HER2-negative Metastatic Breast Cancer Research Articles

CTNI-10. SACITUZUMAB GOVITECAN FOR BREAST CANCER BRAIN METASTASIS

Abstract Breast cancer brain metastasis (BCBM) is a challenge that significantly impacts patient prognosis and quality of life. Sacituzumab govitecan (SG), an antibody-drug conjugate, has demonstrated antitumor activity and is approved for triple negative and HR+/HER2 negative metastatic breast cancer. It consists of a humanized anti-Trop-2 monoclonal antibody linked to a potent topoisomerase I inhibitor, SN-38. SG activity was tested in a breast cancer intracranial mouse model. We conducted a prospective, single center, window of opportunity trial (NCT03995706) to examine the intra-tumoral concentrations of SN-38 in patients undergoing craniotomy for breast cancer brain metastases (n = 13). We enrolled patients aged ≥18 years diagnosed with brain metastatic breast cancer to receive a single intravenous dose of SG at 10 mg/kg one day before surgical resection. Tumor and corresponding serum were collected during surgery to measure their levels of SN-38. Following recovery, patients resumed SG treatment at 10 mg/kg on days 1 and 8 of 21-day cycles and were assessed for responses by MRI every third cycle using response assessment in neuro-oncology (RANO) criteria. Trop-2 and carbonic anhydrase IX (CAIX) expression was investigated by IHC. SG significantly inhibited tumor growth and increased overall survival in mice. An average of 1953.79 ng/ml in serum and 134.3 ng/g in tissue of SN-38 was quantified in patient samples. Trop-2 expression was observed in 100% of patient tumors. 41% of the samples showed high expression of CAIX. A positive correlation between the tissue:serum [SN-38], Trop-2 and gH2AX staining was observed. Median overall survival of 34.5 months (5.7 - 35.6 months) and progression free survival of 7.4 months (2 – 24.4 months) were observed. Our data suggest that SG has therapeutic potential in patients with breast cancer brain metastasis. A prospective multicenter cooperative trial of SG for BCBM, S2007, is ongoing and an update on accrual will be provided.

Circulating Tumor Cells Prediction in Hormone Receptor Positive HER2-Negative Advanced Breast Cancer: A Retrospective Analysis of the MONARCH 2 Trial.

The MONARCH 2 trial (NCT02107703) showed the efficacy of abemaciclib, a cyclin-dependent kinase 4 & 6 inhibitor (CDK4/6i), in combination with fulvestrant for hormone receptor-positive, HER2-negative metastatic breast cancer (MBC). The aim of this analysis was to explore the prediction of circulating tumor cells (CTCs) stratification using machine learning for hypothesis generation of biomarker-driven clinical trials. Predicted CTCs were computed in the MONARCH 2 trial through a K nearest neighbor (KNN) classifier trained on a dataset comprising 2436 patients with MBC. Patients were categorized into predicted Stage IVaggressive (pStage IVaggressive, ≥5 predicted CTCs) or predicted Stage IVindolent (pStage IVindolent, <5 predicted CTCs). Prognosis was tested in terms of progression-free-survival (PFS) and overall survival (OS) through Cox regression. Patients classified as predicted pStage IVaggressive and predicted pStage Stage IVindolent were, respectively, 183 (28%) and 461 (72%). After multivariable Cox regression, predicted CTCs were confirmed as independently associated with prognosis in terms of OS, together with ECOG performance status, liver involvement, bone-only disease, and treatment arm. Patients in the pStage Stage IVindolent subgroup treated with abemaciclib experienced the best prognosis both in terms of PFS and OS. The treatment effect of abemaciclib on OS was then explored through subgroup analysis, showing a consistent benefit across all subgroups. This study is the first analysis of CTCs modeling for stage IV disease stratification. These results show the need to expand biomarker profiling in combination with CTCs stratification for improved biomarker-driven drug development.

63P Efficacy and safety of eribulin plus carboplatin combination for HER2-negative metastatic breast cancer

63P Efficacy and safety of eribulin plus carboplatin combination for HER2-negative metastatic breast cancer

Relationship Between Daily Dose of Everolimus and Treatment Effect in Patients With Luminal HER2-negative Metastatic Breast Cancer.

Everolimus (EVE)-based treatment is an option for hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), but a predictive marker has not yet been established. The recommended dose of EVE in combination with endocrine therapy is 10 mg/day, but due to adverse effects, patients are frequently forced to reduce the dose. However, the correct maintenance dose to achieve a therapeutic effect is still under debate. Employing real-world data, we examined clinicopathological factors to predict the efficacy of EVE-based treatment, particularly focusing on daily dose intensity (DDI). Ninety-five patients with MBC who received EVE-based treatment in combination with exemestane during the period from 2014 to 2022 were retrospectively investigated. Doses of EVE were reduced as needed and DDI was calculated with total doses of EVE and the duration of the treatment. Mean time-to-treatment-termination (TTT) was 25.4 weeks. Patients with tumors with a high Ki67 labeling index, low absolute lymphocyte count, and small DDI of EVE had significantly shorter TTT (p=0.006, 0.043, and 0.030, respectively). When patients were categorized based on DDI of EVE, patients with DDI ≤5 mg/day had significantly shorter TTT (p=0.002). There were no correlations between RDI and factors such as age, body weight, and numbers of previous treatments for MBC. Maintaining a DDI of at least 5 mg/day seems crucial to achieving a therapeutic effect. Our data might be useful for determining the dosage of EVE in clinical practice.

LBA6 A phase II, single arm, open label, Simon two-stage study of pembrolizumab in metastatic HER2-negative breast cancer patients: Evaluation of impact of germline variants in APOBEC3B (AUROR)

LBA6 A phase II, single arm, open label, Simon two-stage study of pembrolizumab in metastatic HER2-negative breast cancer patients: Evaluation of impact of germline variants in APOBEC3B (AUROR)

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.

‘Inner world’ of luminal HER 2-negative metastatic breast cancer: Efficacy of ribociclib in different intrinsic subtypes

The heterogeneity of breast cancer (BC), which determines various clinical scenarios of the disease, is still inaccessible to our understanding. Heterogeneity is based primarily on intrinsic subtypes of breast cancer, determined using genomic tests. Currently, four intrinsic subtypes are generally recognized: luminal A and B, HER-enriched (HER2-E) and basal-like. HER2-E subtype in luminal HER-negative (ER+HER–) breast cancer accounts for 11–22 per cent of cases. The efficacy of a combination of hormone therapy (HT) and the CDK4/6 inhibitor ribociclib in the HER2-E subtype was evaluated in a large exploratory analysis of MONALEESA-2, -3, and -7 trials. The gain in progression-free survival (PFS) and overall survival (OS) from the addition of ribociclib to HT was observed in all intrinsic subtypes, except for basal-like, and reached maximum in HER2-E subtype: Ribociclib increased the median PFS to 16.4 months from 5.5 months on HT (HR = 0.389; p &lt; 0.0001) and median OS to 40.3 months from 29.4 months (HR = 0.600; p = 0.0180). The significant frequency of occurrence of the HER2-E subtype in ER+HER-BC, the low efficiency of monoHT in this subtype is another argument in favor of prescribing combination therapy in early lines. Information about the intrinsic subtype not only brings us closer to understanding tumor heterogeneity, but may also become a significant factor in determining treatment tactics in the future.

Preferences for the sequencing of first-line systemic treatments in metastatic hormone receptor-positive, HER2-negative breast cancer.

Metastatic breast cancer (MBC) is a diverse disease. Therapeutic options include hormonal therapy, chemotherapy, and targeted therapies. The optimal treatment sequence for patients with hormone receptor-positive (HR-positive), HER2-negative metastatic breast cancer remains unknown. This was a retrospective and prospective study. The data was collected from the medical records of patients in a tertiary healthcare center in Lebanon between the years 2016 and 2019, and patients were followed up for a 3-year duration. The main aim was to identify oncologists' preferences in the choice and sequence of treatment for newly diagnosed and/or recurrent cases of HR-positive, HER2-negative MBC. A total of 51 patients were included. 24 patients received chemotherapy, while 27 received endocrine therapy as first-line treatment after a diagnosis of MBC, with a median overall survival (OS) of 13 months and a median progression-free survival (PFS) of 12 months after first-line treatment with chemotherapy, compared to 27 months and 18 months with endocrine therapy. A higher percentage of patients have received chemotherapy in the first-line setting compared to the data reported in the literature, with the choice being multifactorial. Factors to consider in MBC management include the choice of first-line treatment, the optimal sequence of treatment, and the combination of available treatment options.

Clinical activity of nivolumab in combination with eribulin in HER2-negative metastatic breast cancer: A phase IB/II study (KCSG BR18-16)

AimWe evaluated the efficacy and safety of nivolumab and eribulin combination therapy for metastatic breast cancer (BC) in Asian populations. MethodsIn this parallel phase II study, adult patients with histologically confirmed recurrent/metastatic hormone receptor-positive/HER2-negative (HR+HER2-) or triple-negative BC (TNBC) were prospectively enroled from 10 academic hospitals in Korea (ClinicalTrials.gov Identifier: NCT04061863). They received nivolumab (360 mg) on day 1 plus eribulin (1.4 mg/m2) on days 1 and 8 every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was the investigator-assessed 6-month progression-free survival (PFS) rate in each subtype. Secondary endpoints included investigator-assessed objective response rate (ORR) as per Response Evaluation Criteria in Advanced Solid Tumors version 1.1, disease control rate, overall survival, and treatment toxicity. The association between PD-L1 expression and efficacy was investigated. ResultsForty-five patients with HR+HER2- BC and 45 with TNBC were enroled. Their median age was 51 (range, 31–71) years, and 74 (82.2%) received one or two prior treatments before enrolment. Six-month PFS was 47.2% and 25.1% in the HR+HER2- and TNBC cohorts, respectively. Median PFS was 5.6 (95% confidence interval [CI]: 5.3–7.4) and 3.0 (95% CI: 2.1–5.2) months in the HR+HER2- and TNBC groups, respectively. ORRs were 53.3% (complete response [CR]: 0, partial response [PR]: 24) and 28.9% (CR: 1, PR: 12). Patients with PD-L1+ tumours (PD-L1 expression ≥1%) and PD-L1- tumours (ORR 50% versus 53.8% in HR+HER2-, 30.8% versus 29.0% in TNBC) had similar ORRs. Neutropenia was the most common grade 3/4 adverse event; the most common immune-related adverse events (AEs) were grades 1/2 hypothyroidism and pruritus. Five patients discontinued therapy because of immune-related AEs. ConclusionNivolumab plus eribulin showed promising efficacy and tolerable safety in previously treated HER2- metastatic BC. Trial registrationNCT04061863

Upfront Taxane Could Be Superior to Pegylated Liposomal Doxorubicin (PLD): A Retrospective Real-World Analysis of Treatment Sequence Taxane-PLD versus PLD-Taxane in Patients with Metastatic Breast Cancer.

Background: Patients with endocrine-resistant metastatic breast cancer (MBC) require cytostatic therapy. Single-agent taxanes and anthracyclines, including pegylated liposomal doxorubicin (PLD), are standard treatment options. There are no prospective data regarding optimal treatment sequences, and real-world data regarding both treatment options are limited. Methods: We analyzed electronic records of all patients with Her2-negative MBC treated with either first-line PLD or first-line taxane and subsequent crossover at the University Hospital Basel between 2003 and 2021. The primary endpoint was time to next chemotherapy or death (TTNC). Secondary endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). We used the Kaplan-Meyer method and logrank test to compare time-to-event endpoints and the Fisher exact test to compare discrete variables. Results: We retrospectively identified 42 patients with Her2-negative MBC who have received either single-agent PLD or single-agent taxane as first-line chemotherapy with subsequent crossover, including 23 patients who received first-line PLD and 19 patients who received first-line taxane. Baseline characteristics were similar between treatment groups. Treatment sequence PLD-taxane was significantly inferior to taxane-PLD regarding all endpoints: median TTNC 4.9 vs. 9.9 months (p = 0.006), median OS 17.8 vs. 24.6 months (p = 0.05), median PFS 4.4 vs. 9.0 months (p = 0.005), and ORR 13% vs. 53% (p = 0.01). Conclusions: Here, we report a first retrospective head-to-head comparison of the treatment sequence PLD-taxane versus taxane-PLD in patients with MBC, showing a substantial advantage of using taxanes first, followed by PLD. An inherent treatment bias in favor of first-line taxanes cannot be excluded, thus calling for prospective validation.

Interplay between ESR1/PIK3CA codon variants, oncogenic pathway alterations and clinical phenotype in patients with metastatic breast cancer (MBC): comprehensive circulating tumor DNA (ctDNA) analysis

Backgroundalthough being central for the biology and druggability of hormone-receptor positive, HER2 negative metastatic breast cancer (MBC), ESR1 and PIK3CA mutations are simplistically dichotomized as mutated or wild type in current clinical practice.MethodsThe study analyzed a multi-institutional cohort comprising 703 patients with luminal-like MBC characterized for circulating tumor DNA through next generation sequencing (NGS). Pathway classification was defined based on previous work (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, PI3K). Single nucleotide variations (SNVs) were annotated for their oncogenicity through OncoKB. Only pathogenic variants were included in the models. Associations among clinical characteristics, pathway classification, and ESR1/PIK3CA codon variants were explored.ResultsThe results showed a differential pattern of associations for ESR1 and PIK3CA codon variants in terms of co-occurring pathway alterations patterns of metastatic dissemination, and prognosis. ESR1 537 was associated with SNVs in the ER and RAF pathways, CNVs in the MYC pathway and bone metastases, while ESR1 538 with SNVs in the cell cycle pathway and liver metastases. PIK3CA 1047 and 542 were associated with CNVs in the PI3K pathway and with bone metastases.ConclusionsThe study demonstrated how ESR1 and PIK3CA codon variants, together with alterations in specific oncogenic pathways, can differentially impact the biology and clinical phenotype of luminal-like MBC. As novel endocrine therapy agents such as selective estrogen receptor degraders (SERDS) and PI3K inhibitors are being developed, these results highlight the pivotal role of ctDNA NGS to describe tumor evolution and optimize clinical decision making.

Neratinib+ fulvestrant+ trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial.

HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib+ fulvestrant, or neratinib+ fulvestrant+ trastuzumab (N+ F+ T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant+ trastuzumab (F+ T) versus N+ F+ T. Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N+ F+ T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8mg/kg then 6 mg/kg q3w) or F+ T or fulvestrant alone. Those whose disease progressed on F+ T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing. ORR for 57 N+ F+ T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F+ T-treated patients; responses in patients crossing over to N+ F+ T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response. The benefit of N+ F+ T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N+ F+ T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.

457P Disparities in receipt of CDK4/6 inhibitors with endocrine therapy as therapy for hormone receptor-positive, HER2-negative metastatic breast cancer in the real-world setting

457P Disparities in receipt of CDK4/6 inhibitors with endocrine therapy as therapy for hormone receptor-positive, HER2-negative metastatic breast cancer in the real-world setting

380MO SKB264 (MK-2870) in previously treated hormone receptor-positive (HR+)/ HER2-negative metastatic breast cancer (mBC): Results from a phase I/II, single-arm, basket trial

380MO SKB264 (MK-2870) in previously treated hormone receptor-positive (HR+)/ HER2-negative metastatic breast cancer (mBC): Results from a phase I/II, single-arm, basket trial

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

473P Predictive factors for drug-induced liver injury in patients with ER-positive HER2-negative metastatic breast cancer treated with first-line cyclin-dependent kinase 4/6 inhibitors

473P Predictive factors for drug-induced liver injury in patients with ER-positive HER2-negative metastatic breast cancer treated with first-line cyclin-dependent kinase 4/6 inhibitors

462P Health outcomes of treatment sequences with eribulin or other single agents’ chemotherapy for treating relapsed metastatic HER2-negative breast cancer

462P Health outcomes of treatment sequences with eribulin or other single agents’ chemotherapy for treating relapsed metastatic HER2-negative breast cancer

The Treatment Landscape of Elderly Patients with Hormone Receptor-Positive Her2 Negative Advanced Breast Cancer: Current Perspectives and Future Directions.

Breast cancer (BC) in elderly women is an increasing health issue due to demographic changes. BC tends to present later and may receive less than standard treatment options. More often, BC in elderly patients is endocrine-positive (HR+). The treatment of elderly patients with metastatic BC (mBC) represents a therapeutic challenge. In recent years, the treatment landscape of patients that are HR+/Her2-negative has changed due to the introduction in clinical practice of new targeted drugs, which have improved patient outcomes. Elderly patients are a small percentage of all patients enrolled in clinical trials and, to date, there are no standardized guidelines that define the best treatment option for this patient population. This can lead to undertreatment or overtreatment, impacting patient morbidity and mortality. Geriatric Assessment tools to tailor the treatment in elderly patients are underused because they are long and difficult to apply in a busy routine clinical practice. For all these reasons, there is an urgent need to produce data about the best treatment for elderly patients with HR+ mBC. Herein, we report data from randomized clinical trials and real-world evidence on the therapeutic options for HR+ Her2-negative mBC elderly patients and explore future treatment directions.

Anti-hormonal maintenance treatment with the CDK4/6 inhibitor ribociclib after 1st line chemotherapy in hormone receptor positive / HER2 negative metastatic breast cancer: A phase II trial (AMICA)

PurposeThis phase II study evaluated the impact of adding ribociclib to maintenance endocrine therapy (ET) treatment of physicians’ choice following the first palliative chemotherapy in pre- and post-menopausal women with hormone receptor positive (HR+)/human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (mBC). Patients and methodsThe initial randomized study design was later amended into a single-arm study, and all subsequent patients received ribociclib and ET. The primary end point was locally assessed progression-free survival (PFS). Secondary end points included overall survival (OS), clinical benefit rate (CBR), safety, compliance, and quality of life (QoL). ResultsA total of 43 patients received ribociclib + ET and 10 patients received ET only. Median PFS was 12.4 months [95% CI 8.7–24.4] for patients who received ribociclib + ET and 4.75 months [95% CI 1.0–10.3] for those who received ET only. Median OS was not reached for patients who received ribociclib + ET, and 28 (65.1%) patients experienced clinical benefit [95% CI 49.1–79.0]. For patients who received ribociclib + ET, grade 3–4 hematological adverse events (AEs) occurred in 25 (58.1%) patients, and grade 3–4 non-hematological AEs occurred in 17 (39.5%) patients. During the study, 15 patients died – 14 of whom due to tumor-related reasons, and one patient due to pneumonia, which was not treatment-related. ConclusionThe results of the AMICA study show a promising efficacy and safety of maintenance treatment with ribociclib added to ET after at least stable disease following the first metastatic chemotherapy in patients with HR+/HER2-mBC. Trial registrationAnti-hormonal Therapy With Ribociclib in HR-positive/HER2- Negative Metastatic Breast Cancer (AMICA), NCT03555877, https://clinicaltrials.gov/ct2/show/NCT03555877.