05). We confirmed a significant higher CTC-count in samples that had at least one HER2-postive CTC in an independent patient set (n=233, p< 0.001). Conclusions: Although this study was performed in a limited number of patients, no clinical benefit of trastuzumab was observed. Firstly, we conclude that our strategy was not feasible for clinical implementation due to high numbers needed to screen. And, second, due to the strong correlation between CTC numbers and detected CTC HER2 positivity, the prognostic value of the CTC numbers precludes judgement of any predictive value of the HER2 status of CTCs. Citation Format: Noortje Verschoor, Manouk Bos, Inge de Kruijff, Ngoc M Van, Jaco Kraan, Jan Drooger, Johanna Zuetenhorst, Saskia M Wilting, Stefan Sleijfer, Agnes Jager, John WM Martens. Trastuzumab and taxane chemotherapy in the first-line in MBC patients with a HER2-negative primary tumor and HER2-positive circulating tumor cells: a phase II trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-16-02.

Abstract PO1-16-05: Matched multi-analyte and multi-omic liquid biopsy of cell-free DNA, circulating tumor cells and extracellular vesicles in HER2-positive metastatic breast cancer patients

Abstract Background: Liquid biopsy, specifically cell-free DNA (cfDNA) mutation analysis, has recently entered clinical practice for treatment decision-making in hormone receptor (HR)-positive (+)/HER2-negative (-) metastatic breast cancer (mBC) patients. However, we showed that the analysis of multiple liquid biopsy analytes in the course of treatment in this BC subgroup has additive value. Since no multi-analyte studies are currently available for the subgroup of HER2+ mBC patients, we here studied multiple analytes [cfDNA, circulating tumor cells (CTCs) and extracellular vesicles (EVs)] and utilized our multi-omics perspective (CpG island methylation, mutations and mRNA expression) to get insight into their utility in therapy management of HER2+ mBC. Methods: 2x 9 ml blood was drawn from 21 HER2+ (HR+ n=16 and HR- n=5) mBC patients at the time of disease progression and at two consecutive staging time points. CTCs and their mRNA were isolated from 2x5 ml blood by positive immunomagnetic selection targeting EpCAM, EGFR and HER2 (AdnaTest EMT2/StemCell Select/Detect). Plasma of CTC-depleted blood was used for cfDNA isolation, while mRNA from EVs was isolated from 4 ml pre-filtered plasma by affinity-based binding to a spin column (exoRNeasy) using the remaining blood. The mRNA purified from CTCs and EVs by Oligo-dT beads was reverse transcribed, pre-amplified and analyzed by a multi-marker (18 genes) qPCR panel. qPCR data was normalized to CD45 (for CTC analysis) and data of 20 healthy female donor controls to identify BC specific overexpression signals with a specificity of >90% for all targets. Variants in the cfDNA were analyzed with a customized QIAseq Targeted DNA Panel with unique molecular indices (UMIs) and high coverage (mean 22.000x), while CpG island methylation in the cfDNA was analyzed with a customized QIAseq Targeted Methyl Panel with UMIs covering 9786 CpG sites (mean 900x). Consumables: QIAGEN, Germany. Results: In general, substantial differences occurred between the CTC and EV mRNA profiles. Transcripts involved in the PI3K pathway (mTOR, AKT2, PIK3CA) as well as ERBB2 signals were significantly more prevalent in CTCs compared to EVs and mTOR, ERCC1, SRC, AKT2 und PIK3CA CTC overexpression signals were found in >50% of these patients. In contrast, PARP1, AURKA, SRC und ERCC1 signals were significantly more prominent in the EVs and detected in >50% of the patients. ERCC1 signals were present in EVs with highest prevalence whereas ERBB2 signals were only present in CTCs. ERBB3+ CTCs were only detected in patients showing disease progression. Currently, cfDNA mutations as well as cfDNA CpG island methylation are under evaluation and the complete multi-analyte and multi-omic data set as well as their relation to clinical outcome will have been finalized to be presented at the meeting. Conclusion: We successfully established a workflow for parallel isolation of multiple liquid biopsy analytes from a minimized blood volume in HER2+ mBC. Preliminary mRNA profile results for CTCs and EVs show the complementary nature of these two liquid biopsy analytes. Besides the multi-analyte nature of this workflow, the pending results for genomic and epigenomic information will show which one of the analytes, alone or in combination, will help to optimize therapy management in HER2+ mBC patients. Citation Format: Sabine Kasimir-Bauer, Markus Storbeck, Ioanna Andreou, Siegfried hauch, Oliver Hoffmann, Rainer Kimmig, Corinna Keup. Matched multi-analyte and multi-omic liquid biopsy of cell-free DNA, circulating tumor cells and extracellular vesicles in HER2-positive metastatic breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-16-05.

Abstract PO1-05-10: Clinical effectiveness of CDK4/6 inhibitors in HER2-low metastatic breast cancer

Abstract Introduction: There is growing evidence indicating that human epidermal growth factor 2 (HER2)-low is a unique subtype of breast cancer that comprises a substantial share of patients historically classified as HER2 negative. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are important in the treatment of hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC). Whether HER2-low status or the level of HER2 gene amplification have prognostic significance for HR+/HER2-negative MBC patients treated with ET and CDK4/6i remains an area of active investigation. Methods: Patients diagnosed with HR+/HER2-negative MBC and who were treated with palbociclib, ribociclib, or abemaciclib from 6/10/2015 to 12/28/2022 were selected from the Montefiore Health system database and followed until 3/24/2023. HER2-0 was defined as immunohistochemistry (IHC) 0, and HER2-low was defined as IHC 1+ or IHC 2+/in situ hybridization negative by 2018 ASCO/CAP guidelines. Median values were used to establish cutoffs for HER2/CEP17 ratio and HER2 gene copy number (GCN). Characteristics of the patients and tumors in the subgroups were compared using chi-squared/Fisher’s exact test for categorical data and Kruskal-Wallis/Wilcox signed rank tests for continuous data. Kaplan-Meier and Cox proportional hazards analysis were used to compare overall survival (OS) and progression free survival (PFS). Results: 239 patients received CDK4/6i, with 46 HER2-0 and 193 HER2-low patients. There was no statistically significant difference in clinicopathological characteristics between both cohorts. No significant differences were observed in median OS (36 vs 34 months, P > 0.9) and median PFS (44 vs 35 months, P = 0.4) between HER2-0 and HER2-low patients. Adjusting for HER2 status, multivariable analysis showed no statistically significant association between HER2-low status and worse OS (HR: 1.03, P = 0.9) or worse PFS (HR: 1.37, P = 0.4). The median HER2/CEP17 ratio was 1.25 (Interquartile range (IQR): 1.18-1.39), and the median HER2 GCN was 2.58 (IQR: 2.10-3.18). Median OS (25 vs 37, P = 0.15) and median PFS (35 vs 37, P = 0.15) showed no significant differences between ratio-below vs above-median patients. However, patients with GCN-below-median had significantly worse OS (25 vs 37 months, P = 0.026), with no significant difference in median PFS (38 vs 35 months, P = 0.3). Multivariate analysis revealed a significant effect of GCN-below-median on OS (HR: 0.50, P = 0.022) but not on PFS. Conclusion: The clinical effectiveness of CDK4/6i is not influenced by HER2-low status; however, the extent of HER2 gene amplification may have a substantial impact on therapy responsiveness in MBC patients undergoing CDK4/6i treatment. Table 1. Baseline characteristics of patients with MBC comparing HER2-0 vs HER2-low, above/below median HER2/CEP17 ratio, and above/below median HER2 GCN. Table 2. Median OS and PFS in patients with MBC comparing HER2-0 vs HER2-low, above/below median HER2/CEP17 ratio, and above/below median HER2 GCN. Table 3. Multivariable analysis of OS and PFS for patients with MBC comparing HER2-0 vs HER2-low, above/below median HER2/CEP17 ratio, and above/below median HER2 GCN. Citation Format: Frank Zhang, Jesus Anampa Mesias. Clinical effectiveness of CDK4/6 inhibitors in HER2-low metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-10.

Abstract 121: Gut microbiome association with dietary habits and abemaciclib-induced diarrhea:A multicenter, prospective study

Abstract Background: Abemaciclib, a leading treatment used for HR-positive, HER2-negative metastatic and primary breast cancer patients, often causes diarrhea. Understanding the reasons machinery behind this adverse event leads to reduce the toxicity and improve the quality of life. This study explores a hypothesis that specific gut microbiota profiles are engaged in gastrointestinal toxicities caused by abemaciclib and may be influenced by patients' dietary habits. We assessed it using the Brief Diet History Questionnaire (BDHQ). Materials and Methods: Our research involved collecting blood and stool samples, as well as dietary data through the BDHQ from 39 patients diagnosed with HR-positive, HER2-negative metastatic breast cancer. These were obtained prior to the start of abemaciclib treatment, at the first imaging evaluation, and at either disease progression or treatment discontinuation due to adverse effects. Incidence and severity of diarrhea were evaluated by the Bristol stool scale at baseline, from day 1 to day 14, and at day 90 of treatment. Stool samples were collected at baseline and at day 90 after the start of abemaciclib treatment. We conducted 16S metagenomic sequencing for gut microbiome analysis and used mass cytometry along with RNA-sequencing to profile immune cells. Results: Our findings indicate a significant association between the gut microbiota composition and abemaciclib-induced diarrhea, which also appears to be modulated by dietary patterns. An increase in Dorea was observed with higher Bristol Stool Scale scores, while Bifidobacterium and Sellimonas abundances were inversely related to changes in stool characteristics. The presence of Dorea was also positively associated with the consumption of specific food items such as tea, root vegetables, and dietary minerals. In contrast, Collinsella abundance decreased as the frequency of diarrhea increased and it was associated with the consumption of fried foods and certain fats. Conclusion: The prevalence of diarrhea as a side effect of abemaciclib treatment highlights the need for better management strategies. Our study indicates that gut microbiota, altered by dietary habits, is linked to this adverse effect. The data suggest a possibility of using specific gut bacteria as probiotics to alleviate this condition, pointing towards personalized dietary interventions as a potential avenue for improving treatment tolerance. Citation Format: Yuri Fujimoto, Kosuke Kawaguchi, Yurina Maeshima, Hiroshi Ishiguro, Kazuhiko Yamagami, Sachiko Takahara, Hirofumi Suwa, Masae Torii, Shigenori Nagai, Yasuaki Sagara, Wakako Tsuji, Hiroyasu Yamashiro, Takeshi Kotake, Shinji Fukuda, Kuniaki Saito, Yasuko Yamamoto, Masako Kataoka, Yuki Himoto, Atsushi Yonezawa, Yukiko Fukui, Yuki Nakamura, Wei Li, Sunao Tanaka, Masahiro Takada, Satoshi Morita, Masakazu Toi. Gut microbiome association with dietary habits and abemaciclib-induced diarrhea:A multicenter, prospective study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 121.

Trastuzumab and first-line taxane chemotherapy in metastatic breast cancer patients with a HER2-negative tumor and HER2-positive circulating tumor cells: a phase II trial

PurposeHER2 overexpressing circulating tumor cells (CTCs) are observed in up to 25% of HER2-negative metastatic breast cancer patients. Since targeted anti-HER2 therapy has drastically improved clinical outcomes of patients with HER2-positive breast cancer, we hypothesized that patients with HER2 overexpressing CTCs might benefit from the addition of trastuzumab to chemotherapy.MethodsIn this single-arm, phase II trial, patients with HER2-positive CTCs received trastuzumab as addition to first-line treatment with taxane chemotherapy. Patients with detectable CTCs but without HER2 overexpression that received taxane chemotherapy only, were used as control group. The primary outcome measure was progression-free rate at 6 months (PFR6), with a target of 80%. In November 2022, the study was terminated early due to slow patient accrual.Results63 patients were screened, of which eight patients had HER2-positive CTCs and were treated with trastuzumab. The median number of CTCs was 15 per 7.5 ml of blood (range 1–131) in patients with HER2-positive CTCs, compared to median 5 (range 1–1047) in the control group. PFR6 was 50% in the trastuzumab group and 54% in the taxane monotherapy group, with no significant difference in median PFS (8 versus 9 months, p = 0.51).ConclusionNo clinical benefit of trastuzumab was observed, although this study was performed in a limited number of patients. Additionally, we observed a strong correlation between the number of evaluable CTCs and the presence of HER2-positive CTCs. We argue that randomized studies investigating agents that are proven to be solely effective in the HER2-positive patient group in patients with HER2-positive CTCs and HER2-negative tissue are currently infeasible. Several factors contribute to this impracticality, including the need for more stringent thresholds, and the rapidly evolving landscape of cancer treatments.

Efficacy, safety, and predictive model of Palbociclib in the treatment of HR-positive and HER2-negative metastatic breast cancer

PurposeThis research designeded to: 1. Analyze the efficacy and safety of Palbociclib treatment in HR-positive and HER2-negative (HR + /HER2-) metastatic breast cancer(MBC) patients. 2. Establish and validate a nomogram model for predicting the progression-free survival (PFS) rates of 6 months, 12 months, and 18 months in HR + /HER2- MBC patients after receiving Palbociclib plus endocrine therapy (ET).Patients and methods1. This research retrospectively analyzed the efficacy and safety of Palbociclib combined with ET in 214 patients with HR + /HER2- MBC. 2. A nomogram was designed and constructed with the retrospective clinical data of 214 patients with HR + /HER2- MBC who received Palbociclib plus ET at Zhejiang Cancer Hospital in China from August 2018 to August 2022. Among these patients, 161 were randomly assigned to the training cohort, while 53 to the validation cohort. The predictive accuracy of the nomogram was assessed through the analysis the area under the receiver operating characteristic(ROC) curve, calibration curve, and decision curve analysis(DCA).Results1. Median PFS was 7.17 months (95% CI: 7.61—10.05 months), with an objective response rate (ORR) of 2.80% and a disease control rate (DCR) of 34.58%. The most prevalent grade 3–4 adverse event was neutropenia (38.79%). 2. Multiple variable analysis of the training set revealed that age < 60 years old, PR < 20%, Ki-67 ≥ 20%, luminal B molecular subtype, primary resistance to ET, receipt of late-stage chemotherapy, and presence of liver metastasis or ≥ 2 visceral metastases were independent prognostic factors associated with poor PFS (P < 0.05). Then, the predictive model underwent development and validation utilizing the aforementioned parameters. On the one hand, the area under the ROC curve (AUC) values of the training set at 6 months, 12 months, and 18 months were 0.771, 0.783, and 0.790, respectively, indicating a strong predictive ability of the developed model. On the other hand, the AUC of the validation set at 6 months, 12 months, and 18 months were 0.720, 0.766, and 0.754, respectively, suggesting the favorable discriminatory ability of the model. The calibration curves also exhibited a good fit with the ideal curves, and the DCA demonstrated the clinical applicability of the model. The nomogram's different scores could distinguish PFS.ConclusionThis retrospective study demonstrates the efficacy of Palbociclib in Chinese breast cancer patients. Moreover, the clinical parameters showed a significant association with the prognosis of HR + /HER2- MBC, and the prognostic models constructed based on these variables also displayed robust predictive power, which could offer more intuitive and convenient references for clinical doctors to formulate follow-up treatment plans.

Clinical Outcomes of HER2-Negative Metastatic Breast Cancer Patients in Italy in the Last Decade: Results of the GIM 13-AMBRA Study.

GIM 13-AMBRA is a longitudinal cohort study aimed at describing therapeutic strategies and the relative outcome parameters in 939 HER2-ve MBC patients. Taxanes-based regimens, or taxanes + targeted agents, mainly Bevacizumab, were the preferred first choice in both Luminal (30.2%) and TNBC (33.3%) patients. The median PFS1 was 12.5 months (95% CI 16.79-19.64), without any significant difference according to subtypes, while the median Time to first Treatment Change (TTC1) was significantly lower in TNBC patients (7.7 months-95% CI 5.7-9.2) in comparison to Luminal A (13.2 months, 95% CI 11.7-15.1) and Luminal B patients (11.8 months, 95% CI 10.3-12.8). PFS2 was significantly shorter in TNBC patients (5.5 months, 95% CI 4.3-6.5 vs. Luminal A-9.4, 95% CI 8.1-10.7, and Luminal B-7.7 95% CI 6.8-8.2, F-Ratio 4.30, p = 0.014). TTC2 was significantly lower in patients with TNBC than in those with the other two subtypes. The median OS1 was 35.2 months (95% CI 30.8-37.4) for Luminal A patients, which was significantly higher than that for both Luminal B (28.9 months, 95% CI 26.2-31.2) and TNBC (18.5 months, 95% CI 16-20.1, F-ratio 7.44, p = 0.0006). The GIM 13-AMBRA study is one of the largest collections ever published in Italy and provides useful results in terms of time outcomes for first, second, and further lines of treatment in HER2- MBC patients.

ASCO 2023: highlights in breast cancer

SummaryThe 2023 annual meeting of the American Society of Clinical Oncology (ASCO) was again held in June 2023 in Chicago. While not immediately practice changing, results from several interesting studies in the field of breast cancer (BC) were reported. In the phase III NATALEE trial, the addition of 3 years of ribociclib to standard adjuvant endocrine therapy resulted in a significant improvement in invasive disease-free survival (iDFS), making this the second positive study of CDK4/6 inhibitors in the adjuvant setting. A subgroup analysis from the MONARCHe trial indicated sustained benefit of adjuvant abemaciclib in the subset of patients with low dose intensity. Long-term outcome of the neoadjuvant phase II PHERgain trial indicated excellent iDFS results in patients receiving neoadjuvant trastuzumab and pertuzumab without chemotherapy based upon PET metabolic response as a dynamic biomarker. In a biomarker analysis from the SOFT trial, more high-risk tumors were observed in the very young patient subset, while the PAM50 risk-of-recurrence score was not predictive for benefit of ovarian function suppression. A large retrospective analysis evaluated the role of adjuvant chemotherapy in small, node-negative triple-negative breast cancer. A clear benefit for chemotherapy was only seen in tumors &gt; 10 mm of size. In metastatic HR-positive breast cancer, the PALMIRA trial with palbociclib beyond progression yielded negative results. An update from the PADA-1 trial again indicates the promising role of repeated liquid biopsies for treatment guidance in metastatic disease. Patritumab deruxtecan, a HER3-directed antibody–drug conjugate yielded promising response rates in HER2-negative metastatic breast cancer patients. In addition, several retrospective analyses focused on the important question of treatment sequencing.

Efficacy of anlotinib in Chinese patients with metastatic breast cancer: A retrospective observational study.

Anlotinib, a multitarget tyrosine kinase inhibitor, can inhibit tumour angiogenesis proliferation, metastasis, promote vascular normalization, increase T cell and NK cell activity and infiltration, remodel tumour microenvironment and synergistic immune enhancement. Our study aimes to evaluate the efficacy of anlotinib in the treatment of advanced metastatic breast cancer (MBC) after multiple lines of therapy. Patients included were treated with anlotinib for advanced MBC in the Affiliated Cancer Hospital of Zhengzhou University from 1 January 2019 to 30 June 2023. The objective remission rate, disease-free progression survival and adverse reactions were analysed. We compared and analysed the efficacy of anlotinib in the treatment of advanced metastatic breast cancer, which showed that ORR was 23.6% and DCR was 69.1%. The DCR of monotherapy was 66.7% and that of combination therapy was 69.6% in MBC patients. The combination therapy, combined with chemotherapy had the best effect (79.3%), combined with immunotherapy came second. In addition, the DCR (88.9%) was higher in MBC patients having received prior antiangiogenic therapy. According to the Kaplan-Meier (K-M) survival estimate analysis, the mPFS was 4.17 months (95% CI, 1.758-6.582 months) in Her-2 positive MBC patients, and 7.83 months (95% CI, 2.416-9.104) in Her-2 negative MBC patients. The mPFS was 5.76 months (95% CI, 3.231-8.298 m) in HR positive MBC patients, 7.83 months (95% CI, 3.182-12.478 m) in TNBC patients. Fatigue (20.0%), hypertension (21.8%) and liver dysfunction (18.2%) were common adverse reactions, followed by bone marrow suppression (16.4%), anorexia (14.5%), hypothyroidism (14.5%) and diarrhoea (14.5%). Altogether, Anlotinib monotherapy or combination therapy provides a viable third (or above)-line therapeutic strategy in patients with metastatic breast cancer. The adverse reactions of anlotinib are well tolerated and controllable.

415P Patterns of time-to-progression intervals across clinical and liquid biopsy (LB) features in hormone receptor-positive (HR+) HER2-negative (HER2-) metastatic breast cancer (MBC) patients (pts) treated with first-line endocrine therapy (ET)

415P Patterns of time-to-progression intervals across clinical and liquid biopsy (LB) features in hormone receptor-positive (HR+) HER2-negative (HER2-) metastatic breast cancer (MBC) patients (pts) treated with first-line endocrine therapy (ET)

478P Germline BRCA1/2 pathogenetic variants (gBRCA1/2 PV) affect outcome of hormone (HR)-positive HER2-negative metastatic breast cancer (MBC) patients (pts) treated with cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) plus endocrine therapy (ET): The BREAK study

478P Germline BRCA1/2 pathogenetic variants (gBRCA1/2 PV) affect outcome of hormone (HR)-positive HER2-negative metastatic breast cancer (MBC) patients (pts) treated with cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) plus endocrine therapy (ET): The BREAK study

HORMON RESEPTÖR POZİTİF, HER-2 NEGATİF METASTATİK MEME KANSERLİ HASTALARDA CDK4/6 İNHİBİTÖRÜ TEDAVİSİ ÖNCESİ SİSTEMİK İMMÜN İNFLAMASYON İNDEKSLERİNİN VE PROGNOSTİK NUTRİSYONEL İNDEKSİN PROGNOSTİK ÖNEMİ

Abstract&#x0D; Purpose: As systemic inflammatory indices and prognostic nutritional index are associated with poor prognosis in many tumor types, the goal of the present study was to ascertain their effect along with the neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, lymphocyte/monocyte ratio, C-reactive protein/albumin ratio, and systemic inflammatory response index on the progression-free survival (PFS) and overall survival (OS) of hormone receptor-positive HER2-negative (HR+/HER2−) metastatic breast cancer patients before CDK4/6 inhibitor treatment. &#x0D; Materials and Method: The medical records of 79 patients with HR+/HER2− metastatic breast cancer who presented at the Medical Oncology Outpatient Clinic between January 2018 and May 2022 were retrospectively analyzed to gather relevant data measured before CDK4/6 inhibitor treatment in order to establish the effect of key markers on their PFS and OS.&#x0D; Results: The median age of the participating patients, 70 (88.6%) of whom were postmenopausal, was 53 years (range 26−80 years). While 68 patients (86.1%) had a 0 performance score, 10 (12.7%) developed metastases during adjuvant endocrine therapy. Factors affecting PFS were age

Abstract OT2-01-01: Trial in Progress: Clinical Utility of Fluoroestradiol F18 PET/CT in Metastatic Breast Cancer Patients with ER-Positive and HER2-Negative Primary Lesions after Progression on First Line Hormonal Therapy

Abstract BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy are the recommended first-line standard-of-care (SOC) treatment for estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) patients. After progression on first-line treatment, current clinical practice guidelines (NCCN, ESMO) recommend to sequence endocrine therapy (in absence of visceral crisis) until there is no clinical benefit after up to 3 regimens, and subsequently initiate chemotherapy regimens. However, clinical benefit for endocrine monotherapy after progression on first-line standard-of-care is limited, with median progression-free survival (PFS) of 2-5 months. Multiple factors can contribute to endocrine therapy resistance, including changes in ER expression, (epi)genetic mutations, and/or clonal selection under therapeutic pressure. ER heterogeneity can occur over time (temporal) as well as between lesions in a patient (spatial). As confirmed by tissue biopsy, greater than 20% of MBC patients have discordance in ER expression between their primary tumor and a metastatic lesion. Measuring total ER heterogeneity in a patient – the variation in ER expression at whole body level across all MBC lesions – is not clinically feasible by tissue biopsy alone. Fluoroestradiol F18 (Cerianna), also called 18F-FES, is a radioactive diagnostic agent that can be used with PET/CT for in vivo detection of ER-positive lesions in MBC with high accuracy. Results from 18F-FES PET/CT studies have shown that ER expression across MBC lesions at whole body level is heterogeneous in approximately half of ER-positive, HER2-negative MBC patients. In this study, we aim to evaluate the clinical utility of 18F-FES PET/CT to guide second-line treatment decision in ER-positive, HER2-negative MBC patients with progressive disease on first-line SOC hormonal therapy. METHODS: Fluoroestradiol F18 (Cerianna) is being evaluated in a phase 4, open-label, prospective cohort study enrolling 206 patients at 20-30 centers in the United States. Patients diagnosed with ER-positive, HER2-negative MBC who have progressive disease on first-line aromatase inhibitor therapy with or without CDK4/6 inhibitor will be included in the study; patients with isolated hepatic metastases will be excluded. All patients will undergo an 18F-FES PET/CT scan. The treating physician will complete a standardized questionnaire to indicate the second-line therapeutic management plan before the scheduled 18F-FES PET/CT. After interpretation of 18F-FES PET/CT by local radiologist or nuclear medicine physician, imaging results will be provided to the treating physician who will then fill out a similar questionnaire to specify the final therapeutic decision. The proportion of patients with a change in therapeutic management plan based on incorporation of 18F-FES PET/CT results will be the primary endpoint. During the study follow-up period of 18 months, data on SOC imaging, treatments/procedures received, and clinical outcomes will be collected. Secondary endpoints include visual and quantitative heterogeneity assessment of tumor 18F-FES uptake, and PFS rates at 6 months and 18 months after 18F-FES PET/CT, which will be assessed between patients with and without a change in therapeutic management plan. The trial is planned to begin enrollment in Q3 2022. Clinical trial information: NCT05068726 Citation Format: Stephanie van de Ven, Feng Luo, Nicholas DiGregorio, Adolfo Fuentes-Alburo, Francois Tranquart. Trial in Progress: Clinical Utility of Fluoroestradiol F18 PET/CT in Metastatic Breast Cancer Patients with ER-Positive and HER2-Negative Primary Lesions after Progression on First Line Hormonal Therapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-01.

Abstract OT3-11-02: SOLTI-1910: Predicting olaparib sensitivity in patients with unresectable locally advanced/metastatic HER2-negative breast cancer with BRCA1/2, PALB2, RAD51C/D mutations or HRD by the RAD51 test: RADIOLA TRIAL

Abstract Background The OlympiAD trial evaluated the PARP inhibitor (PARPi) olaparib versus a non-platinum standard chemotherapy in HER2-negative metastatic breast cancer (MBC) patients with a germline BRCA1/2 (gBRCA) mutation. Olaparib resulted in improved progression-free survival (PFS) and doubled the response rate vs chemotherapy. Nevertheless, the response rate to PARPi is 60% in the gBRCA1/2 population with MBC (current approval), suggesting a limited positive predictive value of gBRCA1/2 status. Moreover, patients with other relevant Homologous Recombination Repair defects (HRD) such as PALB2 or RAD51C/D mutation carriers, or HRD epigenetic silencing, are not captured with a gBRCA analysis. We have previoulsy shown that the functional HRD biomarker RAD51, tested in FFPE tumor samples using an optimized immunofluorescence-based assay, is associated with platinum response in early TNBC and PARPi response in preclinical BC models. We hypothesize that the RAD51 test would help to expand the clinical benefit of PARPi by predicting response to olaparib in MBC with germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation and beyond. Study design RADIOLA is an open-label, single-arm, multicentre phase II study evaluating treatment with olaparib in male or female ≥18 years patients with HER2-negative MBC with ≤ two prior chemotherapy lines in two cohorts: cohort 1 (N=41) with known germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation; cohort 2 (N=25) with functional HRD, namely RAD51-low score (≤10%), in wild-type/unknown mutation status at study entry. All patients will receive olaparib 300mg po BID until progression or unacceptable toxicity. Primary objective will assess, in terms of overall response rate (ORR), the capacity of the RAD51 score to predict olaparib efficacy in cohort 1. Secondary objectives include PFS, clinical benefit rate, duration of response, safety in both cohorts and ORR in cohort 2. Recruitment Recruitment (11 sites) started in March 2022. As of July 2022, 7 patients have been enrolled in Spain. Funding This study is financially supported by AstraZeneca. Citation Format: Judith Balmaña, Tomás Pascual, Alba Llop-Guevara, Pablo Tolosa, Isabel Blancas, Maria-Eva Perez-Lopez, Barbara Adamo, Iris Teruel, Jose Ponce, Marta Gonzalez, Gemma Viñas, Laura Lema, Francisco Javier Salvador, Mª Teresa Martinez, Alejandra Espinosa, Aleix Prat, Violeta Serra. SOLTI-1910: Predicting olaparib sensitivity in patients with unresectable locally advanced/metastatic HER2-negative breast cancer with BRCA1/2, PALB2, RAD51C/D mutations or HRD by the RAD51 test: RADIOLA TRIAL [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-11-02.

Exploring the relationships between hormone receptor, HER2 status, and bone involvement in the first distant metastases of in Chinese breast cancer patients who lacked HER2 targeted therapy

BackgroundThis retrospective study explored the relationship between hormone receptor (HR), human epidermal growth factor receptor 2 (HER2) status, and bone involvement in the first distant metastases (DM) of Chinese breast cancer (BC) patients who lacked the HER2 targeted therapy. Such therapy was rarely received due to its lag approval or high cost in China compared with the developed countries.MethodsAll eligible women with primary unilateral stage I – III BC and first DM diagnosed in 2008—2018 at one cancer center were identified for enrollment. Based on chart records, a full or no/partial compliance status of endocrine therapy (ET) was assigned for HR-positive patients. Multivariate logistic regression was used to estimate the adjusted odd ratio (aOR), its 95%CI and p value.ResultsFour hundred eighteen patients had an average age of 50.7 years and median disease-free survival of 27.1 months at DM. Bone, lung, liver and brain metastasis rates in patients were 55.7%, 34.7%, 33.0% and 8.1%, respectively. Compared to HR-negative patients, HR-positive patients with the full and non/partial compliance of ET were significantly associated with higher risk of bone involvement with an aOR of 2.329 (1.316 – 1.741, p = 0.004) and 2.317 (1.330 – 4.036, p = 0.003), respectively. No difference of such risk was found between the two groups of ET compliance (p = 0.984) nor between HER2-negative and HER2-positive patients (aOR 0.827, p = 0.431). Stratified analyses further indicated that HR-positive was associated with bone involvement only in HER2-negative BC patients (p = 0.006—0.015).ConclusionsHR-positive tumors are significantly associated with bone involvement in HER2-negative metastatic BC patients. ET does not appear to impact this association. HER2 status per se is not associated with such risk.

Clinicopathologic features, genomic profiles and outcomes of younger vs. older Chinese hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer patients.

Poor outcomes have been widely reported for younger vs. older breast cancer patients, but whether this is due to age itself or the enrichment of aggressive clinical features remains controversial. We have evaluated the clinicopathologic characteristics and genomic profiles of real-world hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) patients to examine the determinants of outcome for younger vs. older patients in a single clinical subtype undergoing treatment in the same clinic. This study included patients presenting at the Peking University Cancer Hospital with primary stage IV or first-line metastatic HR+/HER2- breast cancer who consented to an additional blood draw for genomic profiling prior to treatment. Plasma samples were analyzed with a targeted 152-gene NGS panel to assess somatic circulating tumor DNA (ctDNA) alterations. Genomic DNA (gDNA) extracted from peripheral blood mononuclear cells was analyzed for germline variants using a targeted 600-gene NGS panel. Kaplan-Meier survival analysis was performed to analyze disease free survival (DFS), progression free survival (PFS) and overall survival (OS) in association with clinicopathologic and genomic variables. Sixty-three patients presenting with HR+/HER2- MBC were enrolled in this study. Fourteen patients were < 40 years, 19 were 40-50 years, and 30 were > 50 years at the time of primary cancer diagnosis. No significant associations were observed between age and DFS, PFS or OS. Shorter OS was associated with de novo Stage IV disease (p = 0.002), Luminal B subtype (p = 0.006), high Ki67 index (p = 0.036), resistance to adjuvant endocrine therapy (p = 0.0001) and clinical stage (p = 0.015). Reduced OS was also observed in association with somatic alterations in FGFR1 (p = 0.008), CCND2 (p = 0.012), RB1 (p = 0.029) or TP53 (p = 0.029) genes, but not in association with germline variants. In this group of real-world HR+/HER2- MBC breast cancer patients younger age was not associated with poor outcomes. While current guidelines recommend treatment decisions based on tumor biology rather than age, young HR+ breast cancer patients are more likely to receive chemotherapy. Our findings support the development of biomarker-driven treatment strategies for these patients.

Eribulin combined with antiangiogenic agents in women with HER2-negative metastatic breast cancer: a retrospective multicenter study.

The relative lack of specifically targeted agents for HER2-negative metastatic breast cancer (MBC) makes the need for new agents or combination therapies to maximize clinical benefit while reducing toxicity critical. To retrospectively analyze the efficacy and safety of eribulin combined with antiangiogenic drugs in the treatment of Chinese women with HER2-negative MBC. A total of 85 consecutive MBC patients with HER2-negative who were treated with eribulin + antiangiogenic agents between October 2020 and April 2023 in four institutions were retrospectively included in this study. Patients received eribulin 1.4 mg/m2 (day 1 and 8) plus bevacizumab 7.5 mg/kg (day 1, 64 patients) or anlotinib 10 mg daily (day 1-14, 16 patients) or apatinib 250 mg daily (5 patients) on a 21-day cycle until progression or unacceptable toxicity. The primary end-point was progression-free survival (PFS), according to Response Evaluation Criteria in Solid tumors (RECIST) 1.1. Secondary end-points included toxicities, objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Adverse events (AEs) were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The study included 85 HER2-negative MBC patients, with 41 patients (48.2%) in the first to second line group and 44 patients (51.8%) in the greater than or equal to third line group. The median age was 54.0 years. Thirty patients in the first to second line group and 14 patients in the greater than or equal to third line group had triple-negative breast cancer (TNBC). The ORR and DCR were 34.1% (29/85) and 75.3% (64/85). The median PFS (mPFS) of total population was 6.0 months (95% CI: 4.3-7.7), and median OS (mOS) was immature. The mPFS was 7.7 and 4.3 months in the first to second and greater than or equal to third line treatment (p = 0.003), respectively. TNBC patients in first to second line therapy showed a significantly longer PFS (6.5 months versus 2.0 months, p = 0.021) compared to greater than or equal to third line. The incidences of cardiovascular toxicity were 29.4% in grades 1-2 and no grades 3-4. Hematologic toxicity (leukopenia and neutropenia) was the most common grade ⩾3 AEs, and AEs were more common in patients in greater than or equal to third line. The results suggest that eribulin combined with antiangiogenic therapy has a meaningful clinical activity and an acceptable safety profile in HER2-negative MBC.

Circulating tumor DNA profile and its clinical significance in patients with hormone receptor-positive and HER2-negative mBC.

After early-line (first- and second-line) endocrine therapy, hormone-receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancers (mBCs) become resistant to endocrine therapy. Genetic alterations may underlie resistance to endocrine therapies. This study aims to investigate the circulating tumor DNA (ctDNA) alterations and the clinical implication in hormone-receptor-positive, HER2-negative metastatic breast cancer patients with multiline endocrine therapy failure. This registered study (NCT05079074, ClinicalTrials.gov) enrolled 104 patients with hormone-receptor-positive, HER2-negative metastatic breast cancer who progressed after the early-line endocrine therapy. ctDNA alterations were analyzed by next generation sequencing (NGS). ctDNA alterations were ranked and clustered by using R 'ComplexHeatmap' and 'hclust' function. ctDNA-guided therapy was administrated. Progression-free survival (PFS) was assessed COX regression analysis, and Kaplan-Meier curves were plotted. The top ctDNA altered genes were TP53 (39%), PIK3CA (38%), BRCA1/2 (13%), ESR1 (12%), FGFR (11%), ERBB2 (11%), and GATA3 (9%). Among these genes, TP53, PIK3CA helix domain mutation (PIK3CA-HD), FGFR, ESR1 and GATA3 were related to endocrine therapy resistance. The genetic landscapes changed and tumor mutation burden increased in both TP53-altered and PIK3CA-altered patients. Both BRCA1/2 and ERBB2 alterations correlated with TP53 alterations (P=0.02 and P=0.04, respectively). However, while 93% BRCA1/2 alterations concentrated in PIK3CA-wildtype patients, 82% ERBB2 alterations concentrated in PIK3CA-altered patients. Kaplan-Meier curves showed that patients who received druggable ctDNA alteration-guided treatment (DDAT) had significantly longer PFS than those who received physician-chosen therapy, with median PFS of 6.1 months versus 4.6 months (hazard ratio = 0.53, 95% CI: 0.34-0.85, Logrank P = 0.006). Multiple genetic alterations were important reasons for the failure of endocrine therapy for HR-positive and HER2-negative mBC. Targeting these genes might restore the treatment sensitivity and benefit survival.

Concept: A randomised multicentre trial of first line chemotherapy comparing three weekly cabazitaxel versus weekly paclitaxel in HER2 negative metastatic breast cancer

BackgroundPaclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer (MBC) patients. However, with response rates of 21.5–53.7% and significant risk of peripheral neuropathy, there is need for better chemotherapy. Patients and methodsThis open-label phase II/III trial randomised HER2-negative MBC patients 1:1 to either 6 cycles of three-weekly cabazitaxel (25 mg/m2), or, weekly paclitaxel (80 mg/m2) over 18 weeks.The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), time to response (TTR), overall survival (OS), safety and tolerability and quality of life (QoL). Results158 patients were recruited. Comparing cabazitaxel to paclitaxel, median PFS was 6.7 vs 5.8 months (HR 0.87; 80%CI 0.70–1.08, P = 0.4). There was no difference in median OS (20.6 vs 18.2 months, HR 1.00; 95%CI 0.69–1.45, P = 0.99), ORR (41.8% vs 36.7%) or TTR (HR 1.09; 95%CI 0.68–1.75, P = 0.7).Grade ≥3 adverse events occurred in 41.8% on cabazitaxel and 46.8% on paclitaxel; the most common being neutropenia (16.5%) and febrile neutropenia (12.7%) cabazitaxel and neutropenia (8.9%) and lung infection (7.6%) paclitaxel. Peripheral neuropathy of any grade occurred in 54.5% paclitaxel vs 16.5% cabazitaxel.Mean EQ-5D-5L single index utility score (+0.05; 95%CI 0.004–0.09, P = 0.03) and visual analogue scale score (+7.7; 95%CI 3.1–12.3, P = 0.001) were higher in cabazitaxel vs paclitaxel. ConclusionsThree-weekly cabazitaxel in HER2-negative MBC does not significantly improve PFS compared to weekly paclitaxel, although it has a lower risk of peripheral neuropathy with better patient reported QoL outcomes. It is well tolerated and requires fewer hospital visits.