Hormone Receptor-positive Patients Research Articles

High C-reactive protein is associated with the efficacy of neoadjuvant chemotherapy for hormone receptor-positive breast cancer.

C-reactive protein (CRP) is a nonspecific biomarker for systemic inflammatory response and is linked to the prognosis of breast cancer (BC); however, few studies have investigated the correlation between CRP and the effectiveness of neoadjuvant chemotherapy treatment for BC. We recruited 177 patients with BC who underwent neoadjuvant chemotherapy in our clinical trial. the median CRP level (0.24 mg/L), patients were categorized into high and low groups. We examined the relationship between CRP levels and various clinicopathological factors, including pathological complete response (pCR), using the chi-square test or Fisher exact test. Furthermore, we evaluated the predictive capacity of CRP for different molecular subtypes by constructing receiver operating characteristic curves. To identify the independent variables associated with pCR, we conducted logistic regression multivariate analysis. No association was found between C-reactive levels at baseline and pCR rates. CRP level was significantly associated with higher body mass index, and the high CRP group had more overweight patients (47.06% vs. 16.30%, P < .001). In hormone receptor-positive patients, the high CRP group demonstrated a significantly higher pCR rate (OR = 4.115, 95% CI: 1.481-11.36, P = .009). The areas under the curve was 0.670 (95% CI: 0.550-0.792, P < .001). Multivariate logistic analysis showed that the CRP level was a significant independent predictor of pCR (OR = 5.882, 95% CI: 1.470-28.57, P = .017). High CRP levels were found to be associated with a higher pCR rate, indicating their independent predictive value in determining the efficacy of neoadjuvant chemotherapy in hormone receptor-positive BC patients.

7615 Genomic Consequences of GRHL2 Overexpression in ER+ Breast Cancer Cells

Abstract Disclosure: K.O. Allen: None. C. Zheng: None. N. Solodin: None. M.S. Ozers: Owner/Co-Owner; Self; Proteovista, LLC. C.L. Warren: None. P.E. Messa: None. D.T. Vogt: None. E.T. Alarid: None. Breast cancer progression is characterized by the presence and prevalence of metastatic disease. At a genomic level, metastasis can be facilitated via rearrangement of the chromatin landscape to expose oncogenic genes for transcription. Grainyhead like protein 2 (GRHL2) is a nuclear transcription factor implicated in epithelial cell differentiation. The GRHL2 motif has been found near activated estrogen receptor (ER) binding sites, and elevated levels of GRHL2 have been linked to worse prognosis in hormone receptor positive breast cancer patients. In its capacity to contribute to a more severe disease state when overexpressed, GRHL2 may function as either a transcription or pioneer factor to aid in the expression of metastasis-associated genes. Our lab previously showed that GRHL2 genomic binding precedes ER binding at co-regulated binding sites. Also, overexpression of GRHL2 in MCF7 cells for 24 hours did not appreciably alter gene expression by RNA-Seq. These data taken together indicate that GRHL2 may be exhibiting pioneer factor activity. However, the specific role of GRHL2 overexpression in hormone positive breast cancer progression remains unknown. In order to examine the mechanism of GRHL2 action, GRHL2 genomic binding was investigated using a tetracycline-inducible MCF7 model that allows controlled overexpression of GRHL2. ChIP studies were performed to determine GRHL2 binding intensity at specific and genome wide GRHL2 binding sites. Specific focus was given to established GRHL2 binding sites near oncogenic genes responsible for epithelial to mesenchymal transition (EMT), dormancy, and proto-oncogenic behavior. A similar analysis examined H3K27 acetylation to validate active gene transcription. An orthogonal technology, Specificity and Affinity for Protein (SNAP) microarrays, which characterizes direct GRHL2 binding to tiled genomic regions identified in ChIP-Seq analyses from multiple labs, was utilized to discriminate direct and indirect GRHL2 binding sites. The requirement for GRHL2 transactivation function in regulation of EMT related genes was further interrogated using transactivation GRHL2 dominant negative mutants. This work aims to distinguish the transcriptional and non-transcriptional activities of GRHL2 in breast cancer cells on a genome wide level and thereby, provide a deeper understanding of how overexpressed GRHL2 contributes to hormone positive breast cancer. Presentation: 6/3/2024

Unveiling the mysteries of HER2-low expression in breast cancer: pathological response, prognosis, and expression level alterations

BackgroundThe novel anti-HER2 antibody drug conjugates (ADCs) can effectively improve the long-term survival of patients with HER2-low expression breast cancer. However, pathological responses to neoadjuvant therapy (NAT) within HER2-low expression breast cancer, the relationship between pathological response and prognosis and the transformation of HER2 status are all now poorly understood.MethodsThe patients with HER2-0 and HER2-low expression breast cancer receiving NAT at Harbin Medical University Cancer Hospital between Jan. 2014 and Nov. 2018 were retrospectively explored. HER2 low expression refers to the IHC 1 + or 2 + and FISH negative. The Kappa test was utilized for analyzing the consistency rate of HER2 expression. To evaluate disease-free survival (DFS) and overall survival (OS), this research employed both the Kaplan-Meier analysis and the Cox regression.ResultsIn this study, 178 patients with HER2-0 and 344 patients with HER2-low expression breast cancer were included. In comparison with the HER2-0 group, it is shown that patients in the HER2-low group have more possibility to be younger compared to those 50 years old (P < 0.014), have more premenopausal patients (P < 0.001), a higher proportion of hormone receptor (HR) positive patients (P < 0.001), and less proportion of stage III V patients (P < 0.034). When NAT was finished, the pCR rate became 23.6% in the HER2-0 group while 22.1% in the HER2-low group, and there was also a higher pCR rate in HR- patients in comparison with that in HR + patients (P < 0.01). Considering HER2 expression inconsistency, the overall HER2 inconsistency rate was 30.4% (Kappa = 0.431, P < 0.01). Among patients initially diagnosed as HER2-0, 34% (N = 61) were re-diagnosed as HER2-low after NAT. After stratification by HR expression status, HR+/HER2-0 patients transformed to HER2-low after NAT in 37%, and 32% of HR- patients changed from HER2-0 to HER2-low. In this survival analysis, there were both better DFS rates (P = 0.009) and OS rates (P = 0.026) in the HR-/HER2-low patients in comparison with the HR-/HER2-0 patients, while the HER2-0 and HER2-low patients in the HR + group had no significant survival difference. Additionally, for non-pCR patients, there was better DFS (P = 0.029) and OS (P = 0.038) in the HER2-low group in comparison with that of the HER2-0 group, while no significant survival difference exists between pCR patients.ConclusionAfter HR stratification, there are unique clinical characteristics and prognostic outcomes in HER2-low expression breast cancer, which indicates the potential to become a specific molecular subtype of breast cancer. The significant instability of HER2-low expression status between primary tumor and residual invasive disease suggests that multiple detections of HER2 status should be emphasized in NAT strategies.

Outcomes of De Novo Oligometastatic Breast Cancer Treated With Surgery of Primary and Metastasis Directed Radiotherapy.

With sensitive imaging for breast cancer, the question arises whether present-day oncologists treat dOMBC with palliative systemic therapy (ST), which, a few years earlier, would have been treated with curative intent. We retrospectively analyzed outcomes of dOMBC treated with curative intent using a combination of surgery, metastasis-directed radiotherapy (RT), and adjuvant/neoadjuvant ST and have also explored the possible role of total lesional glycolysis of metastases and p53 immunohistochemistry in predicting outcomes. Data were collected from a prospectively maintained database using electronic medical records and Radiation Oncology Information System. In the study, dOMBC was defined as up to 3 metastatic sites, all amenable to treatment with ablative RT and primary and axillary disease amenable to curative surgery. Patients were treated with surgery, ST, and RT. Patients underwent either breast conservation surgery or modified radical mastectomy. Patients were treated with 6 to 8 cycles of chemotherapy in the neoadjuvant and/or adjuvant setting. Hormone receptor-positive patients received either tamoxifen or aromatase inhibitors. Trastuzumab was offered to Her-2-neu receptor-positive patients. RT included locoregional RT and metastases-directed ablative body RT. The median progression-free survival was 39 months (95% CI: -28.7 to 50.1mo). Two and 3 year estimated disease-free survival (DFS) was 79% and 60.5%, respectively. The median overall survival was not reached. The estimated 3-year overall survival was 87.3%. Total lesional glycolysis of metastases score and p53 status did not affect DFS. Combination treatment of surgery, metastases-directed ablative RT, and ST may provide prolonged DFS in dOMBC.

Loss of Hormone Receptor Expression after Exposure to Fluid Shear Stress in Breast Cancer Cell Lines.

Following metastatic spread, many hormone receptor positive (HR+) patients develop a more aggressive phenotype with an observed loss of the HRs estrogen receptor (ER) and progesterone receptor (PR). During metastasis, breast cancer cells are exposed to high magnitudes of fluid shear stress (FSS). Unfortunately, the role for FSS on the regulation of HR expression and function during metastasis is not fully understood. This study was designed to elucidate the impact of FSS on HR+ breast cancer. Utilizing a microfluidic platform capable of exposing breast cancer cells to FSS that mimics in situ conditions, we demonstrate the impact of FSS exposure on representative HR+ breast cancer cell lines through protein and gene expression analysis. Proteomics results demonstrated that 540 total proteins and 1473 phospho-proteins significantly changed due to FSS exposure and pathways of interest included early and late estrogen response. The impact of FSS on response to 17β-estradiol (E2) was next evaluated and gene expression analysis revealed repression of ER and E2-mediated genes (PR and SDF1) following exposure to FSS. Western blot demonstrated enhanced phosphorylation of mTOR following exposure to FSS. Taken together, these studies provide initial insight into the effects of FSS on HR signaling in metastatic breast cancer.

Clinical, pathological and gene expression profiling of estrogen receptor discordance in breast cancer.

Breast cancer (BC) is the world's largest tumor species in which hormone receptor-positive patients have relatively good prognosis. However, majority of patients will develop late resistance, one of the important factors is due to the loss of the original estrogen receptor (ER) expression. We conducted this study in 115 patients with BC who experienced second biopsy at Jiangsu Province Hospital (JSPH) and divided patients into two subgroups ER + to - and ER + to + . First, clinicopathological characteristics between two groups were evaluated. Second, we explored candidate genes related to BC ER intratumor heterogeneity by applying next-generation sequencing (NGS) in 42 patients. Multi-omics integrative analysis of tumor transcriptomic, cancer-related pathway, diagnostic and prognostic value and immune profile were conducted. Besides, preliminary assay were also used to evaluate the correlation between KMT2C and ERα (ESR1) expression. The CCK-8, 5-Ethynyl-2'-deoxyuridine (EdU) assays, Transwell assays and the wound scratch tests were applied to explore the cellular interactions between KMT2C and BC. We find the histological type (p = 0.008) and disease-free survival (DFS) (p = 0.004) were significantly different in two subgroups. In Cox survival analysis, metastasis (Hazard ratio (HR) > 1, p = 0.007) and neo-adjuvant (HR < 1, p < 0.001) are independent prognostic factors of DFS. Besides, by analyzing NGS results, we found four genes KMT2C, FGFR19, FGF1 and FGF4 were highly mutated genes in ER + to - subgroup. Furthermore, the gene KMT2C displayed significant diagnostic value and prognostic value in BC and pan-cancer. In addition, a positive correlation between KMT2C expression and immune infiltrating levels of T cell CD4 + , macrophage and neutrophil was found. In the end, Western blot and RT-qPCR assay were used and found KMT2C and ERα (ESR1) expressions are strongly positive correlated in mRNA and protein level. Inhibition of KMT2C significantly reduced proliferation, invasion, and migration of MCF7 cells. People in two cohorts from JSPH presented different clinical characteristics and prognosis. The gene KMT2C may affect the progression of BC by regulating the molecular, epigenetic activity and immune infiltration. It may also serve as a novel prognostic biomarker for BC patients who underwent ER status converted from positive to negative.

Real-world Outcomes of Dual HER2 Blockade Therapy in Metastatic HER2-Positive Breast Cancer: from Induction to Maintenance.

Dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab combined with taxane-based chemotherapy (Cht) has been the standard first-line treatment for HER2-positive metastatic breast cancer (mBC) for years, due to the impressive results of the CLEOPATRA study. Real-world (RW) studies have become critical for assessing treatment effectiveness and safety in real-life circumstances. The aim of this study was to analyze the treatment outcomes of first-line therapy for HER2-positive mBC in RW clinical practice, specifically focusing on the use of maintenance endocrine therapy (ET) in hormone receptor positive (HR-positive) patients. This retrospective analysis included 106 HER2-positive mBC patients treated with trastuzumab and pertuzumab combined with taxane-based Cht from October 2015 to December 2020 at the University Hospital Centre Zagreb. At a median follow-up of 30 months, median progression-free survival (PFS) was 25 months for the total population (95% confidence interval [CI] 16- not analyzed). Patients with de novo mBC had longer median PFS than patients with recurrent disease (not reached vs. 18 months; hazard ratio 1.99; 95% CI 0.69-3.64, p<0.022). Age, hormone receptor positivity, visceral involvement, number of Cht cycles and previous adjuvant trastuzumab did not impact PFS. Most HR-positive patients (N=55, 88.7%) received maintenance ET after induction Cht. This retrospective study provides additional data on patient characteristics, treatment and outcomes of RW HER2-positive mBC patients treated with pertuzumab and trastuzumab as first-line therapy. In our institution, maintenance ET after induction Cht has become standard clinical practice.

Efficacy and safety of eribulin-based chemotherapy in patients with advanced breast cancer: A single-centre retrospective study.

e13121 Background: Eribulin, a nontaxane microtubule dynamics inhibitor, which was approved for the third-line treatment of advanced breast cancer (ABC) in China in 2019. This retrospective study aimed to assess efficacy and safety of Eribulin-based chemotherapy in ABC patients, especially for patients exhibiting HER2-0 and HER2-low status (immunohistochemistry [IHC] 1+ or IHC 2+with a negative in situ hybridization assay). Methods: This single-center retrospective study planned to include 126 ABC patients from January 2020 to December 2023. Enrolled participants received Eribulin either as monotherapy or in combination with other regiments such as anti-angiogenic therapy, PD-1 inhibitor, or alternative chemotherapy in clinical practice. The primary outcomes included progression-free survival (PFS) and safety assessments. Results: A total of 84 patients with ABC received Eribulin were enrolled. Patients' baselines were summarized as follows: The median age was 53.3 years (range 30.0–86.0 years). 53 (63.1%) patients were HER2-low while 40 (47.6%) patients were hormone receptor (HR) positive. 63.1% patients have received at least one line chemotherapy before the use of Eribulin. According to the K-M survival analysis, the median PFS was 6.0 (range 3.2-11.3) months for all patients. The median PFS was longer for patients received aromatase inhibitors (AI) for over 6 months than patients with AI naive (median 10.1 vs 6.6 months; p=0.192) in HR positive patients. Patients who received CDK4/6 therapy had longer PFS than patients (median 10.7 vs 6.6 months; p=0.38). There was a trend toward prolonged PFS in the HER2-0 group compared with HER2-low group (median 10.13 vs 6.03 months; p=0.154), although there was no significant difference. A nonsignificant improvement of PFS was observed in HR-/HER2-0 patients, compare with HR-/HER2-low patients (median 16.4 vs 4.7mo; p=0.21). Meanwhile the median PFS of HER2-0 and HER2-Low was similar in HR positive patients. The objective response rate was 35.5% in HER2-0 group and 30.2% in HER2-low group. In multivariate cox regression, Eribulin as first line treatment (HR, 4.028; 95% CI, 1.131-14.337) and HER2-0 (HR, 2.903; 95% CI, 1.257-6.702) showed prognostic values regarding PFS. Common grade 3 or 4 adverse events that were reported in more than 10% were neutropenia (41.6%) and leukopenia (26.2%). No treatment-related deaths were reported. Conclusions: This single-center study demonstrated encouraging efficacy and safety in the ABC patients treated with Eribulin. Significant PFS benefit was associated with Eribulin treatment in patients with HER2-0 compared with HER2-low. This study still needs longer follow-up to evaluate its efficacy more comprehensively.

Prognostic and Predictive Significance of HER2-low Expression in Metastatic Hormone Receptor Positive Breast Cancer Patients Receiving CDK4-6 Inhibitor Therapy

Objective: This study aimed to analyze the predictive and prognostic value of HER2-low expression in hormone receptor (HR) positive human epidermal growth factor receptor-2 (HER2) negative metastatic breast cancer patients receiving cyclin-dependent kinase-4/6 inhibitor (CDK4/6i) therapy. Methods: This retrospective study included patients who received CDK4/6i plus endocrine therapy (ET). The pathological and clinical characteristics and survival times of the patients were compared and analyzed. Results: Our study included 122 patients. There were HER2-zero 88(72%) and HER2-low 34 (28%) patients. The median progression free survival (mPFS) of all patients who received CDK4/6i+ET was 21 (95% confidence interval (CI),18.5–23.5) months, while mPFS was not reached in the HER2-zero group, and mPFS in the HER2-low group was 12 (95%CI, 6.8–17.1) months (p=0.001). The mPFS was shorter in patients with primary endocrine resistance (6 vs. 21 months, p=0.001). There was a change in the HER2-low status of 26(45%) patients with recurrence compared to the first biopsy. In the HER2-zero and HER2-low groups, 22(25%) and 24(71%) patients, respectively, progressed with CDK4/6i+ET (p=0.001). Estrogen receptor (ER) levels less than and greater than 50% resulted different mPFS (6 and 21 months, respectively) (p=0.025). Median PFS differed based on CDK4/6i+ET combination, treatment line, and best treatment response (all p=0.001). In multivariate analysis, HER2 status(p=0.018), chemotherapy status(p=0.006), best response status with CDK4/6i (p=0.001) for PFS, and best response status with CDK4/6i therapy (p=0.007) for OS were significant. Conclusions: In patients with HR+HER- metastatic breast cancer receiving CDK4/6i therapy, the duration of mPFS was lower in the HER2-low group than that in the HER2-zero group. HER2-low expression is a predictive biomarker of response to CDK4/6 inhibitor therapy.

Abstract PO4-04-10: Selection criteria for second-line treatments after Cyclin-dependent kinase 4/6 inhibitors failure in Hormone Receptor positive metastatic breast cancer patients: the preliminary experience of the HERMIONE-13 trial

Abstract BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represent the standard of care for hormone receptor-positive (HR+)/Human Epidermal Growth Factor 2 negative (HER2-) metastatic breast cancer (MBC); no consensus actually exists for second-line (2L) treatments. The HERMIONE-13 trial evaluates the adopted therapeutic options after CDK4/6i failure and the potential factors that influence these choices. METHODS: HERMIONE-13 is a retrospective and prospective multicentric observational trial involving 15 Italian Centers. Information about therapies after disease progression to CDK4/6i from January 2016 until December 2020 was collected for the present analysis, aiming at evaluating which are the clinical criteria guiding the choice of 2L therapy after CDK4/6i failure. RESULTS: 114 pts have been enrolled: 14 pts (12.3%) received neoadjuvant treatment, 80 (70.2%) adjuvant therapy, of whom 46 (57.5%) chemotherapy (CT)+ endocrine therapy (ET) and 33 (41.3%) ET alone. Among the 79 pts treated with adjuvant ET, 44 pts (55.7%) showed primary or secondary endocrine resistance. 39 pts (34.2%) received first-line (1L) CDK 4/6i in combination with Fulvestrant (F), the remaining with aromatase inhibitors (AIs). Median duration of 1L CDK4-6i was 10.4 months (interquartile range (IQR) 4.7-17.4). Median age at 2L start was 59.5 years (IQR 51-68). As 2L therapy, 79 pts (69.3%) received CT±targeted therapy (TT) and 35 (30.7%) ET±TT. Visceral metastases at the beginning of 2L were documented in 46 pts (40.4%). Comorbidities were present in 48 (42.9%) of the pts, mainly cardiac diseases (25, 22.3%); 71 pts (63.4%) showed a 1L-related adverse events (AEs) (NA: 2 pts), mainly hematological toxicity (60, 53.6%). Among 79 pts treated with adjuvant ET, 60 (76%) were addressed to 2L CT±TT, while 19 (24%) to an ET-based therapy. A longer duration of 1L was observed in pts treated with 2L ET±TT (12.5 months, 7.2-22.2) in comparison with those treated with CT±TT (8.7 months, 4.2-14.9). The majority of pts treated with 1L F+CDK 4/6i underwent 2L CT-based treatment, as summarized in Table 1. Analyzing the population treated with 2L CT±TT, we observed that median age was 58 years (49-67), slightly lower than that of pts treated with ET±TT (63, 54-69). Among pts with visceral metastases, 30 pts (65.2%) were addressed to 2L CT±TT and 16 pts (34.8%) to ET±TT; CT±TT was also the favorite choice for the majority of pts with concomitant disease (33, 68.8%) and with previous CDK4/6i-related toxicity (47, 66.2%). Among age, visceral metastases, comorbidities, adjuvant treatment, duration of 1L therapy, use of 1L F and 1L related AEs, univariate analysis revealed that previous use of adjuvant ET (p=0.021), 1L F (p&amp;lt; 0.001), duration of 1L treatment (p=0.043) and age at 2L start (p=0.053) are all factors influencing the choice of 2L therapy. At the multivariate logistic regression model, only the use of F in association with CDK4/6i as 1L treatment and age at 2L therapy were associated with the choice between ET±TT vs CT± TT, with a backward selection, as summarized in table 2. CONCLUSION: The preliminary results of our study suggest that previous F in combination with CDK4/6i is a statistically confirmed predictor of choice for subsequent CT, whereas the increase in age is significantly associated with the choice for ET. Further research is needed to investigate the optimal sequencing of treatments following CDK4/6i and to determine predictive factors of response to 2L therapies. Table 1 2L choices in 1L F+CDK 4/6i pts. Table 2 Statistical model with the significant variables. Citation Format: Marina Elena Cazzaniga, Emanuela Rossi, Antonella Turla, Massimo Ambroggi, Alice Baggi, Rossana Berardi, Fulvio Borella, Serena Capici, Federica Cicchiello, Luigi Coltelli, Ugo De Giorgi, Antonella Ferro, Ornella Garrone, Monica Giordano, Elisabetta Landucci, Marco Mazzotta, Gabriella Moretti, Raffaella Palumbo, Francesca Fulvia Pepe, Patrizia Vici, Fable Zustovich, Viola Cogliati. Selection criteria for second-line treatments after Cyclin-dependent kinase 4/6 inhibitors failure in Hormone Receptor positive metastatic breast cancer patients: the preliminary experience of the HERMIONE-13 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 PO4-04-10.

Abstract PO4-22-06: Outcomes following Stereotactic Radiotherapy in Oligometastatic Breast Cancer: a single centre retrospective review

Abstract Introduction: Stereotactic radiotherapy (SABR) is an increasingly used treatment for oligometastatic disease with evidence of survival benefit shown in the SABR-COMET trial. However, the benefit in oligometastatic breast cancer has been brought into question following initial results from the NRG-BR002 trial. Methods: A retrospective review of all patients with primary breast cancer treated with stereotactic radiotherapy for oligometastases at our institution was carried out. A total of 31 patients received treatment to 36 lesions between August 2015 and December 2022. Results: Neither median overall survival nor progression free survival were reached after median follow up time of 21.5 months. Hormone receptor status as follows: ER+, HER2- (n=25), ER+, HER2+ (n=4,), TNBC (n=2). The majority of lesions treated were bony metastases (92%, of which 17 vertebral and 11 pelvic lesions). The majority had oligometastatic disease at time of SABR (67%), with 33% treated for oligoprogression. Most patients were on systemic anti-cancer therapy (SACT) at the time of SABR, or had a planned start of SACT shortly following treatment. Breakdown of systemic therapy as follows: Endocrine therapy (ET) alone 9 patients (29%), CDK4/6 inhibitor plus ET 13 patients (42%), chemotherapy 3 patients (10%), antibody drug conjugate 2 (6%), anti-HER2 therapy + ET 2 patients (6%), none 2 patients (6%). All patients also received bone-targeted agents (zoledronic acid or denosumab). Local control was achieved in 33 lesions (92%), all of which were bony lesions. Local control was maintained in both patients who were not on SACT: one patient with ER+ HER2- disease developed distant progression after 27 months, the other with TNBC remains disease free after 13 months. Loss of local control was observed in all non-bony sites (lung, IMC node, peri-ureteric soft tissue mass) at a median interval of 10 months (range 7-43 months). 14 patients subsequently developed distant disease progression at median interval of 15 months (range 0-43 months). 12 month progression free survival was 77%. 13 patients received further SACT at median interval of 16 months. Conclusions: SABR for bony metastases from breast cancer has excellent local control rates in combination with systemic treatment but may also give patients significant time off treatment. Questions remain regarding the ideal sequencing and combination of SABR and SACT, particularly in hormone receptor positive patients where there are a number of lines of effective SACT. Citation Format: Sophie Lynch, Sugeeta Sukumar, Elinor Sawyer, Daniel Smith, Christy Goldsmith. Outcomes following Stereotactic Radiotherapy in Oligometastatic Breast Cancer: a single centre retrospective review [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 PO4-22-06.

Abstract PO1-09-09: The journey of HR positive, HER2 negative metastatic breast cancer’s patients: heterogeneities and barriers in Brazilian public health system- a national survey

Abstract Background: Breast cancer is the most common neoplasm in Brazilian women, with high percent of patients diagnosed in advanced stages. Metastatic breast cancer (mBC) is a challenge in the country, where 75% of the population is covered by public health system (Sistema Único de Saúde, SUS). We conducted an on-line survey to describe the journey of human epidermal growth factor receptor 2-negative (HER2-), hormone receptor positive (RH+) mBC patients across public scenario in Brazil. Methods: An on-line survey comprised of 39 to 48 (depending on the kind of some questions, which could open another question in case of affirmative answer) objective questions were sent by e-mail to180 oncologists working in public and private health care system. Questions were focused on assessing wait time for first treatment after admission in the hospital in both systems, availability of oncological drugs within SUS according to essential medicines list by World Health Organization, and presence of palliative and multidisciplinary teams in both systems. Continuous variables were measured by median and mean. The level of statistical significance adopted was 5% with Teste p two-sided. Analyses were performed using SAS statistical software (version 25.0). Results: We had 150 respondents working in SUS and private health system, which fulfilled the inclusion criteria to participate in this survey. The other 30 respondents were excluded from the study because they worked exclusively in SUS or exclusively in the private system, and their answers were not analyzed. Median wait time for surgery was 60 days in the SUS (N=150) and 30 days in the private health system (N=150) e (p &amp;lt; 0,0001). Regardless of chemotherapy provided, median waiting time was 30 and 15 days in the SUS (N=150) and the private health system (N=150), respectively (p &amp;lt; 0,0001). Most oncologists in the SUS (N=125, 83.3%) pointed to endocrine therapy as their first-choice treatment in mBC. Concerning endocrine therapy in the SUS, Gonadotropin-Releasing Hormone Agonist (GnRHa) was available, and it was prescribed by 54 (36.0%) and Fulvestrant for 72 (48.0%) of respondents. Considering chemotherapy, weekly paclitaxel alone or combined with platin were available and they were prescribed by 124 (82.6%) and 109 (72.6%) of oncologists respectively. Vinorelbine was available and it was prescribed according to oncologists’ report by 109 (72.6%) and Pegylated liposomal doxorubicin (PLD) by 38 (25.3%) of oncologists. Oncologists answered agree or strongly agree that they had a multidisciplinary care team in SUS 77,3% (N =116) versus 87,3% (N=131) in the private system (p=0.022). Concerning palliative care 66,09% (N= 99) in the SUS versus 82,0% (N=123) in the private system answered that they agreed or strongly agreed that this service was available (p=0.001). Conclusions: The Brazilian government has continuously improved delivery of services and medicines via the public system (SUS), but there are still significant differences within this system and versus the private sector. Unavailability of endocrine therapy agents as GnRHa and Fulvestrant, and some chemotherapy agents as PLD and Vinorelbine for high percentage of patients, raises the existence of disparities within SUS. Also, longer waiting times for treatment in the SUS, lower availability of support teams such multidisciplinary and palliative care, they point out disparities between SUS and private health systems. The lack of a National Cancer Control Program and low health investment by Brazilian government might explain the difference in cancer patients’ access. Citation Format: Heloísa Resende, Igor Soares, Angélica Renó, Ana Cunha, Vinícius Aguiar, Letícia Tureta, Viviane Pereira. The journey of HR positive, HER2 negative metastatic breast cancer’s patients: heterogeneities and barriers in Brazilian public health system- a national survey [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 PO1-09-09.

Abstract PO1-04-14: PLK1 Inhibitor Onvansertib Extends the Response and Overcomes Resistance to Paclitaxel in Palbociclib-resistant HR+ Breast Cancer Patient-derived Xenografts

Abstract Paclitaxel is a first-line chemotherapy for hormone receptor positive (HR+) metastatic breast cancer patients after progression on a combination of endocrine and CDK4/6 inhibitor therapy. Response rate to paclitaxel ranges between 20-40%, and most patients progress due to intrinsic or acquired resistance, leaving them with limited treatment choices. Therapeutic strategies to overcome paclitaxel resistance and extend its clinical benefit are urgently needed. Paclitaxel-resistant tumors have increased expression of polo-like kinase 1 (PLK1), a serine-threonine-protein kinase that regulates mitosis and cell cycle progression. PLK1 has also been shown to mediate resistance to CDK4/6 inhibitor palbociclib in HR+ breast cancer. Onvansertib is an orally bioavailable, highly potent, and selective PLK1 inhibitor in clinical development. Onvansertib exhibited synergy in vitro and showed potent anti-tumor activity in vivo in combination with paclitaxel in ovarian cancer and triple negative breast cancer (TNBC) preclinical models. A phase 1b/2 clinical trial is ongoing to evaluate the safety and efficacy of onvansertib plus paclitaxel in advanced TNBC (NCT05383196). Here we investigated whether the potential of onvansertib and paclitaxel combination could be extended to HR+ breast cancer. Co-treatment with onvansertib and paclitaxel synergistically inhibited the viability of HR+ breast cancer cell lines (MCF-7, T-47D, EFM-19, CAMA-1, ZR-75-1). Compared to the single agents, the combination induced increased apoptosis. The combination was further tested in vivo in patient-derived xenograft (PDX) models. To this end, six HR+ breast cancer PDXs with intrinsic or acquired resistance to palbociclib were established from primary breast tumors (n=1) or metastatic bone biopsies (n=5). The PDX tumors were engrafted subcutaneously in nude mice and the effect of onvansertib (45 mg/kg, oral, 5 days a week) and paclitaxel (15-25mg/kg, IP, once a week) was investigated as monotherapy and in combination. The combination of onvansertib and paclitaxel was tolerated with minimal toxicity and showed enhanced anti-tumor activity compared to either agent alone in all 6 PDX models. Paclitaxel and onvansertib monotherapies had little to no anti-tumor activity in 4 out of 6 PDX models (HBCx124palboR25, HBCx-139 palboR5, HBCx-202 and HBCx-131). Importantly, the combination of onvansertib and paclitaxel induced strong anti-tumor activity in these 4 models. Tumor regression was observed in the 2 PDX models with acquired resistance to palbociclib, HBCx-124palboR25 and HBCx-139palboR5, with 62% (5/8 mice) and 54% (6/11 mice) complete response rates, respectively. The combination showed tumor stasis in HBCx-131 and induced tumor regression in HBCx-202, established from patient resistant to palbociclib. In 2 of the 6 PDXs, paclitaxel exhibited anti-tumor activity, inducing tumor regression in HBCx-137paboR26 and tumor stasis in HBCx-86. In comparison, the combination of onvansertib and paclitaxel had greater activity, inducing tumor regression in both models with a higher rate of complete response than the monotherapy. Complete response rates for paclitaxel versus the combination were 62% and 100% in the HBCx-137palboR26 model and 0% and 67% in the HBCx-86 model. Notably, the antitumor activity of the onvansertib and paclitaxel combination was very durable, showing a robust delay in tumor relapse after stopping therapy. Together, our data strongly support that combining paclitaxel with the PLK1 inhibitor onvansertib extends its benefit and overcomes paclitaxel resistance, and represents a promising therapeutic strategy for HR+ breast cancer patients after progression on a combination of endocrine and CDK4/6 inhibitor therapy. Citation Format: Maya Ridinger, Pierre Painsec, Sreeja Sreekumar, Dalia Gonzalez, Davis Klein, Laura Sourd, Elodie Montaudon, Paul Cottu, Tod Smeal, Elisabetta Marangoni. PLK1 Inhibitor Onvansertib Extends the Response and Overcomes Resistance to Paclitaxel in Palbociclib-resistant HR+ Breast Cancer Patient-derived Xenografts [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 PO1-04-14.

Abstract PO1-02-04: The efficacy of endocrine therapy during the waiting period for surgery for hormone receptor-positive breast cancer

Abstract Background: Although neoadjuvant endocrine therapy has been used to improve breast conservation rate, its prognostic relevance is unknown. The search for a valid prognostic factor equivalent to pCR in neoadjuvant chemotherapy is a current challenge in neoadjuvant endocrine therapy. In this study, we investigated the efficacy of short term neoadjuvant endocrine therapy utilizing the waiting period for surgery and the prognostic factor including Preoperative Endocrine Prognostic Index (PEPI) score. Methods: A total of 480 patients with StageⅠ-Ⅲ hormone receptor-positive, HER2-negative breast cancer was treated with endocrine therapy during the waiting period for surgery between October 2012 and December 2021. Premenopausal and postmenopausal patients received tamoxifen (TAM) and non-steroidal aromatase inhibitor (AI), respectively. The primary endpoint was change in tumor size by ultrasound and Ki67 expression before and after short term endocrine therapy. The secondary endpoint was prognosis of patients divided by PEPI score which was calculated using tumor size, lymph node metastasis, Ki67 expression, and ER Allred score. This study was approved by the institutional review board of Teikyo University. Results: Median age and tumor size of the entire 480 patients was 55 years (range, 31 - 89), 1.65 cm (range, 0.4 – 7.5), respectively. The median duration of endocrine therapy was 39 days (range, 1-90). 19 (0.3 %) pts were clinically node-positive. Of the entire 480 patients, 211 and 269 patients had TAM and AI, respectively. After short term endocrine therapy, the tumor size was significantly reduced from 1.83cm to 1.62cm in AI group (p=0.02), although TAM did not decrease the tumor size (p=0.89). The Ki67 expression was significantly decreased from 16.4% to 11.3% in TAM group (p=0.002), and from 15.9% to 6.98% in AI group (p &amp;lt; 0.001). There were significant differences in the distribution of PEPI scores between TAM and AI group (p &amp;lt; 0.05) (Table). At the median follow-up of 1012 days, patients with PEPI score ≥ 4 showed worse disease-free survival compared with patients with PEPI score &amp;lt; 4 in TAM group (Figure1). Overall survival is not available because there were no deaths in TAM group. At the median observation period of 833 days, patients with PEPI score ≥ 4 showed worse disease-free survival compared with patients with PEPI score &amp;lt; 4 in AI group (Figure2). In terms of mortality, patients with PEPI score ≥ 4 had worse overall survival than patients with PEPI score 0 and 1-3 (p=0.07). Conclusions: These results suggested that neoadjuvant endocrine therapy during the waiting period for surgery might be effective in reducing Ki67 expression level and PEPI score might be useful in predicting the prognosis of hormone receptor positive breast cancer patients. Table. Distribution of PEPI score Figure 1. Disease-free survival in patients treated with tamoxifen Figure 2. Disease-free survival in patients treated with non-steroidal aromatase inhibitor Citation Format: Yuka Maeda, Saki Naruse, Yuka Isono, Ayana Sato, Akiko Matsumoto, Tatsuhiko Ikeda, Hiromitsu Jinno. The efficacy of endocrine therapy during the waiting period for surgery for hormone receptor-positive 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 PO1-02-04.

Abstract PO4-03-01: Enhancing Breast Cancer Subtyping: APIS Breast Cancer Subtyping Kit Proliferative Signature's Potential for Improved Proliferation Assessment and Recurrence Prediction

Abstract Background: Ki67, a widely recognized biomarker for measuring tumor cell proliferation in breast cancer (BC), plays a crucial role in classifying BC into luminal A and luminal B subtypes, subsequently aiding treatment decisions. However, the inconsistency in Ki67 assessment and the lack of standardization in methods and interpretation of immunohistochemistry (IHC) staining has hindered its recommendation for routine diagnostic use. The standardization of measurement techniques, especially for Ki67, holds immense potential for improving patient treatment outcomes. The APIS Breast Cancer Subtyping Kit (APIS BCS Kit) addresses these challenges by utilizing RT-qPCR to accurately determine the mRNA expression of BC markers, including Ki67, along with a novel four-gene proliferative signature, comprising four markers (MKI67, CCNA2, KIF23, and PCNA) associated with proliferation and expressed throughout all cell cycle stages, thereby providing a more accurate measure of tumor proliferation. In this study, we present the preliminary findings of our ongoing evaluation of the APIS BCS Kit proliferative signature's ability to distinguish between Luminal A and Luminal B subtypes and to determine the risk of recurrence in hormone receptor-positive (HR+) patients. Method: A total of N=153 retrospectively collected HR+/HER2 negative samples were provided by University of Basel. For each sample the following clinical annotations were included: relapse free survival, treatment regimen (Chemotherapy (ChT) or Hormone Therapy (HT)) as well as OncotypeDx (ODx) risk score (RS). N=40 samples underwent additional testing using PAM50 (Prosigna®) test. Only samples collected since 2018 were included, resulting in 10 observed relapse events (N=7 in HT cohort and N=3 in ChT cohort). RNA isolation from tissue sections and gene expression analysis were performed as per APIS BCS Kit instructions for use. The agreement of subtype calls between IHC, APIS BCS Kit, and PAM50 was assessed. The correlation between RS obtained from ODx, PAM50 and the APIS BCS Kit proliferation signature was also explored. Results: The agreement between IHC and the APIS BCS Kit subtype call, utilizing Ki67 alone as a measure of proliferation, was 67.3% (103/153). Replacing Ki67 with the APIS BCS Kit proliferation signature increased the concordance to 69.9% (107/153). The concordance between IHC and PAM50 subtype calls was comparable at 62.5% (25/40). The agreement between the APIS BCS Kit and PAM50 subtype call was notably higher (80%; 32/40). Significant association was observed between the APIS BCS Kit proliferation signature and ODx RS (P=.0001), and PAM50 RS (P=.002). In the HT cohort, both ODx and the APIS BCS Kit proliferation signature accurately predicted recurrence (by assigning high RS) in n=2 cases. In some cases both the APIS BCS Kit and ODx erroneously assigned low risk and subsequently missed n=4 recurrence events. Notably, APIS BCS Kit proliferation signature correctly identified one recurrence event (high RS), which was missed by ODx (low RS). Conclusion: The APIS Breast Cancer Subtyping Kit exhibits improved agreement with the PAM50 molecular subtype in contrast to the IHC-derived subtype, indicating that molecular testing may be a more suitable method for determining proliferation and distinguishing between luminal A and B subtypes. Furthermore, there is a significant correlation between the RS generated by APIS Breast Cancer Subtyping Kit proliferation signature and both PAM50 and Oncotype RS. These initial findings indicate that the APIS Breast Cancer Subtyping Kit proliferation signature has the potential to accurately identify patients at risk of recurrence, although additional studies including a larger proportion of events are needed to validate these results. Citation Format: Marcus Vetter, Anna Gasior, Elena-Diana Chiru, Joanna Gorniak, Leanne Gough, Mathew Harrison, Sara Rollinson, Simone Muenst, Christian Kurzeder. Enhancing Breast Cancer Subtyping: APIS Breast Cancer Subtyping Kit Proliferative Signature's Potential for Improved Proliferation Assessment and Recurrence Prediction [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 PO4-03-01.

Abstract 3282: Endocrine resistance genes driving cross-resistance to current combination therapies in HR-positive breast cancer

Abstract Introduction: Treatment failure to multiple treatment lines in hormone receptor positive (HR+) patients brings cross-resistance into the stage. The study aimed to determine if tamoxifen resistance genes cause cross-resistance to commonly employed metastatic breast cancer (combination) treatments. Materials &amp; Methods: Parental and tamoxifen resistant MCF7A models (BCAR3, BCAR4, EGFR, AKT1 and AKT2) were cultured for 10 days with different concentrations of tamoxifen and fulvestrant (endocrine therapy), ribo-, abema-, and palbociclib (CDK4/6 inhibitors) and alpelisib (PIK3CA inhibitor). Compounds were tested as mono- and combination therapy in replicate experiments estimating cell growth using the Sulforhodamine B assay and half maximal inhibitory concentration (IC50) was calculated by Graphpad PRISM v5 software. Resistance was declared when IC50 was significantly different from parental (p&amp;lt;0.05, Mann-Whitney U test). Results: The BCAR3, BCAR4 and EGFR models were not only resistant to tamoxifen but also to fulvestrant monotherapy (see table). In the two AKTs models the initial results could not be reproduced and were excluded from the study. The BCAR4 model was also resistant to all CDK4/6- and PIK3CA-inhibitors monotherapy. Analysis of the combination regimens demonstrated cross-resistance in the BCAR4 model for all compound combinations tested, in the EGFR model for all combinations except fulvestrant combined with alpelisib, and in the BCAR3 model only for tamoxifen combined with alpelisib. Discussion/Conclusion: Tamoxifen resistance genes BCAR3, BCAR4 and EGFR show various degrees of cross-resistance to other breast cancer treatments. It might be worthwhile to evaluate these genes or their associated biological pathways as predictive biomarkers for cross-resistance in HR+ breast cancer patients treated with the mentioned (combination) therapies. Summary of median IC50 (IQR) for different conditions parental BCAR3 BCAR4 EGFR AKT1 AKT2 Monotherapy Tamoxifen 9.8 (7.0) 47.3 (121) ** 2210 (1280) ** 515 (495) ** 8.0 (21.3) 3.8 (21.8) Fulvestrant 0.1 (0.35) 0.8 (0.8) ** 309 (407) ** 11.4 (37.7) ** Ribociclib 479 (285) 423 (1102) 3099 (1212)** 719 (669) Abemaciclib 94.9 (82.5) 28.9 (52.6) 206 (197) * 189 (172) Palbociclib 138 (163) 91.1 (107) 608 (347) ** 158 (128) Alpelisib 14.1 (676) 322 (94.0) 1424 (372) ** 375 (356) Combination therapy Tamoxifen with Ribociclib 1.7 (1.0) 17.2 (29.0) 111 (159) * 54.4 (35.8) * Abemaciclib 2.5 (1.9) 6.0 (10.7) 19.5 (15.0) ** 40.0 (53.6) * Palbociclib 1.6 (2.0) 5.4 (4.6) 74.9 (80.9) * 29.2 (3.1) * Alpelisib 2.1 (0.3) 9.6 (12.4)* 157 (69.9) * 17.8 (9.9) * Combination therapy Fulvestrant with Ribociclib 0.07 (0.02) 0.1 (0.3) 14.4 (8.8) * 6.9(16.8) * Abemaciclib 0.07 (0.02) 0.1 (0.1) 4.6 (2.6) ** 2.6 (6.5) * Palbociclib 0.2 (0.1) 0.2 (1.6) 5.6 (0.9) * 1.3 (1.5) * Alpelisib 0.05 (0.05) 1.6 (20.6) 13.3 (8.1) * 2.1 (0.9) *:p&amp;lt;0.05, **:p&amp;lt;0.01 compared to parental cell line. Citation Format: Zhangzan Huang, Noor Wortelboer, Corine Beaufort, Seda N. Ortak, Da-wei Chan, Hamit H. Dag, Jean Helmijr, John Martens, Maurice Jansen. Endocrine resistance genes driving cross-resistance to current combination therapies in HR-positive breast cancer [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 3282.

Abstract 6439: Next-generation sequencing based detection of HER2 copy number predicts pathological response to neoadjuvant therapy in HER2 positive breast cancer

Abstract Purpose: Achieving pathologic complete response (pCR) following neoadjuvant chemotherapy is associated with better prognosis for HER2 positive breast cancer. However, clinical and biological heterogeneity of HER2 positive disease significantly affect prognosis and treatment response. Early prediction of treatment benefit could enable tailored anti-HER2 therapy. Next-generation sequencing (NGS) based genomic tests including copy number (CN) detection are widely used in breast cancer patients. We aim to evaluate the association of HER2 copy number detected by NGS with pCR rate of HER2 positive breast cancer after neoadjuvant chemotherapy. Methods: HER2 positive breast cancer patients underwent neoajuvant chemotherapy in Henan Cancer Hospital From January 2022 to March 2023 were included in the study. Pretreatment tumour specimens were subjected to pan-cancer 1021-gene panel genomic sequencing. Copy number of HER2 was obtained from the panel. Copy number of &amp;gt;=4 was classified as HER2 amplified and HER2 copy number &amp;lt;4 was classified as HER2 non-amplified. All patients underwnt definitive surgery after receieveing neoadjuvant chemotherapy containing taxanes, trastuzumab and pertuzumab. pCR was defined as pathological stage ypT0/Tis ypN0. Results: In total, 299 HER2 positive breast cancer patients were eligible for the analysis. 87 were classified as HER2 non-amplified (29.1%) by copy number and 212 patients were classified as amplified group (70.9%). The HER2 non-amplified group tends to have a higher proportion of hormone receptor positive (HR+) patients (71.3% vs. 50.5%, p=0.002). Other clinicopathological parameters were well distributed between the groups. 91.3% of patients in HER2 amplified group had strong positive HER2 expression (IHC 3+), while only 10.5% of patients in HER2 non-amplified group had HER2 expression of IHC 3+. Patients with HER2 IHC 3+ had a PCR rate of 75.8% and Patients with HER2 IHC 2+ had a pCR rate of 20.0% (20.0% vs. 75.8% p&amp;lt;0.001). Patients in the amplified group had a pCR rate of 76.9% and pCR rate of the non-amplified group was12.6% (12.6% vs. 76.9% p&amp;lt;0.001). In a multivariable logistic regression with HER2 copy number by NGS, HR status and HER2 IHC, the HER2 copy number predicted pCR rate independently of HER2 IHC and HR status. Conclusions: NGS based detection of HER2 copy number could predict response to neoadjuvant therapy in HER2 positive patients. The discordance between IHC/FISH and NGS based detection of HER2 amplification may reflect HER2 heterogeneity. HER2 heterogeneity promotes resistance to anti-HER2 therapy. Noval antibody-drug conjugates (ADC) with bystander effect, such as Trastuzumab deruxtecan, have shown anti-tumor effect even in HER2 low expression tumors. Thus, prospective study is needed to optimize anti-HER2 therapy for patients with HER2 heterogeneity. Citation Format: Hao Dai, Dechuang Jiao, Xuhui Guo, Jianghua Qiao, anfang Li, Zhenduo Lu, Xiuchun Chen, Chengzheng Wang, Min Yan, Zhenzhen Liu. Next-generation sequencing based detection of HER2 copy number predicts pathological response to neoadjuvant therapy in HER2 positive breast cancer [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 6439.

Comprehensive genomic evaluation of advanced and recurrent breast cancer patients for tailored precision treatments

AimThe aim of this study was to investigate genetic alterations within breast cancer in the setting of recurrent or de novo stage IV disease.Patients and methods: This study included 22 patients with recurrent breast cancer (n = 19) and inoperable de novo stage IV breast cancer (n = 3). For next generation sequencing, FoundationOneCDx (F1CDx) (Foundation Medicine Inc., Cambridge, MA, USA) was performed in 21 patients and FoundationOneLiquid CDx was performed in 1 patient.ResultsMedian age was 62.9 years (range, 33.4–82.1). Pathological diagnoses of specimens included invasive ductal carcinoma (n = 19), invasive lobular carcinoma (n = 2), and invasive micropapillary carcinoma (n = 1). F1CDx detected a median of 4.5 variants (range, 1–11). The most commonly altered gene were PIK3CA (n = 9), followed by TP53 (n = 7), MYC (n = 4), PTEN (n = 3), and CDH1 (n = 3). For hormone receptor-positive patients with PIK3CA mutations, hormonal treatment plus a phosphoinositide 3-kinase inhibitor was recommended as the treatment of choice. Patients in the hormone receptor-negative and no human epidermal growth factor receptor 2 expression group had significantly higher tumor mutational burden than patients in the hormone receptor-positive group. A BRCA2 reversion mutation was revealed by F1CDx in a patient with a deleterious germline BRCA2 mutation during poly ADP ribose polymerase inhibitor treatment.ConclusionGuidance on tailored precision therapy with consideration of genomic mutations was possible for some patients with information provided by F1CDx. Clinicians should consider using F1CDx at turning points in the course of the disease.

Individual participant data from digital sources informed and improved precision in the evaluation of predictive biomarkers in Bayesian network meta-analysis

ObjectivesWe aimed to develop a network meta-analytic model for the evaluation of treatment effectiveness within predictive biomarker subgroups, by combining evidence from individual participant data (IPD) from digital sources (in the absence of randomized controlled trials) and aggregate data (AD). Study Design and SettingA Bayesian framework was developed for modeling time-to-event data to evaluate predictive biomarkers. IPD were sourced from electronic health records, using a target trial emulation approach, or digitized Kaplan-Meier curves. The model is illustrated using two examples: breast cancer with a hormone receptor biomarker, and metastatic colorectal cancer with the Kirsten Rat Sarcoma (KRAS) biomarker. ResultsThe model allowed for the estimation of treatment effects in two subgroups of patients defined by their biomarker status. Effectiveness of taxanes did not differ in hormone receptor positive and negative breast cancer patients. Epidermal growth factor receptor inhibitors were more effective than chemotherapy in KRAS wild type colorectal cancer patients but not in patients with KRAS mutant status. Use of IPD reduced uncertainty of the subgroup-specific treatment effect estimates by up to 49%. ConclusionUtilization of IPD allowed for more detailed evaluation of predictive biomarkers and cancer therapies and improved precision of the estimates compared to use of AD alone.

Effect of HER2-low expression on neoadjuvant efficacy in operable breast cancer.

To investigate the effects of HER2-low expression (HER2-low) and HER2-zero expression (HER2-0) on the pathological complete response (pCR) rate and survival of patients following neoadjuvant chemotherapy. Eighty-six patients were followed up. Patients were divided into HER2-0 (immunohistochemistry (IHC) score of 0 (IHC0)) and HER2-low (IHC1+ or IHC2+/in situ hybridization non-amplified (ISH-)) groups according to the IHC detection of puncture tissues. After neoadjuvant chemotherapy, the clinical characteristics, pCR rate and DFS were compared between the two groups. There were 24 (27.9%) cases with HER2-0 and 62 (72.1%) cases with HER2-low. Hormone receptor-positive (HR+) patients accounted for 77.4% of the HER2-low group, which was higher than 70.8% in the HER2-0 group, and there was no significant difference between the two groups (p = 0.524). There were statistical differences in the pT and pN stages between HER2-low and HER2-0 subgroups in the triple-negative breast cancer (TNBC) group after neoadjuvant chemotherapy. The HER2-low subgroup had an earlier T stage (p = 0.009), and the ratio of N0 to N1 in the HER2-low and HER2-0 subgroups was 92.9% and 71.4%, respectively (p = 0.037). The Ki-67 index and median PR value were significantly lower in the HER2-low group after neoadjuvant chemotherapy (p = 0.002, p = 0.018). The HER2 IHC score was altered in the HER2-low group, and the HER-2 (2+) score changed significantly (p = 0.002). Seventy-eight patients with complete immunohistochemical data were analyzed. The discordance rate of the IHC score of HER2 after neoadjuvant chemotherapy was 38.5%, and eight patients with HER2-low showed HER2-0 status, with a discordance rate of 10.3%. After neoadjuvant chemotherapy, The pCR rate was significantly lower in the HER2-low group compared with that in the HER2-0 group (4.8% vs. 8.3%; p = 0.914), but the recurrence and metastasis rates were lower in the HER2-low group (9.7% vs. 20.8%; p = 0.165). There were no differences in DFS between the two groups at 6, 12, 24, and 36months (p = 0.076; p = 0.518; p = 0.245; p = 0.406). The subgroup analysis demonstrated no significant difference in DFS between HER2-low and HER2-0 subgroups in the HR + and TNBC groups (p = 0.141, p = 0.637). This retrospective study indicates that HER2-low has no significant effect on neoadjuvant efficacy in operable breast cancer. There were no statistical differences in clinical characteristics, pCR rate, and DFS between the HER2-low and the HER2-0 groups. There was no evidence that a HER2-low status constitutes a unique biological subtype, suggesting that more clinical data might be needed to verify these observations.