Chemotherapy For Metastatic Breast Cancer Research Articles

Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer.

Outcomes in patients with hormone receptor-positive metastatic breast cancer worsen after one or more lines of endocrine-based therapy. Trastuzumab deruxtecan has shown efficacy in patients with metastatic breast cancer with low expression of human epidermal growth factor receptor 2 (HER2) after previous chemotherapy. We conducted a phase 3, multicenter, open-label trial involving patients with hormone receptor-positive metastatic breast cancer with low HER2 expression (a score of 1+ or 2+ on immunohistochemical [IHC] analysis and negative results on in situ hybridization) or ultralow HER2 expression (IHC 0 with membrane staining) who had received one or more lines of endocrine-based therapy and no previous chemotherapy for metastatic breast cancer. Patients were randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival (according to blinded independent central review) among the patients with HER2-low disease. Secondary end points included progression-free survival among all the patients who had undergone randomization, overall survival, and safety. Of the 866 patients who underwent randomization, 713 had HER2-low disease, and 153 had HER2-ultralow disease. Among the patients with HER2-low disease, the median progression-free survival was 13.2 months (95% confidence interval [CI], 11.4 to 15.2) in the trastuzumab deruxtecan group and 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy group (hazard ratio for disease progression or death, 0.62; 95% CI, 0.51 to 0.74; P<0.001); the results were consistent in the exploratory HER2-ultralow population. Data for overall survival were immature. Adverse events of grade 3 or higher occurred in 52.8% of the patients in the trastuzumab deruxtecan group and in 44.4% of those in the chemotherapy group. Adjudicated interstitial lung disease or pneumonitis occurred in 49 patients (11.3%; three events were grade 5 in severity) and in 1 patient (0.2%; grade 2), respectively. Among patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer who had received one or more lines of endocrine-based therapy, treatment with trastuzumab deruxtecan resulted in longer progression-free survival than chemotherapy. No new safety signals were identified. (Funded by AstraZeneca and Daiichi Sankyo; DESTINY-Breast06 ClinicalTrials.gov number, NCT04494425.).

Cytotoxic and cytostatic activity of five new imidazotetrazine derivatives on breast cancer cell cultures MDAMB231, BT474, and MCF-7

Introduction: The work presents the results of the study of new imidazotetrazine derivatives to establish the possibility of using them as anticancer agents, including for chemotherapy of metastatic breast cancer. The relevance of the work is due to the wide spread of oncological diseases and high cancer mortality, which dictates the need to constantly obtain cell lines and improve cultivation protocols for testing new antitumor drugs. The goal of this study is to check the potential of five new imidazotetrazine derivatives to become new antitumor drugs, in the scope of studying their cytotoxic and cytostatic activities on breast cancer cell cultures. Materials and Methods: The culturing MCF-7, MDAMB231, BT474, and MCF-10a cells with determining cytotoxic and cytostatic activities of five new azolotetrazine derivatives are base methods used in this study. Results: For the MCF-7 culture, MCS of comparison drug temozolomide was equal to 2.44 and IC50 was 6.81 mM/L; for other cultures CTA indicators were worse. Imidazotetrazine 2 and imidazotetrazine 3 demonstrated CTA indicators lower than those of temozolomide. IC50 was not achieved, and the MCS value varied between 1.34 and 1.74. These two derivatives were classified as the compounds with an extremely low CTA. Imidazotetrazine 1 and iminothiotriazine 5 showed cytotoxic activity higher than that of the comparison drug and we classified these compounds as the ones with a moderate CTA. Finally, we found imidazotetrazine 4 with IC50 of 0.85 mM/L and CTA of 7.34 as a compound with a potentially strong anticancer effect for further investigation. The cytostatic activity of four of the five azoloazine derivatives studied was in a narrow range corresponding to the survival rate from 0.21 to 0.32, depending on the compound and cell culture. Against this background, imidazotetrazine 4 demonstrated a higher CSA, determined by the survival rate from 0.17 to 0.20. Conclusion: As a result of an in vitro study, we found that five new azolotriazine derivatives can be evaluated in the ascending order of these properties, as a combination of CTA+CSA in order imidazotetrazine 2, imidazotetrazine 3 &lt; temozolomide &lt; imidazotetrazine 1, iminothiotriazine 5 &lt; imidazotetrazine 4, although the CSA of all the studied compounds turned out to be high. Thus, 3-Cyclohexyl-4-oxoimidazo[5,1-d]-[1,2,3,5]tetrazine-8-N-piperidinyl-carboxamide (imidazotetrazine 4) is an unconditional leader in the tested series of new azoloazine derivatives and we recommend it for further preclinical trials.

HOPE: Harnessing olaparib, palbociclib, and endocrine therapy for BRCA1/2-associated HR+, HER2- metastatic breast cancer.

10616 Background: Thepoly (ADP-ribose) polymerase inhibitor olaparib yields superior progression-free survival, response rates and patient-reported outcomes compared with chemotherapy in patients with BRCA1- or BRCA2- ( BRCA1/2) associated metastatic breast cancer (MBC). Fulvestrant and palbociclib improve outcomes in patients with hormone receptor-positive (HR+) MBC. HOPE (NCT03685331) is a phase I trial to evaluate combination olaparib (O), fulvestrant (F), and palbociclib (P) in patients with BRCA1/2-associated HR+, HER2 negative MBC. Methods: A 3+3 dose escalation was used to assess safety and preliminary efficacy of O, F and P. Eligible participants (pts) had HR+ MBC, a germline (g) or somatic (s) mutation in BRCA1/2, measurable/evaluable disease, any/no prior endocrine therapy, and 0-2 prior lines of chemotherapy for MBC. Prior PARPi and CDK4/6i were permitted but not in combination. Palbociclib was added after a 28-day safety run-in (Cycle 0) of O + F alone. Fulvestrant dose was 500mg IM on day 1 of each 28-day cycle. Dose level 0 (DL0, starting level) was F, O 300mg orally BID continuously, P 75mg orally daily on days 1-21; DL-1 was F, O 250mg orally BID, P 75mg orally daily on days 1-21. The primary endpoint was MTD (adverse events (AEs) based on CTCAE v5.0). Dose limiting toxicity (DLT) period included Cycles 0 and 1. A 30% DLT rate was acceptable; 6 pts had to be treated at a dose for it to be declared MTD. RECIST v1.1 was used to evaluate response. Results: Eight treated pts (s BRCA1:1 ;g BRCA2:6; s BRCA2:1 ) had median (M) age 47; M 0 (0-2) prior lines of endocrine therapy and 0 (0-1) prior chemotherapies for MBC. Three pts each had received O, F, and CDK4/6i as part of their standard of care treatment before study. At DL0, 2/2 pts had DLT with persistent grade(G) 3 neutropenia. Among 6 pts treated at DL-1, none experienced DLT, but 3 pts missed doses of study treatment due to cytopenias (G3 neutropenia, G3 leukopenia, G3 thrombocytopenia) during the DLT period. Following the DLT period, 1 pt reduced O to 200mg orally daily and 1 discontinued P based on provider discretion due to cytopenias (G3 neutropenia, G3 thrombocytopenia). Grade 3 AEs occurring in &gt;1 pt related to study treatment were: neutrophil count decrease (G3/2, n=5/2); white blood cell decrease (G3/2/1, n=3/2/2); platelet count decrease (G3/2/1, n=2/0/1). Overall related AEs in &gt;50% of pts were anemia (n=7), fatigue (n=6) and nausea (n=5). Best responses were CR/PR/SD/PD in 1/1/5/1 pts. Conclusions: MTDof O, F and P (DL-1) was reached and demonstrated antitumor activity. Although no AEs meeting protocol-specified DLT criteria were observed at MTD, hematologic toxicity at this dose complicated drug delivery and required close monitoring during and after the DLT period. Combinations utilizing PARP1 selective inhibitors, lower doses of therapy or sequential rather than combination therapy may improve feasibility. Clinical trial information: NCT03685331 .

Dalpiciclib and chidamide in patients with HR+/HER2- advanced breast cancer and resistance to CDK4/6 inhibitors: A phase Ib trial.

e13072 Background: The combination of CDK4/6 inhibitors and endocrine therapy (ET) as first or second-line therapy could improve PFS and OS for patients with HR-positive/HER2-negative breast cancer. However, the standard treatment for patients who have failed CDK4/6 inhibitors has not been established. Histone deacetylase inhibitors (HDACi) inhibit the proliferation of tumor cells through a variety of ways, such as improving the expression level of p21 and other genes. In China, dalpiciclib (a CDK4/6 inhibitor) in combination with ET has been approved for patients with metastatic HR-positive/HER2-negative breast cancer. Chidamide (an HDAC inhibitor) has been approved for the treatment of metastatic HR-positive/HER2-negative breast cancer. The investigator's previous retrospective study has shown that chidamide combined with ET may be an optional sequential strategy for patients who have progressed on CDK4/6 Inhibitor. The aim of this study was to explore the efficacy and safety of dalpiciclib in combination with chidamide in locally advanced or metastatic HR+/HER2- breast cancer patients who have failed CDK4/6 inhibitors (NCT 05586841). Methods: This study is a single-arm, open-label, prospective, phase Ib, dose escalation clinical trial. Before entering this trial, all patients with HR-positive/HER2-negative locally recurrent or metastatic breast cancer (MBC) must have received ≤1 previous line of chemotherapy for MBC, and have failed CDK4/6 inhibitor therapy. The primary endpoint is maximum tolerated dose (MTD) of dalpiciclib in combination with chidamide. Patients were assigned to four groups to receive dalpiciclib and chidamide (Group A: dalpiciclib 125mg/d and chidamide 25mg/BIW; Group B: dalpiciclib 125mg/d and chidamide 20mg/BIW; Group C: dalpiciclib 100 mg/d and chidamide 25mg/BIW; Group D: dalpiciclib 100 mg/d and chidamide 20mg/BIW). Results: Fourteen patients were enrolled between 19/1/2023 and 30/1/2024 (Group A, N=4; Group B, N=3; Group C, N=4; Group D, N=3). All the patients were received ≥ 1 line CDK4/6 inhibitors and 11 patients (78.6%) received chemotherapy in advanced breast cancer. Two patients experienced dose-limiting toxicities (DLT, Group A, n=1; Group B, n=1). The incidence of adverse events of any grade was 100%. The most frequent grade 3-4 adverse events were neutropenia (100%) and thrombocytopenia (35.7%). The median follow-up was 251 days (range, 188.486-313.514), and median PFS was 201 days (95%CI: 158.49-243.51). 2 of 14 patients achieved partial response (PR; Group C, n=2), 10 of 14 patients achieved stable disease (SD) and 2 of 14 had progressive disease (PD; Group A, n=2). In this study, dose group C was identified as recommended phase II dose (RP2D). Conclusions: The combination of dalpiciclib and tucidinostat is an alternative treatment strategy in patients who have failed CDK4/6 inhibitors. Clinical trial information: NCT05586841 .

4CAST: A phase 1b dose exploration, open-label, single-center study evaluating the safety of INO-464 in combination with chemotherapy in patients with metastatic breast cancer.

e13112 Background: Metastatic triple negative breast cancer (TNBC) has a poor prognosis and the development of new targeted therapies is an area of unmet need. The androgen receptor (AR) antagonist, INO-464, but not abiraterone or enzalutamide, blocks chemotherapy induced cell plasticity to inhibit and primary and metastatic breast cancer (MBC) growth. Single agent INO-464 at a dose of 450mg/d is well tolerated but has low efficacy. Laboratory data demonstrates suppression of metastatic TNBC and an increase in survival with the combination of INO-464 and taxane chemotherapy. Methods: We designed a Phase 1b open-label, single center dose exploration (Part 1) and dose expansion (Part 2) clinical trial of INO-464 450mg/d with docetaxel (IV 75mg/m2 q3wkly) or nab-paclitaxel (IV 100mg/m2 D1/8/15 q4wkly) in any subtype of MBC. The primary objective was to assess the safety and tolerability of INO-464 (450mg/d) and docetaxel or nab-paclitaxel utilizing a rolling 6 design, as well as to determine the maximum tolerated dose (MTD) and the recommended dose of INO-464 to be given with a taxane in the dose expansion study. Secondary objectives included anti-tumor activity and testosterone levels. Results: Recruitment began in August 2022. The cut-off date for this analysis was 19 January 2024. Eight patients have been treated to date and 6 patients were DLT evaluable. All were women with MBC with mean age of 56 (range 48-64) years. Patients had received a median of 5 (range 2 to 7) lines of chemotherapy for MBC. Patient 001 had G3 anaphylaxis due to docetaxel that resolved with adrenaline but came off study and was not DLT evaluable. The protocol was amended to give INO-464 with 1mg of dexamethasone. No DLTs were subsequently observed. Adverse events (AEs) were mostly low grade and chemotherapy related although G2 pneumonitis occurred beyond the DLT period in two patients, one of whom had prior sacituzimab govotecan-related pneumonitis. INO-464-related AEs were G1 fatigue/headache in 4/6 patients. Seven of seven patients had a best response (RECIST1.1) SD, and CA15.3 stability was seen in 4/7 patients. Baseline serum testosterone was detectable in 4/6 patients (range 0.5-1.3 nmol/L, lower limit of detection of &lt;0.5), and remained undetectable or at the lower limit of detection throughout treatment. Conclusions: The MTD of INO-464 is 450mg daily with 0.5mg dexamethasone in combination with docetaxel or nab-paclitaxel chemotherapy. The combination is well tolerated with early efficacy signals. Dose expansion will test the combination in metastatic TNBC with nuclear AR positive breast cancer. Clinical trial information: NCT04947189 .

Abstract PO5-05-03: Phase 1/2 Dose Expansion Study Evaluating First-In-Class eIF4A Inhibitor Zotatifin in Patients with ER+ Metastatic Breast Cancer

Abstract Background Zotatifin (eFT226) is a first-in-class, potent and sequence selective inhibitor of RNA helicase eIF4A that promotes a stable mRNA:eIF4A:drug ternary complex at specific polypurine motifs present within the 5’-UTR of select transcripts, thereby blocking production of the encoded proteins. In preclinical models zotatifin treatment simultaneously down-regulated translation of numerous oncogenes including CDK4, ERα, ERBB2, KRAS, and CCND1. Previous clinical research has demonstrated the activity of zotatifin in combination with other agents in ER+ metastatic breast cancer (MBC). Methods Part 1 is a 3+3 dose escalation portion of the protocol followed by Part 2 as a Simon’s two-stage design in patients with ER+ MBC enrolled at the recommended phase 2 dose (RP2D) of zotatifin (0.07 mg/kg IV two weeks on/one week off) in combination with fulvestrant (ful) and abemaciclib (abema) (Z+F+A). Part 1a and Part 1b are 3+3 dose escalation portions evaluating zotatifin in combination with ful (Z+F) at QW IV and Q2W IV dosing schedules, respectively. Key eligibility criteria included at least one line of therapy for advanced/metastatic disease, progression on hormone therapy, and in addition, the Z+F cohorts required prior CDK 4/6 inhibitor (CDKi). Primary endpoint of Part 1a/1b was determination of RP2D and primary endpoint of part 2 was objective response rate (ORR) per RECIST v1.1. Additional endpoints included safety, progression-free survival (PFS) and other efficacy analyses, and characterization of pharmacodynamic (PD) markers and pharmacokinetics. Results As of a data cut-off of July 6, 2023, 20 pts were enrolled in the Z+F+A cohort and had a median of four prior metastatic lines of therapy. In 19 evaluable pts in Z+F+A cohort, there were four confirmed partial responses (PR), one unconfirmed PR, and 10 pts with best overall response (OR) of stable disease (SD). All pts with PR/unconfirmed PR received prior CDKI, ful, and chemotherapy for MBC. Confirmed PRs were observed in patients with and without mutations in ESR1 and PIK3CA. mPFS, while not yet mature, exceeds 20 weeks. In Z+F+A the most common adverse events (AEs) were diarrhea (80%, all grades (Gr)) and nausea (75%, all Gr 1/2) and the most common Gr 3/4 AE was diarrhea (15%). In Z+F cohorts of 0.07 mg/kg QW (n=3), 0.1 mg/kg Q2W (n=3), and 0.14 Q2W (n= 2) there were no dose-limiting toxicities or Gr 5 adverse events (AEs). There was one confirmed PR and one SD in 0.1 and 0.14 mg/kg Q2W cohorts, respectively, and no PR or SD in the 0.07 mg/kg QW cohort. In Z+F+A, 9 pts had paired pre- and on-treatment ctDNA analyzed by Guardant assay. Of the remaining 11 pts, 4 came off study prior to scheduled collection of the on-treatment sample and 5 had unavailable samples. Of the 9 patients with paired samples, 8 had ctDNA decreases of &amp;gt;50%, all of whom had SD or PR. In the Z+F Q2W cohort, 2 of 3 patients had ctDNA decreases &amp;gt;50%, one of whom had a PR. Reduction below the limit of detection was seen for mutant alleles in ESR1, PIK3CA and other genes with potential to confer resistance to endocrine therapy. Conclusion Z+F+A showed encouraging efficacy in heavily pretreated ER+ MBC patients, with results that compare favorably to other treatment options available after progression on CDKi plus endocrine treatment. Efficacy was seen independent of ESR1 or PIK3CA mutations, suggesting the potential to treat a broad, unrestricted patient population. Initial results with Z+F Q2W dosing are encouraging and support continued dose escalation of this regimen. Citation Format: Ezra Y. Rosen, Manish Sharma, David Berz, Jennifer Caswell-Jin, Georgina Fulgar, Mark Densel, Gary Chiang, Samuel Sperry, Douglas Warner, Funda Meric-Bernstam. Phase 1/2 Dose Expansion Study Evaluating First-In-Class eIF4A Inhibitor Zotatifin in Patients with ER+ Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-05-03.

Abstract PO5-01-01: The comparison of HER2 low and HER2 0 in ductal carcinoma in situ (DCIS) for breast cancer

Abstract Background: Trastuzumab deruxtecan is a standard of care after prior chemotherapy for metastatic breast cancer with HER2 low. HER2 low recognized as a new category of breast cancer. The definition of HER2 low is IHC 1+ or IHC 2+/ISH- in invasive ductal components. We have already reported the frequency and prognosis of HER2 positive and low in invasive cancer (Breast Cancer. 2022;29:234-241), but the distribution and characteristics of HER2 low in ductal carcinoma in situ (DCIS) is unknown. It is also well known that HER2 expression is higher in DCIS than in invasive cancer. We focused on the frequency of HER2 low in DCIS, performed an analysis of its frequency and characteristics, and compared to DCIS with HER2 0. Methods: We retrospectively examined breast cancer patients with DCIS and invasive ductal carcinoma (IDC) who underwent surgery at our institution between 2005 and 2015. Regarding the expression status of HER2, we classified cases into three groups: HER2 0, HER2-low (defined as IHC 1+ or IHC 2+/ISH-), and HER2-positive (IHC 2+/ISH+ or IHC 3+), and investigated their frequency. We analyzed the relationship between HER2 expression and Van Nuys classification, as well as the relationship between HER2 expression and ER expression, using the chi-square test. Results: A total of 726 DCIS patients were included in this analysis. The patient demographics showed a median age of 52 years (range: 20-84), with 413 patients (56.9%) undergoing total mastectomy and 311 patients (42.8%) undergoing breast-conserving surgery (two cases had unknown surgical procedures). The expression of HER2 in DCIS patients was observed as HER2-0, low and positive in 100 (13.8%), 474 (65.3%) and 152 patients (20.9%), respectively. The expression of HER2 in IDC was observed as HER2 0, low and positive in 838 (17.1%), 3169 patients (64.4%) and 911 patients (18.5%) (Table 1). DCIS tended to have higher HER2 expression(P=0.048). Then we compared the characteristics of HER2 0 and HER2 low in DCIS. Table 2 shows the relation between Van Nuys classification and HER2 expression. Van Nuys classification was evaluated in 346 cases. Van Nuy grade 3 accounted for 4.8% of the HER2 0 cases and 15.8% of the HER2 low cases. HER2 low cases tend to have higher grades(P &amp;lt; 0.01). Table 3 shows the relation between ER expression and HER2 expression. ER negative accounted for 5% of HER2 0 cases and 8.4% of HER2 low cases. ER negatives tended to be more common in Her2 low cases(P &amp;lt; 0.01). Conclusion: HER2 low is not considered a molecular biological classification, but rather a classification of the target of treatment for Trastuzumab deruxtecan. In our study, comparing HER2 0 and HER2 low, HER2 low tended to have higher grade and lower ER expression. Further investigation including basic research is needed to clarify the biological meaning of her2 low. Table1: The frequency of HER2 expression in DCIS and IDC Table2: The relationship between Van Nuys classification and HER2 expression Table3: The relationship between ER status and HER2 expression Citation Format: Nari Kureyama, Maho Kusudo, Akira Nakakami, Rie Komaki, Yuka Endo, Kazuki Nozawa, Ayumi Kataoka, Haruru Kotani, Akiyo Yoshimura, Masaya Hattori, Masataka Sawaki, Hiroji Iwata. The comparison of HER2 low and HER2 0 in ductal carcinoma in situ (DCIS) for 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 PO5-01-01.

Abstract PO1-15-10: Lower pre-treatment B-cell gene expression signatures correspond with improved overall survival with palbociclib + endocrine therapy in HR+/HER2- metastatic breast cancer: a biomarker analysis from the GEICAM/2013-02 PEARL trial

Abstract Introduction: CDK4/6 inhibitors (CDK4/6i) with endocrine therapy (ET) is standard-of-care for HR+/HER2- metastatic breast cancer (MBC), but little is known about which gene expression and microenvironment features are associated with benefit from CDK4/6i or differentiate response compared to chemotherapy. We examined the relationship of gene expression signatures (GES) to progression-free (PFS) and overall survival (OS) in the GEICAM/2013-02 PEARL phase III randomized study of palbociclib + ET vs. capecitabine in aromatase inhibitor-resistant HR+/HER2- MBC (NCT02028507). Methods: RNA sequencing (RNAseq) was performed on baseline tumor samples from 328 patients. Intrinsic subtype was derived by the PAM50 predictor after HER2/estrogen receptor subgroup-specific normalization. Correlations to intrinsic subtype signatures, PAM50 proliferation signature, CCNE1 expression, and 10 GES were selected for analysis. After excluding 15 Normal-like samples, Cox models were fitted for PFS and OS endpoints on each selected variable for the combined study population as well as for each treatment arm, adjusted for disease site, prior ET sensitivity, prior chemotherapy for MBC, number of involved sites, treatment arm, and intrinsic subtype. P-values were adjusted based on the Bonferroni method, with an adjusted p-value &amp;lt; 0.05 defined as significant. Results: PAM50 intrinsic subtype (54.95% Luminal A, 38.98% Luminal B and 6.07% non-luminal (4.79% Her2-enriched and 1.28% Basal-like)) was associated with worse PFS with palbociclib + ET for non-luminal vs. Luminal A tumors (HR 3.19, 95% CI 1.65-6.16) and for Luminal B vs. Luminal A tumors (HR 1.90, 95% CI 1.28-2.82). PAM50 luminal status (Luminal A vs. Luminal B vs. non-luminal) was significantly associated with PFS with palbociclib + ET (p=0.0003) but not capecitabine (p=0.89). In the palbociclib + ET arm, lower expression of two B-cell-associated signatures (BCAS) correlated with improved OS - the Immune1 TCGA BRCA GES (PMID: 32573490) (HR 1.52, 95% CI 1.20-1.92, p=0.009) and the B-cell/T-cell cooperativity GES (PMID: 31730857) (HR 1.42, 95% CI 1.14-1.79, p=0.04). Interaction analysis for OS showed that when stratified by low and high expression using the median, the Immune1 TCGA BRCA GES had a significant interaction with treatment arm (p=0.014). On comparison of outcomes between treatment arms, low Immune1 TCGA BRCA GES expression was significantly associated with improved OS with palbociclib + ET compared to capecitabine (HR 0.44, 95% CI 0.26-0.74, p=0.03), whereas high expression was not associated with a significant OS difference (HR 1.73, 95% CI 1.07-2.79, p=0.40). Further exploratory analysis of 164 immune GES found that, after adjustment for confounders, the top eight GES associated with OS with palbociclib + ET were BCAS (unadjusted p-values &amp;lt; 0.005), including our pre-selected Immune1 TCGA BRCA and B-cell/T-cell cooperativity GES, and all eight negatively correlated with OS. In the capecitabine arm, this exploratory analysis failed to demonstrate a similar association between the immune GES and OS. Conclusion: PAM50 intrinsic subtype was significantly associated with PFS with second-line palbociclib + ET. Lower expression of BCAS was associated with improved OS outcomes with palbociclib + ET independent of intrinsic subtype, and for the Immune1 TCGA BRCA GES, lower expression corresponded with improved OS with palbociclib + ET compared to capecitabine. This informs recent findings that in HR+/HER2- breast cancer, tumor immune activity may be a negative predictor of CDK4/6i benefit. Citation Format: Yash Agrawal, Aranzazu Fernandez-Martinez, Miguel Gil-Gil, Christoph Zielinski, Manuel Ruíz- Borrego, Eva Ciruelos, Montserrat Muñoz, Mireia Margelí, Begoña Bermejo, Antonio Antón, Zsuzsanna Kahan, Tibor Csöszi, José L Alonso-Romero, Jose Angel García-Sáenz, Pedro Sánchez-Rovira, Elena Álvarez, J. Ignacio Chacón, Santiago González-Santiago, César A Rodríguez, Sonia Servitja, Adam D. Pfefferle, Jesús Herranz, Yuan Liu, Lisa A. Carey, Isabel Romero - Camarero, Rosalía Caballero, Charles M. Perou, Miguel Martín. Lower pre-treatment B-cell gene expression signatures correspond with improved overall survival with palbociclib + endocrine therapy in HR+/HER2- metastatic breast cancer: a biomarker analysis from the GEICAM/2013-02 PEARL 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 PO1-15-10.

Abstract PS12-02: Exploration of ctDNA Dynamics in the PACE Trial: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for HR+/HER2- Metastatic Breast Cancer

Abstract Background The PACE trial for HR+/HER2- metastatic breast cancer (MBC) prospectively evaluated whether continuation of the CKD4/6 inhibitor (CDK4/6i) palbociclib (P) beyond progression on prior CDK4/6i and aromatase inhibitor (AI), with a change in endocrine therapy (ET) to fulvestrant (F), improved outcomes beyond change to F alone, as well as explored the activity of a palbociclib, fulvestrant, and avelumab (P+F+A) triplet. The primary analysis did not show improvement in progression-free survival (PFS) with F+P versus F alone. In this analysis, an evaluation of serial translational PACE samples was performed to gain insights into the mutational landscape of HR+/HER2- MBC after prolonged exposure to CDK4/6i, evaluate early mutational dynamics with ongoing therapy, and identify potential genetic markers predictive of treatment response. Additionally, the identification of acquired mutations at the time of tumor progression could provide valuable information about mechanisms of treatment resistance. Methods PACE is a multicenter randomized open-label investigator-initiated phase II trial. Eligible patients (pts) had HR+/HER2- evaluable MBC with prior progression on AI and any CDK4/6i after &amp;gt; 6 months (mo) of therapy in the MBC setting, or during/within 12 mo in the adjuvant setting, with no more than 1 prior line of chemotherapy for MBC. Pts were randomized 1:2:1 to F alone, F+P, or F+P+A, with tumor assessments every 8 weeks. Correlative samples including circulating tumor DNA (ctDNA) were collected at baseline (BL), times of tumor assessments (C3D1), and end of study/progression (EOT). Targeted NGS (Guardant360) to evaluate mutations (somatic single nucleotide variants and indels) was performed. Kaplan-Meier survival curves were used for assessing PFS and the log-rank test for comparisons. McNemar’s test with continuity correction was used to test the changes in the frequency of mutations. Results Of the 220 randomized pts, 211 contributed ctDNA samples (200 at BL, 129 at C3D1, 146 at EOT). Characteristics of the correlative science population were similar to the intention to treat population. At BL, the most common mutations observed were ESR1 (57%), TP53 (38%), PIK3CA (36%), GATA3 (20%) ATM (12%) and Rb1 (12%). The presence of a PIK3CA mutation vs WT-PIK3CA at BL was associated with shorter PFS in the F alone arm (p=0.001) but not in the F+P or F+P+A arms. ESR1 mutations present at baseline were D538G (34%), Y537S (21%), Y537N (15%), E380Q (10%) and L536H (4%). At C3D1, the most common mutations observed were ESR1 (47%), TP53 (33%), PIK3CA (26.1), GATA3 (18.1), ATM (13%) and PTEN (8.6%). Including only BL and C3D1 matched samples (N=124), the prevalence of ESR1 mutations decreased after 2 cycles of treatment (57% at BL vs 44% at C3D1), predominantly observed in the F+P+A arm. For those in any arm with at least 6 months of disease stability on study (N=53), the presence of an ESR1 D538G mutation decreased during therapy, with 38% having a mutation at BL, 24% at C3D1, and no pts gaining ESR1 D538G at C3D1. The prevalence of PIK3CA mutations also decreased on treatment (32% at BL to 24% at C3D1), with the greatest decrease in the F+P arm. A predictive model correlating early genomic dynamics and associations with outcome will be presented. Conclusions The PACE trial offers one of the largest clinical trial cohorts describing the genomic landscape of HR+/HER2- MBC post-CDK4/6 exposure. Results from this correlative study provide a comprehensive mutational landscape post-CDK4/6i, demonstrate associations between mutations and clinical outcomes, and suggest the potential value of early ctDNA dynamics in this setting. Citation Format: Rinath Jeselsohn, Jingxin Fu, Yue Ren, Reshma Mahtani, Cynthia Ma, Angela DeMichele, Massimo Cristofanilli, Jane Meisel, Kathy Miller, Yara Abdou, Elizabeth Riley, Rubina Qamar, Priyanka Sharma, Sonya Reid, Naomi Ko, Yuan Liu, Harold Burstein, Michelle DeMeo, Sara Tolaney, Erica Mayer. Exploration of ctDNA Dynamics in the PACE Trial: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for HR+/HER2- Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS12-02.

Abstract PO1-05-12: Pooled clinical trial data analyses comparing the biology of HER2-low vs HER2-0 breast cancer in patients with metastatic breast cancer following treatment with standard single agent chemotherapy

Abstract Background: Prior analyses of observational data suggest that for patients with metastatic breast cancer (MBC), tumor biology does not vary by HER2-low vs. HER2-0 expression given similar overall survival (OS) times after accounting for patients’ clinicopathologic features including hormone receptor (HR) status. We sought to evaluate potential differential biology by HER2-low status by (1) studying data pertaining to patients treated in historic clinical trials (i.e., data collected to measure associations between protocol defined treatments and outcomes) and (2) evaluating the endpoint of progression-free survival (PFS) in addition to OS following treatment with standard single agent chemotherapy for MBC. Methods: Pooling anonymized clinical trial data from studies within the Medidata Enterprise Data Store, we identified 142 women with HER2-negative MBC who received treatment with an NCCN recommended single agent chemotherapy in the context of a clinical trial. Using patient-level immunohistochemistry (IHC) results, we categorized patients as either HER2-low (IHC 1+/2+ and not amplified by in situ hybridization) or HER2-0 (IHC 0). We compared patients’ baseline demographic and clinicopathologic features according to HER2-low vs HER2-0 status. We used Cox proportional-hazard models stratified by HR status to estimate OS and PFS according to HER2-low vs HER2-0 classification while adjusting for patients' baseline demographic and clinicopathologic attributes. Results: Patients with HER2-low disease represented 20% (28/142) of the HER2-negative cohort. Twenty-five percent (7/28) of HER2-low patients had tumors that expressed hormone receptors compared with 17% (19/114) of HER2-0 patients (p=0.31). In this cohort, the maximum follow up time was 38.4 months. For HER2-low patients vs HER2-0 patients, the median OS was 10.7 vs. 12.7 months (p=0.37), and the median PFS was 3.5 vs. 2.9 months (log rank test, p=0.53) respectively. In Cox proportional-hazard models that adjusted for patient demographic and clinicopathologic features and were stratified by HR status, patients with HER2-low tumors had an 16% elevated (non-significant) hazard of death compared with patients with HER2-0 tumors (HR 1.16, 95% CI: 0.69-1.95) and a 22% reduced (non-significant) hazard of progression or death (HR 0.78, 95% CI: 0.45-1.35). Conclusions: Analyses of pooled historic clinical trial data pertaining to women with HER2-negative MBC who were treated with single agent chemotherapy revealed no meaningful clinical differences in either OS or PFS endpoints according to HER2-negative subtypes (i.e., HER2-low vs. HER2-0) after accounting for patient demographic and clinicopathologic features. These results support prior findings from observational research suggesting that there are no biological differences associated with HER2-negative subtypes. Table. Multivariable Cox Proportional Hazards Models for OS and PFS Stratified by Hormone Receptor Status, (N=134) Variable OS PFS HR* 95% CI HR* 95% CI Age (decade) 0.84 0.70-1.01 0.86 0.72-1.01 Race White 1.00 (referent) 1.00 (referent) Black 1.75 0.84-3.63 1.57 0.66-3.73 Asian 0.93 0.47-1.80 1.33 0.71-2.51 Other 1.69 0.45-6.38 2.10 0.62-7.15 Ethnicity Non-Hispanic or Latino 1.00 (referent) 1.00 (referent) Hispanic or Latino 2.10 0.95-4.64 1.02 0.44-2.35 HER2 Characterization HER2-0 1.00 (referent) 1.00 (referent) HER2-1+/2+ 1.16 0.69-1.95 0.78 0.45-1.35 Prior Lines of Chemotherapy for Metastatic Disease 0 1.00 (referent) 1.00 (referent) 1 0.82 0.46-1.46 1.13 0.65-1.95 2 0.69 0.35-1.36 1.00 0.52-1.93 3 0.59 0.10-3.42 2.18 0.45-10.50 ECOG Performance Status 0 1.00 (referent) 1.00 (referent) 1 1.65 1.07-2.54 1.57 1.02-2.43 Legend: OS=overall survival; PFS=progression-free survival; HR=hazard ratio; HER2=human epidermal group factor receptor 2; ECOG=Eastern Cooperative Oncology Group. *Analyses adjusted for clinical trial membership (coefficients not reported) Citation Format: Elizabeth Lamont, Emily Stein, Paolo Tarantino, Sara Tolaney, Corinne Ahlberg, Krishna Chinnathambu, Jiezhi Qi, Kala Tummagunta, Jackie Bilan, Ruthanna Davi, Lisa Ensign. Pooled clinical trial data analyses comparing the biology of HER2-low vs HER2-0 breast cancer in patients with metastatic breast cancer following treatment with standard single agent chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-12.

Recurrent severe hypocalcemia following chemotherapy regimen changes in advanced breast cancer: two case reports

BackgroundAs an oncologic emergency related to abnormalities in calcium metabolism, hypercalcemia associated with paraneoplastic syndrome and bone metastases is well known. Meanwhile, the incidence of hypocalcemia is low, except in cases associated with bone-modifying agents used for bone metastases. Hypocalcemia induced by bone-modifying agents typically occurs early after the initial administration, and its incidence can be significantly reduced by preventive administration of calcium and vitamin D3 supplements.Case reportWe report two cases of recurrent severe hypocalcemia occurring during chemotherapy for metastatic breast cancer with multiple bone metastases.Case 1: A 35-year-old Japanese woman developed metastases in the bone, liver, and ovaries during postoperative endocrine therapy for invasive lobular carcinoma of the breast. She underwent chemotherapy and treatment with denosumab. She experienced recurrent episodes of severe hypocalcemia subsequent to a change in the chemotherapy regimen. Case 2: A 65-year-old Japanese woman encountered multiple bone metastases after postoperative anti-human epidermal growth factor receptor 2 therapy and during endocrine therapy for invasive ductal carcinoma of the breast. She underwent anti-human epidermal growth factor receptor 2 therapy and treatment with denosumab. She experienced recurrent severe hypocalcemia subsequent to a change in the chemotherapy regimen to letrozole + lapatinib, trastuzumab emtansine, and lapatinib + capecitabine.ConclusionsWe observed two cases of recurrent severe hypocalcemia in patients with advanced breast cancer and bone metastases after modifications to their therapy regimens. These cases differed from the typical hypocalcemia induced by bone-modifying agents. It is possible that antitumor drugs affect calcium and bone metabolism associated with bone metastases. While these cases are rare, it is crucial for oncologists to be aware of hypocalcemia not only at the initiation of bone-modifying agents but also throughout the entire antitumor therapy, as hypocalcemia can lead to fatal outcomes.

Efficacy and safety of nanoparticle albumin-bound paclitaxel in taxane-pretreated metastatic breast cancer patients.

Taxanes are the basic components of breast cancer chemotherapy. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) shows improved antitumor effects because of more targeted delivery. However, the effects of nab-paclitaxel have not been systematically studied in patients with metastatic breast cancer (MBC) pretreated with taxanes. Considering the limited treatment options for MBC, this study retrospectively evaluated the clinical efficacy and adverse effects of nab-paclitaxel in patients with taxane-pretreated MBC. Patients who had previously received taxanes and subsequently received nab-paclitaxel chemotherapy for MBC at Jiangsu Cancer Hospital between October 2014 and April 2022 were included for analysis. The primary end point was progression-free survival (PFS), and the secondary end points were the objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and side effects. A total of 236 female patients with MBC were included. The median PFS was 7.20months (95% confidence interval [CI], 6.63-7.80months), and the ORR, DCR, and CBR were 29.55% (95% CI, 23.50%-35.60%), 83.64% (95% CI, 78.70%-88.60%), and 56.36% (95% CI, 49.80%-63.00%), respectively. Following nab-paclitaxel treatment, the median PFS of patients who were sensitive to taxanes during previous treatments was significantly longer than that of patients who were resistant to taxanes (7.57months vs. 4.43months, p<.001). The most common adverse events were sensory neuropathy (89.83%), neutropenia (48.73%), leukopenia (46.61%), and anemia (35.59%). Nab-paclitaxel demonstrated clinical activity in taxane-pretreated patients with MBC. This beneficial effect was observed both in patients who were sensitive and resistant to taxanes during previous treatments. These results suggest nab-paclitaxel as the preferred chemotherapy regimen in patients with MBC, regardless of their sensitivity to taxanes during previous treatments.

D-dimer as a Predictive Biomarker of Response to Chemotherapy in Patients With Metastatic Breast Cancer.

Tumor-induced coagulation is widely observed in cancer patients. Moreover, it is associated with tumorigenesis, tumor progression and metastasis, by creating a proliferative and proangiogenic microenvironment. Therefore, D-dimer, a fibrin degradation product, correlates with tumor prognosis in several cancer types. This study aims to investigate whether D-dimer levels can be a predictive and monitoring indicator for chemotherapy response in metastatic breast cancer (MBC) patients. This was a prospective study. This study included two groups, 76 patients diagnosed with metastatic breast carcinoma and 25 patients with primary breast carcinoma. Plasma D-dimer levels were measured prospectively before chemotherapy initiation, and after the fourth treatment cycle in MBC patients. D-dimer levels before chemotherapy (D0) were analyzed using Receiver Operating Characteristic (ROC) curves to determine the optimal cut-off baseline values of D0, and to evaluate their discriminatory abilities in predicting response to chemotherapy. In the preliminary response evaluation, the mean level of D-dimer significantly decreased by 0.65 μg/ml in patients with partial response patterns, and by 0.5 μg/ml in patients with stable disease. In the disease progression group, a marked increase was seen in D-dimer levels by 1.2 μg/ml. Analysis of ROC curves showed that D-dimer levels at D0 could discriminate the response to chemotherapy, whereas progressive disease rate correlated with higher levels of D-dimer. D-dimer level in plasma is a useful predictive and monitoring marker of response to chemotherapy in metastatic breast cancer.

A Cohort Study of the Antitumor Efficacy and Toxicity Profile of Alpelisib for Metastatic or Locally Advanced HR+, HER2− Breast Cancer: A Single-Institution Experience

Introduction: Alpelisib is approved in combination with endocrine therapy (ET) to treat patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) progressive metastatic breast cancer (MBC). The SOLAR-1 trial demonstrated the efficacy of this oral agent and showed that, while alpelisib improves outcomes compared to placebo, it is also associated with clinically relevant adverse events (AEs). There is a pressing need for improved knowledge on the effectiveness and tolerability of this agent in real-world patient populations. Methods: We conducted a retrospective cohort study of patients with HR+, HER2− MBC treated with alpelisib and ET. We assessed the safety, tolerability, and effectiveness of alpelisib in a real-world population. Deidentified patient-, tumor-, and outcome-related data, including AEs, were collected and summarized. Kaplan-Meier methods were applied for survival analyses, and stratified analyses of interest were conducted. A p value <0.05 was considered statistically significant. Results: A total of 76 women treated with alpelisib + ET were included in our cohort. Most had been previously treated with cyclin-dependent kinase (CDK) 4/6 inhibitors and chemotherapy for MBC. The estimated median progression-free survival was 5.2 months (95% CI, 4.1–8.0). The median overall survival was longer among patients without prior everolimus therapy (hazard ratio, 4.28 [95% CI, 1.64–11.16]; p = 0.0012), and no significant outcome differences were observed between patients treated with different starting doses of alpelisib. Approximately 31.6% of patients permanently discontinued alpelisib due to AEs, and 32.9% had at least one dose reduction. The most common grade 3/4 AEs were hyperglycemia (21%), fatigue (13.2%), and diarrhea (10.5%). Conclusions: For progressive HR+, HER2− MBC, alpelisib + ET showed effectiveness in a real-world patient population that was comparable to published clinical trial data, regardless of starting dose. However, the effectiveness of alpelisib following previous everolimus exposure may be limited and, hence, should be a consideration to decide sequencing of therapy in these patients. Patients treated with alpelisib are at risk for clinically relevant AEs and require close monitoring.

P45-5 A case report of pneumothorax after treatment with bevacizumab-containing chemotherapy for metastatic breast cancer

P45-5 A case report of pneumothorax after treatment with bevacizumab-containing chemotherapy for metastatic breast cancer

Phase II study of apatinib plus exemestane in estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer

ABSTRACT Purpose Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR)-2. This study was conducted to assess the efficacy and safety of apatinib combined with exemestane in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Methods This single-center, single-arm phase II study enrolled patients with ER+/HER2- MBC progressed on previous letrozole or anastrozole. Stratified analysis was performed according to the number of chemotherapy regimens for metastatic disease. The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS) and toxicity. Patients received apatinib at a starting dose of 500 mg/d and exemestane 25 mg/d on days 1–28 of each 4-week cycle. Results Thirty patients were enrolled with median four prior anticancer therapies. Eighty percent of patients received chemotherapy for metastatic disease. The median PFS (mPFS) and OS were 5.6 (95%CI: 4.3–6.9) months and 15.7 (95% CI: 9.7–21.7) months, respectively. The ORR, DCR, and CBR were 21.4%, 71.4%, and 46.4%, respectively. Patients with 0–1 line chemotherapy for MBC showed a slightly longer mPFS compared to those with ≥2 lines chemotherapy (mPFS: 6.4 months vs 4.8 months, P = .090). Most of the AEs were grade 1/2. One patient (3.3%) who suffered bone marrow metastases experienced grade 4 thrombocytopenia, and 14 experienced grade 3 AEs. Fifty percent of patients were given reduced dose for apatinib. Conclusions Apatinib plus exemestane exhibited objective efficacy in patients with ER+/HER2- MBC who have failed multiple lines of treatment. The AEs of apatinib required close monitoring and most of patients were well tolerated.

412P Sacituzumab govitecan versus chemotherapy for metastatic breast cancer: A meta-analysis on safety outcomes

412P Sacituzumab govitecan versus chemotherapy for metastatic breast cancer: A meta-analysis on safety outcomes

Cost-effectiveness of extended DPYD testing before fluoropyrimidine chemotherapy in metastatic breast cancer in the UK.

The aim of this study was to evaluate the cost-effectiveness of ToxNav©, a multivariant genetic test, to screen for DPYD followed by personalized chemotherapy dosing for metastatic breast cancer in the UK compared with no testing followed by standard dose, standard of care. In the main analysis, ToxNav© was dominant over standard of care, producing 0.19 additional quality-adjusted life yearsand savings of £78,000 per patient over a lifetime. The mean additional quality-adjusted life years per person from 1000 simulations was 0.23savings(95% CI: 0.22-0.24) at £99,000 (95% CI: £95-102,000). Varying input parameters independently by range of 20% was unlikely to change the results in the main analysis. The probabilistic sensitivity analysis showed ~97% probability of the ToxNav©strategy to be dominant.

D-dimer as a predictive biomarker of response to chemotherapy in patients with metastatic breast cancer.

e13000 Background: Tumor-induced coagulation is considerably observed in cancer patients. Moreover, it is associated with tumorigenesis, tumor progression, and metastasis, by creating a proliferative and proangiogenic microenvironment. Therefore, D-dimer, a fibrin degradation product, correlates with tumor prognosis in several cancer types. This study aims to investigate whether D-dimer levels can be a predictive and monitoring indicator for chemotherapy response in metastatic breast cancer (MBC) patients. Methods: This study included two groups, 76 patients diagnosed with metastatic breast carcinoma, and 25 with early breast carcinoma as a control group. Plasma D-dimer levels were measured prospectively before chemotherapy initiation, and after the fourth treatment cycle in MBC patients. The levels of D-dimer before chemotherapy (D0) were analyzed using receiver operating characteristic (ROC) curves to determine the optimal cutoff baseline values of D0, and to evaluate their discriminatory abilities in predicting response to chemotherapy. Results: In the preliminary response evaluation, the mean level of D-dimer significantly decreased by 2.74 μg/ml in patients with partial response, and by 2.17 μg/ml in patients with stable disease. In the progression disease group, a considerable increase was seen in D-dimer levels by 2.16 μg/ml. Analysis of ROC curves showed that D-dimer levels at D0 could discriminate the response to chemotherapy, whereas the progressive disease rate correlated with higher levels of D-dimer (&gt;1.055 μg/ml; P= 0.000). Conclusions: D-dimer level in plasma is a useful predictive and monitoring marker of response to chemotherapy in metastatic breast cancer.

The efficacy of metformin as adjuvant to chemotherapy on IGF levels in non-diabetic female patients with progressive and non-progressive metastatic breast cancer.

Some studies have shown that metformin inhibits the proliferation of breast cancer (BC) cells via multiple ways. One of these mechanisms is through the indirect control of the IGF-route mediated via the activation of the AMPK-LKB1 pathway in the liver, which leads to a decrease in blood glucose and insulin levels. The objective of this study was to investigate the effects of metformin as adjuvant to chemotherapy on IGF levels in female patients with progressive and non-progressive metastatic BC. In this trial, 107 women receiving chemotherapy for metastatic breast cancer (MBC) were divided into two groups: the metformin group received 500 mg of metformin twice daily, whereas the control group did not receive any metformin. All patients received chemotherapy according to the South Egypt Cancer Institute's (SECI) established regimen. The level of IGF-1 was determined in the blood at the initiation of therapy (baseline) and at six months post treatment. No substantial differences were noted regarding IGF-1 levels in both groups at baseline (IGF-1 average level was 40.74 ± 36.16 vs. 32.06 ± 20.00 in the metformin and the placebo group, respectively, p = 0.462). While after six months, the mean IGF-1 level was 37.62 ± 31.35 vs. 39.12 ± 2 5.93 in the metformin and placebo groups, respectively, (p = 0.170). Metformin as an adjuvant to chemotherapy in MBC patients had no significant effect on reducing IGF-l levels which promotes the inhibition of the proliferation of BC cells in MBC patients.