Luminal Metastatic Breast Cancer Research Articles

Clinicopathogenomic analysis of PI3K/AKT/PTEN-altered luminal metastatic breast cancer in Japan.

This rapid communication highlights the correlation between protein kinase B alpha (AKT1)-phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)- phosphatase and tensin homolog (PTEN) alterations and clinicopathological factors in Japanese patients with metastatic recurrent breast cancer (mBC). This study analyzed 1967 patients with luminal-type breast cancer who underwent cancer gene panel testing. The results demonstrated that AKT pathway alterations, including PI3K/AKT/PTEN, occurred in 1038 (52.8%)cases. Patients with AKT pathway mutations were older (p = 0.002) and had a higher rate of invasive lobular carcinoma (ILC) histology (p = 0.001), progesterone receptor (PgR) positivity (p = 0.006), and bone metastases (p = 0.001), and a lower rate of germline BRCA2 (p < 0.001). Comprehensive genomic profile results demonstrated a higher tumor mutational burden (TMB) (< 0.001) and lower tumor BRCA1/2 expression (< 0.001) in patients with mutations in the AKT pathway. These results are crucial for characterizing candidates for AKT pathway-targeted molecular therapies and conceptualizing optimal treatment strategies. Clinical trial registration: This study is an observational study and is therefore not registered with the clinical trials registration.

Absolute lymphocyte count predicts efficacy of palbociclib in patients with metastatic luminal breast cancer

BackgroundAbsolute lymphocyte count (ALC) is a predictive and prognostic factor for various tumor types, including breast cancer. Palbociclib is a CDK4/6 inhibitor widely used for the treatment of metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer. However, predictive biomarkers of the efficacy of palbociclib remain unelucidated. We conducted a retrospective study to examine the predictive value of the baseline ALC in patients treated with palbociclib.MethodsThe medical records of patients with ER-positive, HER2-negative breast cancer treated with palbociclib plus hormonal therapy between December 2017 and December 2021 were analyzed retrospectively. The cutoff value of ALC was set at 1800 cells/μL at the initiation of palbociclib treatment. The clinical benefit rate (CBR) was defined as the rate of complete or partial response or stable disease for at least 6 months. Progression-free survival (PFS) rates were estimated using the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards regression.ResultsAll of the 202 patients were women, with a median age of 59 years and a performance status (PS) of ≤ 2. The median numbers of lines of chemotherapy and endocrine therapy before palbociclib treatment were 0 (range, 0–9) and 1 (range, 0–7), respectively. Fifty-one patients had liver metastases. Forty-six patients tested negative for progesterone receptor (PgR) expression. The median follow-up time was 9.1 months. The CBR was significantly higher in the ALC-high group than in the ALC-low group (79% vs. 60%; P = 0.018). The median PFS was significantly longer in the ALC-high group than in the ALC-low group (26.8 months vs. 8.4 moths, respectively; P = 0.000013). ALC, age, PS, PgR status, prior chemotherapy, prior endocrine therapy, and liver metastasis were entered into the multivariate analysis. ALC was identified as an independent factor for PFS (P = 0.00085), along with liver metastasis (P = 0.0020), PS (P = 0.026), and prior endocrine therapy (P = 0.019).ConclusionALC can serve as a predictor of palbociclib efficacy in patients with metastatic ER-positive, HER2-negative breast cancer.

How overall survival is conditioned in the progression to treatment with cyclin inhibitors plus endocrine treatment in metastatic breast cancer with luminal phenotype.

e13079 Background: CDK4/6 inhibitors plus endocrinotherapy (ET) is the standard first-line treatment for metastatic breast cancer with a luminal phenotype. However, the response to this treatment is highly dependent on its previous efficacy. Methods: We analyzed the overall survival in a cohort of 127 patients with metastatic luminal breast cancer in progression after treatment with CDK4/6 inhibitors plus ET. Results: The median age of the group was 67 years (41-96), the interval time between initial diagnosis and first recurrence was 0 in 41 (32%), 1-60 months in 37 (29%) and more than 60 months in 39 (38%). The first line in the metastatic setting was CDK4/6 plus ET in 81 patients (64%), ET in 15 (12%) and 31 (24%) were treated with chemotherapy. The status of HER2 expression was HER2 low in 77% and 43 % had visceral metastases disease. The median progression-free survival for the patients treated with CDK4/6 inhibitors plus ET was 9 months, with a total of deaths of 69 (55%). Overall survival after progression on CDK4/6 plus ET was 38 months (28 – 47) and the most important factor for overall survival was the response time to treatment with CDK4/6 inhibitors plus ET. Conclusions: The most important factor for overall survival is the duration of treatment with CDK4/6 inhibitors plus ET. Patients with a response time of less than 6 months had a median overall survival after progression of 11 months (3 – 19), while the 6- to 12-month group had a median of 39 months (19 – 59) and the group with more than 12 months had the best prognosis with a median overall survival of 53 months (37 – 68). We need to improve the new treatment options for patients who respond for less than 6 months to treatment with CDK4/6 plus ET.

Abstract PO4-04-14: Change of first-line treatment pattern in metastatic luminal breast cancer: Results from the Austrian AGMT_MBC-Registry

Abstract Background: For patients with HR+/HER2- (luminal) metastatic breast cancer (MBC), international guidelines recommend endocrine-based first-line therapy [ET] in combination with a CDK4/6 inhibitor for most patients. Only for patients with imminent organ failure, first-line chemotherapy should be considered. To clarify changing patterns of first-line treatments over time in an Austrian population of luminal MBC patients, we analyzed the data from the MBC registry of the Austrian Study Group for Medical Tumor Therapy (AGMT-MBC-Registry). Methods: The AGMT-MBC-Registry is an ongoing multicenter registry for MBC patients in Austria. Only patients with luminal MBC and sufficient outcome data were included in this analysis. Patients were assigned to one of the following groups according to the year of start of first-line treatment for MBC: 2001-2010, 2011-2013 (no CDK4/6i available for first-line in both periods), 2014-2016 (CDK4/6i available in early access programs and clinical trials for first-line only), 2017-2019, and 2020-2022 (CDK4/6i available in both periods). Time to first chemotherapy (TTC) defined as start of first-line treatment until first application of a cytotoxic agent, and overall survival (OS) defined as start of first-line treatment until death were calculated by the Kaplan-Meier method and compared using the log-rank test. OS analysis was adjusted for disease free survival (DFS) category (de novo, DFS &amp;lt; 24 month, DFS ≥ 24 month), menopausal status (pre-, postmenopausal, unknown), age at diagnosis of metastatic disease (continuous), number of metastatic sites at diagnosis (1, 2-3, &amp;gt; 3), visceral disease (no, yes), and Charlson comorbidity index at diagnosis (continuous). Results: As of May 16th 2023, 1,330 patients with HR+/HER2- disease receiving at least one treatment-line for MBC were evaluable. First-line treatments significantly changed over time (P &amp;lt; 0.001). In patients diagnosed between 2001 and 2010, 61.4% were treated with first-line chemotherapy compared to 10.0% in patients diagnosed between 2020 and 2022 (Table 1). Additionally, TTC also significantly increased over time (P &amp;lt; 0.001; Table 2). In contrast, the proportion of patients treated with a first-line CDK4/6i plus endocrine therapy combination increased over time from 4.4% in 2014-2016 up to 75.5% in the period of 2020-2022. Additionally, adjusted median overall survival estimates significantly increased over time (P &amp;lt; 0.001; Table 2). Conclusion: In our registry, the proportion of patients with luminal MBC treated with first-line chemotherapy significantly decreased over time, whereas the proportion or patients treated with first-line CDK4-6 inhibitors significantly increased. This is in line with the change of guideline recommendation as well as the availability of CDK4-6 inhibitors over the last 2 decades. The availability of new treatment options has significantly increased median overall survival over time. Table 1: First-line treatment pattern over time Period N ET ET plus CDK4/6i Chemotherapy Others* 2001-2010 220 84 (38.2%) 0 (0.0%) 135 (61.4%) 1 (0.5%) 2011-2013 238 116 (48.7%) 0 (0.0%) 110 (46.2%) 12 (5.0%) 2014-2016 318 174 (54.7%) 14 (4.4%) 99 (31.1%) 31 (9.7%) 2017-2019 293 60 (20.5%) 190 (64.8%) 36 (12.3%) 7 (2.4%) 2020-2022 249 22 (8.8%) 188 (75.5%) 25 (10.0%) 14 (5.6%) Overall 1,318 456 (34.6%) 392 (29.7%) 405 (30.7%) 65 (4.9%) Legend: N - number of patients, ET - endocrine therapy (tamoxifen, aromatase inhibitor and/or fulvestrant), CDK4/6i - CDK4/6 inhibitor; * e.g. endocrine treatment plus everolimus or investigational study treatment Table 2: Time to first chemotherapy (TCC) and overall survial (OS) over time Period Median TTC [months] Adjusted median OS [months] 2001-2010 0.0 (0.0 - 0.0) 49.4 (41.2 - 56.6) 2011-2013 4.3 (0.0 - 13.8) 48.2 (38.3 – 69.7) 2014-2016 20.0 (14.0 - 26.4) 60.3 (50.2 - 77.5) 2017-2019 40.1 (33.3 - 59.8) 60.8 (52.8 - NR) 2020-now 30.4 (27.6 - NR) NR (NR - NR) Legend: N - number of patients, NR - not reached Citation Format: Gabriel Rinnerthaler, Simon Gampenrieder, Angelika Pichler, Walter Herz, Andreas Petzer, Renate Pusch, Marija Balic, Christoph Suppan, Sonja Heibl, Lukas Scagnetti, Margit Sandholzer, Clemens Schmitt, August Zabernigg, Daniel Egle, Petra Pichler, Christopher Hager, Florian Roitner, Johannes Andel, Kathrin Strasser-Weippl, Rupert Bartsch, Michael Hubalek, Michael Knauer, Christian F. Singer, Richard Greil. Change of first-line treatment pattern in metastatic luminal breast cancer: Results from the Austrian AGMT_MBC-Registry [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 PO4-04-14.

Abstract PO5-21-10: Efficacy and Safety of Alpelisib in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor: An Open-label, Multi-centre, Prospective, Single Arm Clinical Trial

Abstract Introduction: Currently, patients with luminal metastatic breast cancer receive a CDK4/6 inhibitor in combination with endocrine therapy as a first or second line of treatment. When tumors become resistant to the CDK4/6 inhibitors, treatment with alpelisib (PI3K inhibitor) in combination with an endocrine agent can be a next treatment option if an activating PIK3CA mutation is confirmed (cfr. SOLAR-1 trial). However, limited data is available after treatment with CDK4/6 inhibitors (cfr. BYLieve trial) and even less about alpelisib in later lines of therapy. Therefore, we aim to investigate the therapeutic efficacy and safety of alpelisib in combination with an endocrine agent in PIK3CA-mutated advanced breast cancer patients in later lines after prior CDK4/6i treatment. Methods: This is an open-label, prospective, multi-centre, single arm clinical trial enrolling patients from both the University Hospital of Leuven (UHL) and Ghent University Hospital (GUH). For each patient, metastatic tumor was tested for PIK3CA mutations using the UHL 96 gene panel. Our endpoints are clinical benefit rate, progression-free survival, time to treatment discontinuation (defined as the date of starting alpelisib to the date of treatment discontinuation or death) and safety. Descriptive statistics were used. Results: Between June 18th 2019 and August 23rd 2021, 38 patients have been included with confirmed PIK3CA hotspot mutations. All patients had CDK4/6 inhibitor in an earlier treatment line. Median age at alpelisib initiation was 64 years (range: 39-82 years). Included patients had a median of four lines of systemic therapy for advanced disease prior to starting alpelisib (range: 1- 11). Clinical benefit rate (patients receiving ³ 6 months of treatment) was 26.3% (10/38). The median progression-free-survival as well as time to treatment discontinuation were 3 months (range: 1 – 18). Dose reduction due to toxicity occurred in 11 patients (29%), of which 7 due to hyperglycemia grade 3, 2 due to diarrhea grade 3, 1 due to rash grade 2 and 1 due to anorexia. Finally, 84% of patients (32/38) stopped alpelisib treatment because of progressive disease, 8% (3/38) because of intolerance, one patient died because of cerebral hemorrhage during treatment, one patient withdrew their informed consent and one patient is still ongoing with the treatment. Conclusion: Our trial demonstrates activity of alpelisib in patients with PIK3CA mutated advanced breast cancer in later lines of treatment after treatment with CDK4/6 inhibitors with a clinical benefit rate of 26.3%. Discontinuation of therapy due to toxicity was seen in only 8% of patients, although toxicity induced dose reduction was needed in 29% of patients. These findings support the results of the BYLieve trial and additionally show efficacy of alpelisib in later lines of treatment for hormone receptor-positive advanced breast cancer. Citation Format: Rik Van Severen, Anne-Sofie De Crem, Hava Izci, Laurence Slembrouck, Isabelle Vanden Bempt, Hans Wildiers, Kevin Punie, Eline Naert, Ingeborg Hilderson, Ann Smeets, Ines Nevelsteen, Anne Deblander, Nynke Willers, Patrick Berteloot, Ignace Vergote, Sileny Han, Adriaan Vanderstichele, Giuseppe Floris, Christine Desmedt, Hannelore Denys, Patrick Neven. Efficacy and Safety of Alpelisib in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor: An Open-label, Multi-centre, Prospective, Single Arm Clinical 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 PO5-21-10.

TWIST1 Upregulation Is a Potential Target for Reversing Resistance to the CDK4/6 Inhibitor in Metastatic Luminal Breast Cancer Cells.

Cyclin-dependent kinase (CDK) 4/6 inhibitors have significantly improved progression-free survival in hormone-receptor-positive (HR+), human-epidermal-growth-factor-receptor-type-2-negative (HER2-) metastatic luminal breast cancer (mLBC). Several studies have shown that in patients with endocrine-sensitive or endocrine-resistant LBC, the addition of CDK4/6 inhibitors to endocrine therapy significantly prolongs progression-free survival. However, the percentage of patients who are unresponsive or refractory to these therapies is as high as 40%, and no reliable and reproducible biomarkers have been validated to select a priori responders or refractory patients. The selection of mutant clones in the target oncoprotein is the main cause of resistance. Other mechanisms such as oncogene amplification/overexpression or mutations in other pathways have been described in several models. In this study, we focused on palbociclib, a selective CDK4/6 inhibitor. We generated a human MCF-7 luminal breast cancer cell line that was able to survive and proliferate at different concentrations of palbociclib and also showed cross-resistance to abemaciclib. The resistant cell line was characterized via RNA sequencing and was found to strongly activate the epithelial-to-mesenchymal transition. Among the top deregulated genes, we found a dramatic downregulation of the CDK4 inhibitor CDKN2B and an upregulation of the TWIST1 transcription factor. TWIST1 was further validated as a target for the reversal of palbociclib resistance. This study provides new relevant information about the mechanisms of resistance to CDK4/6 inhibitors and suggests potential new markers for patients' follow-up care during treatment.

Place of fulvestrant in the treatment of patients with metastatic luminal Her2-negative breast cancer

Hormone therapy alone or in combination with targeted agents (CDK4/6 inhibitors, alpelisib, everolimus) is currently the standard treatment of metastatic luminal Her2-negative breast cancer. Aromatase inhibitors and fulvestrant are the main hormone therapy agents. Fulvestrant belongs to a special class of antiestrogens – selective estrogen receptor degraders (SERD) and does not have estrogen receptor agonist activity, unlike tamoxifen. In addition, the efficacy of fulvestrant does not depend on the presence of ESR1 mutations in the tumor. The combination of aromatase inhibitors with CDK4/6 inhibitors is the standard first-line treatment in patients with hormone-sensitive tumors, that is, with progression of more than 1 year after the end of adjuvant hormone therapy. Whereas fulvestrant ± CDK4/6 inhibitors are used for disease progression on adjuvant hormonal therapy in the 1st line or as 2nd line for progression on aromatase inhibitor therapy for metastatic cancer. The choice of treatment for patients with a PIK3CA mutation with progression on the 1st line of fulvestrant with a CDK4/6 inhibitor is difficult. This article presents a clinical example of the use of a combination of fulvestrant and alpelisib in a patient with secondary hormone resistance (progression on the adjuvant therapy with aromatase inhibitors) and progression on the first-line therapy with fulvestrant and palbociclib. Carrying out therapy with fulvestrant and alpelisib as the 2nd line provided a long-term (for 14 months) stabilization of the tumor process.

Co-targeting RANK pathway treats and prevents acquired resistance to CDK4/6 inhibitors in luminal breast cancer

The combination of endocrine therapy (ET) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (CDK4/6i) was a hallmark in metastatic luminal breast cancer (BC). However, intrinsic and acquired resistance affects long-term efficacy. Here, we study the role of the receptor activator of nuclear factor-κB (RANK) pathway in CDK4/6i resistance. We find that RANK overexpression in luminal BC is associated with intrinsic resistance to CDK4/6i, both invitro and in mouse xenografts, and decreased proliferation rate and chronic interferon (IFN) γ response are highlighted as resistance drivers. Gene expression data from the NeoPalAna CDK4/6i clinical trial, and studies with palbociclib-resistant cell lines, show that RANK is upregulated after treatment with CDK4/6i, supporting a role in acquired resistance. Our study shows that RANK ligand (RANKL) inhibitors can restore sensitivity to CDK4/6i and prevent acquired resistance. On the basis of these findings, we conclude that pharmacological inhibition of the RANK pathway through RANKL blocking could represent an add-on to ET+ CDK4/6i, warranting further clinical studies.

Is HER2 expression related to CDKi efficacy in HER2-negative luminal metastatic breast cancer?

e13073 Background: Cyclin kinase inhibitors (CDKi) are the standard of care in the first line of luminal (Lum) metastatic breast cancer (MBC). HER2 overexpression is a classic risk factor in BC, however, the use of targeted therapy has changed the prognosis of this disease, even with anti-HER2 efficacy data in cases of low HER2 expression. We wonder if the level of HER2 expression can be a predictor of efficacy in treatment with CDKi. Methods: Descriptive, observational, retrospective and analytical study of patients with MBC treated with CDKi, in the period 2018-2022. Descriptive and analytical statistical analysis (IBM SPSS Statistics 22) using logistic regression and Kaplan-Meier with long-rank test to analyze the relationship between CKi efficacy and HER2 expression (negative = 0+; HER2 low = 1+ and 2 + with SISH negative). Results: We analyzed 152 patients (p) with Lum MBC under treatment with CDKi (median 58 years), in first and successive lines. HER2 expression: 31% 46p (0+), 54% 81p (1+) and 14% 21p (2+ and SISH negative). 41% were treated with palbociclib, 34% with ribociclib, and 26% with abemaciclib. Radiological response (RR) to CDKi was achieved by 34.1% (CRR 2.4%, PRR 31.7), and the rest stable disease (SD) or progressive disease (PD): SD 42% and PD 22%. In the overall OR, there was no evidence of a risk association between the response to CDKi and the level of HER2 expression. We obtained similar results in the analysis stratified by type of CDKi. In the multivariate study, for the variables CDKi type and HER2 expression, the logistic regression model was not statistically significant either. Regarding the Kaplan-Meier analysis, we compared the median PFS and OS using the Long-rank test, based on the expression of HER2. In the complete series we did not find statistically significant differences between the curves. In the palbociclib subgroup the curves split in favor of HER2 0+ vs. HER2 low: 44 months 95%CI (7.6-80) vs 16 months 95%CI (7.9-24); p = 0.01. Regarding OS, we found no significant differences. With ribociclib, the curves separate in favor of HER2 low versus HER2 0+: 33 months 95%CI (7.2-18) vs. 13 months 95%CI (23-42); p = 0.03. In OS we did not find significant differences either. In the subgroup with abemaciclib, we observed a trend towards greater survival in HER2 0+ patients, but with no significant difference between the PFS or OS curves. Conclusions: Based on our study, the expression of HER2 could be considered a predictor of efficacy depending on the CDKi used. We assume greater survival with palbociclib in HER2 negative patients (0+) and with ribociclib in HER2 low patients. We consider it essential to develop studies with a larger sample size and clinical trials that allow us to demonstrate the hypothesis of our work with scientific evidence.

Cyclin E cytoplasmatic isoform to predict outcome and benefit to capecitabine treatment in patients with HR+/HER2- metastatic breast cancer from the GEICAM/2013-02 PEARL study.

1023 Background: Cytoplasmic cyclin E protein expression, serving as a surrogate for the low molecular weight cyclin E isoform (LMW-E), is a biomarker associated with aggressive breast cancer and predicts resistance to aromatase inhibitors in luminal breast cancer. We investigated the prognostic and predictive value of cytoplasmic and nuclear isoforms of cyclin E in HR+/HER2- metastatic breast cancer (MBC) patients receiving palbociclib CDK4/6 inhibitor and endocrine therapy (PALBO+ET) versus capecitabine (CAPE) in the GEICAM/2013-02 PEARL trial (NCT02028507). Methods: Expression of Cytoplasmic and Nuclear isoforms of cyclin E were assessed by immunohistochemistry (IHC). An H-score based on the proportion and intensity of stained cells was explored using median value to categorize in Low / High expression the Nuclear and Cytoplasmic scores (N and C, respectively). In addition, N and C were independently assigned according to staining intensity (1 = no staining, 2 = weak, 3 = intermediate and 4 = strong staining) and then, combined in 4 phenotypes (Ph): Ph1 (N-/C-); Ph2 (N+/C-); Ph3 (N+/C+); and Ph4 (N-/C+), where negative=1-2, and positive=3-4. Cox regression models’ analysis were assessed to predict outcome and benefit to treatment, in terms of PFS and OS. Multivariate models were adjusted for confounders: age, site of disease, sites of metastasis, prior chemotherapy for MBC and treatment. Interaction analysis with treatment arm were performed. Results: Cyclin E protein was obtained from 344 tumors, with 73% being primary tumors and 27% metastatic. High expression of the Nuclear isoform was independently associated with significantly worse OS (median OS [mOS]=34.23 months [m] for low expression vs 25.72m for high expression; adjusted HR=1.48; p-value=0.016). Phenotype analysis supported this finding, with Ph3 (N+/C+) and Ph4 (N-/C+) demonstrating the worst (mOS=19.55m) and best (mOS=37.19m) outcomes, respectively (using Ph1 as reference, Ph3 HR=2.92; p-value=0.0013). The interaction between the treatment arm and Cytoplasmic cyclin E expression was significant (p=0.0052). Patients with high expression of the Cytoplasmic isoform had significantly better PFS with CAPE (mPFS=14.8m) than with PALBO + ET (mPFS=5.73m) (HR=1.9, p-value=0.0418). Ph4 (N-/C+) had also significantly better PFS for CAPE (mPFS=22.67m) than for PALBO + ET (mPFS=8.51m) (HR=2.94; p-value=0.036). Conclusions: This study confirms Cyclin E as a poor prognostic marker associated with worse overall survival in luminal MBC patients. Low molecular weight Cyclin E, detected as Cytoplasmic Cyclin E, identifies luminal MBC that benefit more from CAPE than from PALBO + ET. The low molecular weight Cyclin E isoform appears to be a promising predictive biomarker for the benefit of CAPE and resistance to PALBO + ET treatments in this population. Clinical trial information: NCT02028507 .

Abstract P1-05-13: Clinical impact of whole-body magnetic resonance imaging on subsequent management in luminal/HER2-negative breast cancer patients

Abstract Background: Routine imaging can be inaccurate, especially in metastatic breast cancer (MBC) with bone-only disease or mainly bone disease. This analysis investigates how the use of whole-body magnetic resonance imaging (WB-MRI), in addition to routine computed tomography (CT) and bone scintigraphy (BS), can influence treatment decisions in patients with known MBC. Methods: In a prospective observational study, in our Institute, we performed WB-MRI as baseline and follow-up examination in addition to routine imaging (CT, BS) in luminal/HER2-negative BC patients with prevalence of bone disease potentially candidate to CDK 4/6 inhibitors. All examinations were interpreted by two experienced radiology specialists. Using the results of the examination, a multidisciplinary oncology committee (MOC) reported on the treatment strategy. A positive impact on clinical management was considered if the examination determined a modification in the treatment strategy compared to the MOC decision before WB-MRI. Results: Thirty consecutive luminal breast cancer patients in a metastatic setting at standard imaging were recruited. All these patients underwent CT and BS followed by WB-MRI study. At standard imaging, fourteen patients (46.7%) presented with bone-only disease, while eight patients (26.6%) did not show bone lesions. In 18 of 30 cases (60%) WB-MRI led to a modification of the therapeutic approach. Due to the detection of new metastatic lesions or progression of known metastatic sites, reported on WB-MRI alone, the therapeutic decision changed in 6 (20%) and 3 (10%) patients, respectively. In one patient (3%) the therapeutic decision changed because of both findings. Nine patients (30%) started a new therapeutic line due to evidence of progressive disease on WB-MRI, while 4 patients (13.3%) underwent radiotherapy and 1 patient received orthopaedic counselling for high risk WB-MRI-assessed bone lesions. In 8 patients (26.6%) the disease was re-classified as early breast cancer based on WB-MRI assessment. Conclusions: WB-MRI could play a role in the clinical assessment of luminal MBC. Further studies are needed to better address the potential use of WB-MRI in the assessment and monitoring of bone only/bone predominant luminal MBC and/or in equivocal cases. Citation Format: Filippo Merloni, Michela Palleschi, Alice Rossi, Andrea Prochowski Iamurri, Caterina Gianni, Samanta Sarti, Francesca Mannozzi, Federica Fiori, Giandomenico Di Menna, Lorenzo Cecconetto, Marianna Sirico, Chiara Casadei, Sara Bleve, Lorenzo Gasperoni, Roberto Casadei, Luca Tontini, Antonino Romeo, Domenico Barone, Ugo De Giorgi. Clinical impact of whole-body magnetic resonance imaging on subsequent management in luminal/HER2-negative breast cancer patients [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 P1-05-13.

Abstract P2-11-02: BIOMARKERS RELATED TO SURVIVAL BENEFIT IN THE TREATMENT OF METASTATIC LUMINAL BREAST CANCER (mBC) WITH CYCLIN 4/6 INHIBITORS (CDK 4/6i) PLUS ENDOCRINE THERAPY (ET)

Abstract Treatment with CDK4/6i plus ET is the standard treatment for mBC with a significantly better progression free survival (PFS) and a long treatment duration response, although there’s finally a progression. The expression of cyclin E and progesterone receptor had been related to survival, so analyzing of these potential biomarkers could help to select their effect in patients with a long treatment duration (&amp;gt; 20 months). We evaluate 68 mBC treated with CDK4/6I plus ET as a clinical practice in a single institution. Median age was 68 years, 27(39,7%) patients had de novo metastatic disease, 17 (25%) progressed during ET adjuvant, and 24 (35,3%) progressed after 5 years of ET. Forty-eight patients (70%) received CDK4/6I plus ET in first line and visceral disease was present in 40% of patients. The median expression by histoscore with immunohistochemistry of cyclin E (CycE) was 75,3 (4-97) and progesterone receptor (PR) 121. Median PFS was 16 months (8,3- 23,6) with 45 events, 25 months in patients treated in first line and 12 months in second line (p: 0,0001). We analyzed 59 patients who had already completed CDK4/6I plus ET or had achieved a PFS more than 20 months, 40 (69%) in first line and 18 (31%) in second line. We summarized the related of expression of PR, CycE and this combination with PFS more than 20 month. CONCLUSION: Treatment with CDK4/6i plus ET achieved long treatment duration in patients with low expression of cyclin E (OR 3,1 p:0,045), positive progesterone receptor (OR 3,89 p: 0023) and specially in patients with positive progesterone receptor and low expression of cyclin E (OR 7,22 p:0,016). Patients with negative progesterone receptor and high expression of cyclin E had a poor prognosis with a median disease-free survival of 6 months (2.8 – 9.2), so these patients required other treatment approaches to improve their outcomes. Table Citation Format: Serafin Morales Murillo, Ariadna Gasol Cudós, Noemí Tuset Der-Abrain, Izaskun Urdanibia, Alvaro Rodriguez Galindo, Ana Velasco Sánchez, Felip Vilardell Villellas, Douglas Sánchez Guzmán, Carles Canosa Morales, Jordi Melé Olivé, Laura Arbones Cid. BIOMARKERS RELATED TO SURVIVAL BENEFIT IN THE TREATMENT OF METASTATIC LUMINAL BREAST CANCER (mBC) WITH CYCLIN 4/6 INHIBITORS (CDK 4/6i) PLUS ENDOCRINE THERAPY (ET) [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 P2-11-02.

Abstract P6-05-27: FEASIBILITY, SAFETY AND EFFICACY OF A COMBINED SUPERVISED PHYSICAL EXERCISE AND NUTRITIONAL PROGRAM IN A SELECTED POPULATION OF LUMINAL METASTATIC BREAST CANCER PATIENTS: ONCARE-01 PILOT STUDY

Abstract Background: Supervised exercise programs (SEP) have demonstrated an improvement in quality of life (QoL), cardiovascular health, treatment tolerance and disease outcomes in early breast cancer patients. In metastatic breast cancer (MBC), previous data suggest SEP are safe but no impact on QoL and a low adherence to programs were shown. These studies included a heterogenous population in terms of type of treatments received, numbers of previous lines or comorbidities. From our perspective, MBC profile that could benefit most from SEP needs to be explored. Thus, we conducted a pilot study to assess adherence, safety and impact on QoL of a combined SEP and nutritional program (NP) in a selected population of MBC of patients treated with cyclin-dependent kinase 4/6 inhibitors (iCDK 4/6). Methods: This is a prospective, single center, single arm pilot study. SEP consisted in a 12-week intervention with twice a week in-person resistance exercise session. Patients also completed weekly aerobic exercise goals in self-managed sessions monitored with activity trackers. SEP was conducted by registered Physical Activity and Sports Science instructors that followed American College of Sports Medicine guidelines. In addition, participants had an initial nutritional assessment and personalized counselling by a qualified nutritionist. Adherence to treatment, biological variables and QoL assessments (FACIT-Fatigue and QLQ-C30 questionnaires) were collected at baseline (B) and week-12 (w12). Primary endpoint was global adherence (≥70% of attended sessions relative to scheduled sessions). Secondary endpoints included safety, changes in biological variables and QoL. Paired samples t-tests (Wilcoxon) were used to assess biological changes and QoL. Results: Patients (n=26) were recruited from October 2020 to November 2021. Median age was 47,5 years (45-55); 84,6% of patients were ECOG 0. 42,3% of patients were receiving Abemaciclib; 34,6% Ribociclib and 23,1% Palbociclib in first (73,1%) or second (26,9%) line treatment. Patients had bone (69,2%); visceral metastasis (57,7%) or both (30,8%). 2 patients did not start the intervention and additional 7 patients discontinued the program prematurely, the majority of them due to COVID-related concerns. Considering all patients who at least attended one session, global adherence was 66% (39-77,5%) and 45,8% of patients achieved an adherence of ≥ 70%. Patients reported an improvement in QoL [B global QLQ-C30 66,6 (50-75), w12 75 (66,6-83,3); p 0,0121] and fatigue [B FACIT-Fatigue 37 (30-44), w12 42 (38-48); p 0,0017]. Sit-to-stand repetitions in 30-second period also improved [(B 15 (12-17), 19 (15-23); p 0,0002]. Same benefits were seen in patients with adherence ≥ 70%. No statistically significant changes were seen in body fat or muscular composition and handgrip scores. Importantly, no safety issues related to study intervention were reported. Conclusions: Even though the study was conducted during COVID-19 pandemic, global adherence was 66%. For the first time in MBC, SEP and NP combined program demonstrated to be safe and improved QoL in patients with first or second line MBC treated with iCDK4/6. Further research is needed to identify strategies that improve QoL in MBC. Citation Format: Alfonso Cortés, Alejandro Riquelme, Gemma Ferrero, Federico Longo, Manuel Garví, Lisandro Lamas, Ángela Morales, Lidia García, Patricia Cortez-Castedo, Maria Gión, Cristina Saavedra, Noelia Martínez-Jáñez, María Fernández-Abad. FEASIBILITY, SAFETY AND EFFICACY OF A COMBINED SUPERVISED PHYSICAL EXERCISE AND NUTRITIONAL PROGRAM IN A SELECTED POPULATION OF LUMINAL METASTATIC BREAST CANCER PATIENTS: ONCARE-01 PILOT STUDY [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 P6-05-27.

Abstract P3-01-01: Unicentric experience with icdk4/6 in metastatic breast cancer

Abstract Currently, the standard of care for luminal metastatic breast cancer is the combination of cyclin inhibitors with hormone therapy. Palbociclib and Ribociclib have been approved for marketing since 2017 and Abemaciclib since 2019 in Spain. In our center we have experience with the three cdk 4/6 inhibitors in different lines of treatment and patient profiles. We gather in the present work the unicentric experience with the three icdk 4/6. We have collected a total of 152 patients treated with the different cyclin inhibitors, achieving median PFS of 32.1 months for Palbociclib, 28.6 months for Ribociclib and 18.4 months for Abemaciclib. Overall survival data is still immature. The context of the patient and the disease has a significant impact on the results, as well as the line of treatment used. The toxicity profile of the three drugs does not differ from what the registry trials describe, with neutropenia being the most common side effect. We also describe dose reductions produced by the three icdk4/6. Conclusions: This is a real-life study with experience in a single center with the three icdk4/6 currently marketed with a cohort of more than 150 patients. We present data that conform to what was reported by the clinical trials PALOMA, MONALEESA and MONARCH. The data will be updated on the date of the congress for its presentation. Citation Format: Fernando Henao, Esteban Nogales Fernández, Lourdes Sevilla Ortega, Ruben De Toro Salas, Natalia Palazón Carrión, Maria del Carmen Álamo de la Gala, Alberto Sanchez-Camacho Mejías, Maria Luisa Sanchez Leon, Luis de la Cruz-Merino. Unicentric experience with icdk4/6 in metastatic breast cancer [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 P3-01-01.

Real clinical practice patterns of palbociclib usage in Russian Federation

Introduction. Current treatment of metastatic luminal Her2-negative breast cancer includes combination of endocrine therapy (ET) with CDK4/6 inhibitors. This type of therapy demonstrated impressive efficacy over mono ET in early lines of treatment in phase III randomized clinical trials. Treatment patterns in real clinical practice (RCP) are of great interest. We represent the first available local data for all CDK 4/6 inhibitors in RCP in Russian Federation in accordance with the number of patients (pts).Aim. Analysis of the patterns of palbociclib administration in RCP.Materials and methods. One hundred and 5 pts from 12 regions of Russian Federation were included in this analysis and received palbociclib in combination with ET from 2017 to 2020. Median age was 57 years (29-75), 31/105 (29.5%) of pts were &lt; 50. De novo metastatic disease was observed in 16 (15.2%) pts, 89 pts progressed after radical treatment. Visceral metastases (mts) at palbociclib initiation had 61/105 (58.1%) of pts.Results. Only 22/105 (21%) of pts received palbociclib as 1st line treatment of metastatic disease. The majority of pts was treated with palbociclib in 2nd and 3rd lines (28.5% and 30.5% respectively). In 26/105 (24.8%) pts palbociclib was combined with aromatase inhibitors, in other cases - with fulvestrant. Median follow-up time was 6.5 (1.1-31.9) months, median progression free survival - 6.0 (1.0-28.0) months. Most common adverse events (AE) were leukopenia, neutropenia and thrombocytopenia. Only in 3 cases palbociclib was completely stopped due to toxicity.Conclusions. Our data indicates that there is a need to move palbociclib initiation in first two lines of treatment to get maximal improvement in survival and to increase its usage in young women.

Liver metastasis in estrogen receptor-positive HER 2-negative breast cancer. Ribociclib as prognosis-changing therapy

The life expectancy of patients with metastatic luminal HER 2-negative breast cancer has stagnated at the level of 40 months for many years. The introduction of CDK4/6 inhibitors into practice has changed the standards of therapy, providing not only a significant increase in the time without progression while maintaining a high quality of life, but also significantly increasing overall survival. The presence of liver metastases determines an extremely unfavorable prognosis, with GH+HER 2-mBC reducing life expectancy to a median of 21 months. Endocrine therapy combined with ribociclib significantly increased overall survival rates on average per year, reaching medians of 36.1 and 46.5 months, depending on the line of treatment. This publication is devoted to liver metastases in breast cancer, in particular in the luminal HER 2-negative subtype. Epidemiological aspects are considered, the possibilities of modern systemic therapy are evaluated. A clinical case of successful therapy with ribociclib in a young patient with liver damage is presented.

215 (PB-039) Poster - Characteristics of patients with metastatic luminal breast cancer (MLBC) and ESR1 polymorphism

Background: ESR1 genetic polymorphisms increase the likelihood of the early progress MLBC during the hormonal therapy (HT) with аromatase inhibitors (AI) on average in a third of MLBC patients. Identifying these patients is an expedient factor that facilitates predicting the effectiveness of HT with AI. However, there are no data on the correlation of patients’ clinical features and ESR1 polymorphisms..

Comparison of endocrine therapy and chemotherapy as different systemic treatment modes for metastatic luminal HER2-negative breast cancer patients -A retrospective study.

PurposeThe purpose of this study was to evaluate endocrine therapy and chemotherapy for first-line, maintenance, and second-line treatment of hormone receptor-positive HER-2-negative metastatic breast cancer (HR+HER-2-MBC) and the relationship between different treatment options and survival.Patients and methodsThe patients included in this study were all diagnosed with metastatic breast cancer (MBC) at Shandong Cancer Hospital from January 2013 to June 2017. Of the 951 patients with MBC, 307 patients with HR+HER-2-MBC were included in the analysis. The progression-free survival (PFS) and overall survival (OS) of the various treatment modes were evaluated using Kaplan–Meier analysis and the log-rank test. Because of the imbalance in data, we used the synthetic minority oversampling technique (SMOTE) algorithm to oversample the data to increase the balanced amount of data.ResultsThis retrospective study included 307 patients with HR+HER-2-MBC; 246 patients (80.13%) and 61 patients (19.87%) were treated with first-line chemotherapy and first-line endocrine therapy, respectively. First-line endocrine therapy was better than first-line chemotherapy in terms of PFS and OS. After adjusting for known prognostic factors, patients receiving first-line chemotherapy had poorer PFS and OS outcomes than patients receiving first-line endocrine therapy. In terms of maintenance treatment, the endocrine therapy-endocrine therapy maintenance mode achieved the best prognosis, followed by the chemotherapy-endocrine therapy maintenance mode and chemotherapy-chemotherapy maintenance mode, and the no-maintenance mode has resulted in the worst prognosis. In terms of first-line/second-line treatment, the endocrine therapy/endocrine therapy mode achieved the best prognosis, while the chemotherapy/chemotherapy mode resulted in the worst prognosis. The chemotherapy/endocrine therapy mode achieved a better prognosis than the endocrine therapy/chemotherapy mode. There were no significant differences in the KI-67 index (<15%/15-30%/≥30%) among the patients receiving first-line treatment modes, maintenance treatment modes, and first-line/second-line treatment modes. There was no statistical evidence in this study to support that the KI-67 index affected survival. However, in the first-line/second-line model, after SMOTE, we could see that KI-67 ≥ 30% had a poor prognosis.ConclusionsDifferent treatment modes for HR+HER-2-MBC were analyzed. Endocrine therapy achieved better PFS and OS outcomes than chemotherapy. Endocrine therapy should be the first choice for first-line, maintenance, and second-line treatment of HR+HER-2-MBC.

Alpelisib therapy: from theory to practice

Before the development and implementation of the first PI3K inhibitor (alpelisib), the presence of a mutation in the PIK3CA gene had only prognostic value: it determined the unfavorable course of luminal HER2-negative metastatic breast cancer (testing for mutations was not part of routine screening methods). Achievements in the treatment of HR+HER2- mBC are primarily associated with the use of CDK4/6 inhibitors, which allowed not only a significant increase in the median progression-free survival while maintaining high quality of life, but also significantly increased overall survival of patients with luminal HER2-negative metastatic breast cancer. However, subgroup analyses demonstrate that the presence of the PIK3CA mutation is an independent factor in decreasing progression-free time and overall survival, even in patients treated with CDK4/6 inhibitors. Mutations of the PIK3CA gene are diagnosed in 30-40% of luminal metastatic breast cancer patients, they are associated with an increased risk of relapse and disease progression, are associated with a significant reduction in survival rates and treatment effectiveness, and determine the development of primary and secondary resistance to endocrine therapy. Standard endocrine therapy with fulvestrant combined with alpelisib has significantly improved treatment outcomes in patients with HR+HER2-metastatic breast cancer with the PIK3CA mutation who previously received treatment for advanced disease or had progression during adjuvant therapy. This combination is now included in all major international guidelines and is a priority therapy option. Testing for PIK3CA mutations is the current diagnostic standard in luminal HER2-negative mBC. The review presents an update of the main clinical trials with alpelisib, treatment results from real clinical practice, and also considers aspects of use in pretreated patients with different medical history. The article outlines the main recommendations for the prevention and correction of adverse events, and presents our own experience of using alpelisib in a patient with a classic course of breast cancer with a PIK3CA mutation.

Utility of liquid biopsy for identifying emerging mutations (mut) and novel treatment options in luminal metastatic breast cancer (LMBC).

1061 Background: Molecular characterization of LMBC for the choice of therapy and inclusion in clinical trials is frequently performed in archival biopsies procured several years before. Emerging mut secondary to therapeutic pressure are hence frequently missed but could be detected by real-time analysis of circulating tumor DNA. Aim: 1) To assess the emergence of ERBB2 and other mut upon therapeutic pressure; 2) To compare the concordance of mut in tumor and plasma samples between patients (pts) with metachronous and synchronous sample acquisition. Methods: Pts with LMBC and available tumor biopsy and plasma samples were identified and divided in two groups: 1) Cohort 1 (metachronous) if the time between tissue and plasma acquisition was &gt; 3 months and systemic treatment was given between the sampling; 2) Cohort 2 (synchronous) if sampling occurred with &lt; 3 months interval in the absence of systemic treatment. Tumor and plasma were analyzed using MiSeq Amplicon-based NGS (custom panel of 60 cancer-related genes). The emergent mut in plasma in Cohort 1 and the concordance of ESCAT Tier I and II mut ( PIK3CA, AKT1, ERBB2, ESR1, PTEN) in both Cohorts were determined and correlated with clinical features. Results: 176 pts were included, 112 in Cohort 1 and 64 in Cohort 2. In Cohort 1, emerging mut in PIK3CA were identified in 5 cases (14% of total cases with PIK3CA mut), ESR1 in 22 cases (85% of cases with ESR1 mut) and PTEN in 3 cases (43% of cases with PTEN mut). No emerging ERBB2 or AKT1 mut were seen in plasma. In Cohort 1 ERBB2 mut were identified in 10 pts (8.9%), 5 both in plasma and tissue and 5 only in tissue. Concordance between tumor and plasma was 53% in Cohort 1 and 66% in Cohort 2 (95% CI of the difference -2% to 38%, P =.09). In Cohort 1, concordance was not associated with (neo)adjuvant treatment, number of lines for MBC, presence of visceral metastasis, location of biopsy (primary tumor or metastasis), interval between sampling (range 3.6 – 288 months) or type of systemic treatment before plasma sampling. In Cohort 2, higher concordance associated with shorter interval between primary diagnosis and sampling (p = 0.02). PI3KCA and ESR1 were the two genes most frequently altered in both cohorts. PI3KCA mut had the highest degree of concordance in both groups (70% in Cohort 1 and 76% in Cohort 2). Concordance for ESR1 mut was low in both cohorts (20% and 48%, respectively). Conclusions: A significant number of ESR1 mut emerged upon therapeutic pressure in LMBC. Plasma analysis could also detect the emergence of PIK3CA and PTEN, but not ERBB2 mut. The trend towards lower concordance between metachronous and synchronous tumor and plasma sampling is probably due to increased tumor heterogeneity and clonal diversity secondary to systemic treatment. Our findings confirm that liquid biopsies provide complementary information respect to tumor tissue that may be potentially useful for clinical decisions.