Ribociclib-Induced Hepatitis: A Case Report of Possible Autoimmune Hepatotoxicity

Corticosteroids.

Sir, Chronic urticaria (CU) is a common dermatological disorder characterized by pruritus and weals with or without angioedema. More than 50 million patients are affected globally by CU.[1] Coronavirus disease 2019 (COVID-19) continues to be a threat even today, disrupting the healthcare systems and patient care. Patients with CU are also affected by the variable durations of lockdowns, social distancing measures, and travel restrictions. CU may be severe at times, requiring immediate medical care. However, usual patients of CU can be managed through teledermatology effectively. Teledermatology is a way of communication where personal information such as age, gender, medical history, and images of the skin lesions are shared by a patient to a physician. It can have real-time online consultation (synchronous) with a physician or can undertake sharing personal information through E-mails and messaging platforms (store-and forward technique, asynchronous), which is the most widely used method. Teledermatology can also be hybrid where both asynchronous and synchronous can be combined.[2] A multicenter study by Kocatürk et al.[1] which shared the experiences of Urticaria centers of Reference and Excellence (UCAREs) during this pandemic in managing CU found that there was a significant decrease in the face-to-face consultations during the pandemic due to obvious reasons and simultaneous increase in the teleconsultations by 600%. They have also mentioned that remote consultations have been a useful tool during the COVID-19 pandemic, but the long-term consequences of remote care of CU patients are yet to be characterized. There have been a few studies regarding the long-term outcomes of telehealth especially for allergy consultations. Waibel[3] found that both new and follow-up visits to the allergist were well complied by patients and demonstrated significant monetary savings. In another multicenter study by Waibel et al.,[4] tele-allergy supported most of the patients without in-person consultation with high patient satisfaction and significant time and cost savings. We have been interviewing and providing consultations to CU patients during the pandemic. Most of the old patients under follow-up are satisfied by the teledermatology. However, new-onset urticaria with fever needs attention and face-to-face consultation in lieu of early manifestation of COVID-19. CU patients do not require vigorous mucocutaneous examinations to be performed at every visit in face-to-face consultations. Patient’s disease exacerbations or control can be objectively calculated through the valid Urticaria Activity Scores over 7 days and Urticaria Control Test, which can well be filled and discussed through telephonic consultations or Internet and communication technologies (ICTs). Moreover, antihistamines dosages can also be titrated in CU patients with disease exacerbations or remissions through teledermatology and may alleviate the need to visit the centers amidst the pandemic. Patients have been treating using teledermatology with updosing of antihistamines or short course of corticosteroids to control CU. A recent study during the COVID-19 pandemic by Thomas et al.[5] which was performed in a tertiary allergy center with 23.2% of urticaria/angioedema referrals found that teleconsultation-based allergy service models may be more time and cost-effective and also improve patient accessibility to a specialized care. None of the studies during the literature search demonstrated any counter to remote consultation of urticaria/angioedema during the pandemic. It is also recommended to maintain the ongoing treatments with antihistamines and omalizumab during the present pandemic, but to be cautious with the use of immunosuppressives for CU.[1] This can well be monitored through teledermatology. However, in a resistant-CU patient, short courses of low-dose oral corticosteroids and cyclosporine may be utilized for disease control. Treating dermatologists or allergists should be cautious and should not forbid their use. Recalcitrant or refractory CU in the COVID-19 pandemic may be treated with short courses of corticosteroids and cyclosporine as there are reports of improved clinical outcomes with cyclosporine and low-dose corticosteroids treatment in patients with moderate-to-severe COVID-19.[6] The experience with teleconsultation or ICTs has been satisfactory as per various studies. Moreover, in our experience also, it provided a great relief and satisfaction to the urticaria patients especially who required tailoring of dosages and counseling regularly. Monitoring patients with CU on treatment may be well managed by teledermatology as there is no requirement of repeated clinical examination in already-established cases of CU. Validated scores and questionnaires are sufficient to assess the disease severity or disease control in CU patients and can be obtained through teleconsultation or ICTs. Non-face-to-face consultations during COVID-19 in CU patients may be more time saving and cost effective; moreover, it may also significantly decrease the chances of contracting severe acute respiratory syndrome-coronavirus-2 infection. However, face-to-face consultations may not be replaced fully by teleconsultations using ICTs, but it may be an effective alternative during the present pandemic. Further, large and long-term studies are required in future to provide much improved and validated results. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Introduction According to Globocan 2022, breast cancer ranks number one among the cancers worldwide. South Asian women have a higher incidence comparedto Westerners. Estrogen receptor (ER) and progesterone receptor (PR) positive tumors, termed hormonal receptor-positive tumors, account for most breast cancer presentations. In India, advanced-stage presentations are more common. In metastatic hormone receptor-positive breast cancer, hormonal therapy combined with cyclin-dependent kinase (CDK) 4/6 inhibitors is the standard treatment. Aim This study aimed to analyze the experience with generic palbociclib provided under the Government Health Scheme for metastatic hormone receptor-positive breast cancer at our institution. Methods This retrospective study was conducted on breast cancer patients admitted to a tertiary carecenter in South India. The data of ER and PR receptor-positive metastatic breast cancer patients who received palbociclib were identified and reviewed using medical records from 2023 to 2024. Results A total of 238 patients were analyzed, of which41 received palbociclib for hormone receptor-positive metastatic breast cancer. The median age was 49 (33-75), with 53.5% (22) of women above 50. Denovo stage IV presentation was observed in 21patients (51.2%), while progression to stage IV disease was noted in 11 patients (26.8%), and stages II and IIIwere noted in nine patients (22%). Invasive ductal carcinoma was the most common histology. All patients were ER-positive, and 38 (92.7%) were PR-positive. About 17 patients (41.5%) had visceral metastasis, and 12 (29.3%) had bone-only metastasis. Local recurrence was seen in six patients (14.6%), and bone with visceral metastasis was seen in another six patients (14.6%). Progression within one year of hormonal therapy initiation was observed in 50% (10) of patients. Among 21 patients with upfront metastasis, nine were treated with prior chemotherapy. All patients were given 125 mg of oral palbociclib. Fatigue was the most common side effect in 34.1% (14), followed by myalgia in 21.9% (9), low hemoglobin levels of less than 8 g/dl in 14.6% (6), and nausea and vomiting in only 9.8% (4) of patients. Conclusion Hormone therapy combined with CDK4/6 inhibitors is the backbone of treatment for metastatic hormone-positive breast cancer. However, in developing countries like India, where most patients come from rural areas, using innovator palbociclib may not be feasible for many. With the availability of generic palbociclib under the Government Health Scheme, patients of metastatic hormone receptor-positive breast cancer will receive the protocol-based treatment.

Background: The gut microbiome modulates response and resistance to immune checkpoint inhibitors (ICI) across different cancer types. The objective of this study was to explore the association between fecal microbiome profiles and clinical outcomes in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC) treated with eribulin (E) + pembrolizumab (P) or E alone as part of a randomized phase II study (NCT03051659). Patients and Methods: Metagenomic shotgun sequencing was performed on fecal samples collected prior to randomization from a subset of 26 participating patients (E+P, n = 15; E, n = 11) collected prior to randomization. Sequencing data were processed with MetaPhlAn3 to obtain diversity scores and taxonomic composition profiles. Associations between microbiome diversity, taxonomic composition, and clinical outcomes including survival metrics were assessed using Kaplan-Meier estimation methods and Cox proportional hazard models. Results: In this subset, median follow-up was 21.6 months and median overall survival (OS) was 17.9 months. OS was not statistically significant between two treatment arms as observed in the overall cohort. Metagenomic microbiome analysis revealed higher alpha diversity by inverse Simpson Index values associated with longer survival among all patients (p = 0.004), and in patients in the E + P arm (p = 0.006) but not in the E arm (p = 0.2). At the taxonomic level, longer OS among all patients was associated with a baseline lower relative abundance of Blautia wexlerae (≤0.2%vs >0.2%) (22.1 vs 16.6 months; p = 0.01) and a higher relative abundance of Odoribacter splanchnicus, a common short-chain fatty acid producing gut bacterium (>0.35% vs ≤0.35%) (22.3 vs 11.3 months; p < 0.0001). These associations remained significant after controlling for age, ECOG-PS status, and use or not of prior lines of chemotherapy in the metastatic setting. Conclusions: These results suggest high diversity and composition of the gut microbiome are associated with prolonged OS in HR+ MBC pts receiving eribulin with pembrolizumab. Additional and larger clinical studies are needed to validate these findings and preclinical models are needed to interrogate the mechanisms by which gut microbiome diversity and composition may impact therapeutic response and clinical outcomes in this patient population. Citation Format: Romualdo Barroso-Sousa, Tianyu Li, Ashish V. Damania, Molly K. DiLullo, Tanya Keenan, Gerburg M. Wulf, Laura M. Spring, Elizabeth A. Mittendorf, Jennifer A. Ligibel, Nadim J. Ajami, Jennifer Wargo, Nabihah Tayob, Sara Tolaney. PD11-05 Gut microbiome signatures correlate with overall survival among patients receiving eribulin with or without pembrolizumab for hormone receptor-positive 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 PD11-05.

Background: Hormone-receptor (HR) positive breast cancer is the main subtype of breast cancer. Although overall survival of HR-positive metastatic breast cancer (MBC) patients has improved by various therapies including endocrine therapies, CDK4/6 inhibitors, and cytotoxic chemotherapy, it is still considered incurable. Immune checkpoint inhibitors have rarely been clinically tested in HR-positive breast cancer, despite proving anti-cancer activity in early and metastatic triple-negative breast cancer in various trials. We evaluated efficacy and safety of combined durvalumab and tremelimumab in the HR-positive MBC, which was enriched with high tumor mutational burden (TMB). Methods: HR-positive MBC patients who received prior 1 or more lines of therapy in metastatic setting were prescreened with whole exome sequencing (WES) using metastatic or recurred tumor biopsies. Criterion of high TMB was defined as upper 30%. In the beginning, the criterion of high TMB was 2.1 mutations per Mb, based on the retrospective WES database in Yonsei Cancer Center and this criterion was recalculated every 30 cases. Patients who met upper 30% of TMB were treated with combined durvalumab (1500mg every 4 weeks upto 13 doses) and tremelimumab (75mg every 4 weeks upto 4 doses). Response was evaluated every 2 cycles using RECIST 1.1 and toxicity was evaluated using NCI-CTCAE 4.03. Tumor-infiltrating lymphocyte (TIL) and PD-L1 expression were also analyzed to investigate a correlation with TMB. Results: Biopsies of recurrent or metastatic tumors were taken from a total of 119 patients for WES assay. A median turn-around-time of TMB data was 30.0 days (range, 16~67). Of these 119 patients, a median number of nonsynonymous mutations was 2.0 per Mb (range, 0~21.7) with upper 30% criterion of 3.1. High TMB showed a trend toward old age (P=0.074) and single positivity of estrogen receptor (ER) or progesterone receptor (PR) compared to positivity of both ER and PR (P=0.055). TMB was positively correlated with TILs (r=0.289, P=0.005). Thirty patients with high TMB received study treatment with a median 2 cycles (range, 1~13). A median prior lines of therapies in metastatic setting was 4 (range, 1~9). The objective response and clinical benefit rates were 6.3% (2 PRs of 30) and 20% (2 PRs plus 4 SDs of 30). There was one treatment-related mortality due to pneumonitis. Immune-related adverse events included endocrinopathy (n=3; hypothyroidism in 2, hyperthyroidism in 1), enteritis (n=2), skin rash (n=2), pneumonitis (n=1), and so on. Biomarker analyses are underway. Conclusions: WES-based TMB using metastatic tumor biopsy was a feasible platform to prescreen HR-positive MBC patients. Combined durvalumab and tremelimumab showed a modest activity and good tolerability in heavily treated, HR-positive MBC with high TMB. Citation Format: Yong Wha Moon, Eunyoung Kim, Min Hwan Kim, Gun Min Kim, Seul-Gi Kim, YeeSoo Chae, Jieun Lee, Jae Ho Jeong, Kyung-Hun Lee, Han Jo Kim, Joo Young Jung, Su-Jin Koh, Kyoung Eun Lee, Hee-Jun Kim, Kyong Hwa Park, Seungtaek Lim, Yeon Hee Park, Tae Hoen Kim, Sewha Kim, Yohan Yang, Sangwoo Kim, Joohyuk Sohn. Phase II trial of durvalumab and tremelimumab in the hormone receptor-positive metastatic breast cancer with high tumor mutational burden selected by whole exome sequencing: Korean cancer study group trial (KCSG BR17-04) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-19-03.

Background: Letrozole (LET) and trastuzumab (TRA) are established agents for the treatment of hormone-receptor (HR) positive metastatic breast cancer (MBC) patients and HER2 positive disease, respectively. The “eLEcTRA” trial was designed to compare the efficacy and safety of LET combined with TRA to LET alone in patients that are both HER2 and HR positive. Furthermore, LET alone was compared in patients with HER2 and HR positive disease vs. those with HER2 negative, HR positive tumors.Methods: In this multicenter trial, 92 pts from 32 sites in 7 countries were enrolled from 2003 to 2007. Initially, enrollment of 370 pts was planned, however, due to slow recruitment the trial was prematurely closed in 2007. Patients with HER2 and HR positive MBC were randomized to either LET alone (Arm A, n=31) or LET + TRA (Arm B, n=26) as first-line treatment. In addition, 35 patients with HER2 negative and HR positive tumors were assigned to receive LET alone as first-line treatment (Arm C). Tumor response assessments were based on RECIST. Primary endpoint was time to progression (TTP), secondary endpoints were overall response rate (ORR) and clinical benefit rate (CBR).Results: Median age in the three arms was 61 (arm A), 61,5 (arm B), and 70 years (arm C), respectively. Median TTP in the LET alone arm (A) was 3.3 months compared to 14.1 months in the LET + TRA combination arm (B) (hazard ratio=0.67; p=0.23) and 15.2 months in arm C (hazard ratio=0.71; p=0.03). CBR was 39% for arm A compared to 65% in arm B (odds ratio 3.15, CI 1.07-9.26) and 77% in arm C (odds ratio 5.34, CI 1.83-15.58), respectively. ORRs were 13% for arm A, 27% for arm B, and 11% for arm C.LVEF as cardiac safety parameter showed no change from baseline to the minimum value during the treatment for arms A and C and a slight decrease by 5% for arm B.The incidence of other cardiac adverse events was comparable in all arms (10%, 8%, and 9%). Gastrointestinal disorders or musculoskeletal and connective tissue disorders were slightly more frequent for patients receiving LET and TRA (arm B).Conclusion: The results of the eLEcTRA trial show that the combination of letrozole and trastuzumab can be safely administered and is superior to letrozole alone as first-line therapy in patients with HER2 and HR positive MBC. Our results also confirm earlier evidence that aromatase-inhibitor therapy alone is only associated with a rather short TTP in HER2 and HR positive MBC. In contrast, outcome in letrozole-treated patients with HER2 negative HR positive tumors is significantly better compared to that associated with tumors with both HR and HER2 expression.(Trial was sponsored by Novartis Pharmaceuticals) Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4094.

Background: Approximately 70% of patients with metastatic breast cancer (MBC) are hormone receptor (HR) - positive and the cyclin dependent kinases (CDK) along with their D-type cyclin catalysts, have been shown to play a role in mediating the resistance to endocrine therapy. Several CDK-targeted agents have been recently approved by FDA. Nevertheless, the risk of venous thromboembolism (VTE) with the use of different CDK 4/6 inhibitors has never been reported. We undertook a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of VTE with abemaciclib based regimens versus other CDK 4/6 inhibitor containing regimens in patients with HR-positive HER2-negative MBC. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts through February 2018. The randomized controlled trials that mention deep vein thrombosis and pulmonary embolism as adverse effects of CDK 4/6 inhibitor therapy were incorporated in the analysis. The primary meta- analytic approach was a fixed effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR) and risk difference (RD) with 95% confidence interval (CI). Results: Five phase 3 studies and one phase 2 study with a total of 3,159 patients with HR-positive HER2-negative MBC were eligible for analysis. The study arms used palbociclib-letrozole, palbociclib-fulvestrant, ribociclib-letrozole, abemaciclib-fulvestrant, and abemaciclib-nonsteroidal aromatase inhibitors (either letrozole or anastrozole) while the control arms utilized placebo in combination with letrozole or anastrozole or fulvestrant. The randomization ratio was 2 to 1 in PALOMA-2, PALOMA-3, MONARCH-2 and MONARCH-3 studies and 1 to 1 in PALOMA-1 and MONALEESA-2 trials. CDK 4/6 inhibitors were utilized as first line treatment in PALOMA-1, PALOMA-2, MONALEESA-2 and MONARCH-3. The I2 statistic for heterogeneity was 0, and the heterogeneity X2 (Cochran's Q) was 1 (P= 0.707), suggesting homogeneity among RCTs. The VTE incidence was 25 (3.255%) in the abemaciclib group vs 2 (0.520%) in the control group. The pooled relative risk for VTE was 6.222 (95% CI: 1.481 – 26.145, P = 0.013) and the absolute RD was 0.027 (95% CI: 0.013 – 0.042, P < 0.0001). In other CDK 4/6 inhibitor containing regimens, the VTE incidence was reported at 15 (1.243%) vs 2 (0.374%) in the control arm. The pooled RR for VTE was 2.312 (95% CI: 0.852 –6.272, P = 0.100) and the absolute RD was 0.008 (95% CI: - 0.000 – 0.017, P = 0.259). Conclusion: VTE is a major cause of morbidity and mortality and is particularly common in patients with breast cancer. Our meta-analysis demonstrated that the addition of abemaciclib to endocrine therapy notably contributed to a higher incidence of VTE with a relative risk of 6.22. However, no significant increase in the risk of VTE was noted in other CDK 4/6 inhibitor-based regimen. More randomized trials are required to determine the actual relation and definitive incidence of VTE among different CDK-targeted agents when added to endocrine therapy. Citation Format: Thein KZ, Ball S, Zaw MH, Quirch M, Hardwicke F, Awasthi S, Oo TH, Jones C. Risk of venous thromboembolism with abemaciclib based regimen versus other CDK 4/6 inhibitor containing regimens in patients with hormone receptor-positive HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-16-04.

P16-3 Maintenance therapy in HER2 and hormone receptor-positive breast cancer

Background: Sacituzumab govitecan (SG), an antibody-drug conjugate comprising an anti-Trop-2 antibody coupled to the irinotecan analog, SN-38, is currently approved for use in metastatic triple-negative breast cancer (TNBC) and hormone receptor-positive (HR+) breast cancer. Preclinical studies demonstrate that SG results in increased activity in tumors with homologous recombination deficiency, which may be attributed to the SN-38 payload increasing double-strand DNA breaks. However, biomarker analyses of SG show that patients benefit regardless of germline BRCA 1/2 mutation status and that patients with TNBC expressing higher Trop-2 expression benefit more from SG. Utilizing next-generation sequencing (NGS) data, we sought to identify whether genomic biomarkers were also associated with response to SG in patients with metastatic breast cancer (MBC). Methods: NGS of tissue and circulating tumor DNA from patients with MBC treated with SG were obtained by chart review. Genomic data was obtained through routine clinical practice. Progression-free survival (PFS) was determined from the first day of treatment until disease progression or death. Oncogenic alterations from NGS were analyzed according to PFS with univariate cox proportional hazards analysis. Results: 128 patients treated with SG between April 2020 and November 2023 were included in the analysis. 95 (74%) patients had TNBC, while 33 (26%) had HR+ breast cancer. 32 (25%) patients received SG in the 1st or 2nd line, while 96 (75%) received SG in later lines. The median PFS was 2.7 months (95% CI, 2.4-4.1). 115 (90%) patients had NGS tests available, with a total of 211 NGS tests included. Of these, 160 (76%) tests were performed prior to SG, 46 (22%) after SG, and 5 (2%) at unknown date. 78 different oncogenic alterations were identified in 2 or more patients. Of the 128 patients, the most common oncogenic alterations were TP53 (69%), PIK3CA (20%), PTEN (14%), ERBB2 (12%), and MYC (10%). Five alterations were significantly associated with shorter PFS, including KIT (HR 20.9, p = 0.0001, n=2), MAP3K1 (HR 5.0, p = 0.002, n=4), RAD21 (HR 8.3, p = 0.004, n=2), MTAP (HR 4.5, p=0.01, n=3), and TSC1 (HR 5.0, p = 0.03, n=2). In TNBC, the alterations MTAP (HR 5.8, p=0.004), MAP3K1 (HR 4.8, p=0.01) and CDKN2A (HR 2.5, p=0.02) were associated with shorter PFS. In HR+ disease, the alterations KIT (HR 14.9, p=0.004), FGF19 (HR 6.3, p=0.02), and FGF3 (HR 6.3, p=0.02) were associated with shorter PFS. Conclusions: Five oncogenic alterations were associated with a poor response to SG in MBC, including KIT, MAP3K1, RAD21, MTAP, and TSC1. In TNBC, MTAP, MAP3K1, and CDKN2A were associated with a poor response, whereas in HR+ disease, KIT, FGF19, and FGF3 were associated with a poor response. These results suggest that alterations in these genes may be potential resistance mechanisms to SG which merits further exploration. Citation Format: Alexis LeVee, Megan Wong, Christina Wei, Nora Ruel, Kevin McDonnell, Daniel Schmolze, Joanne Mortimer. Genomic markers of sacituzumab govitecan (SG) response in metastatic triple-negative breast cancer and hormone receptor-positive breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-02-28.

Discovery and development of novel therapies in advanced breast cancer: rapid development of ribociclib

Background Capecitabine is an oral chemotherapy and often a favoured option in metastatic hormone-receptor positive (HR+) breast cancer (BC) progressing under endocrine therapy (ET). As reported in the BOLERO-6 trial, median time to treatment failure of capecitabine after ET is 6.2 months. Addition of cycline-dependant-kinase 4/6 inhibitors (CDKi) to ET improved survival outcomes in metastatic HR+ BC, thus this combination is the new standard of treatment in metastatic first or second-line setting. Evaluation of capecitabine efficiency after the combination ET - CDKi remains scarce in the literature. This retrospective study aims at describing capecitabine efficacy after disease progression under this combination therapy. Methods Fifty-six Patients, with a 62-year median age (IC95% 42-81), were treated with capecitabine after disease progression under ET - CDKi combination between January 2016 and December 2020. For 46% of them combination therapy was used in first-line setting. Twenty-five patients had exclusive bone metastasis while fifteen had hepatic metastasis. Median follow-up since capecitabine initiation was 13.5 months. Primary endpoint was time to treatment failure (TTF). Second endpoints were progression-free survival (PFS) and overall survival (OS). Univariate and multivariate Cox logistic regression were used to identify survival-associated factors : age < versus ≥ 50 years, hormone-receptor status ER+/PR+ versus ER+/PR-, exclusive bone versus visceral metastases, first line versus second line of CDKi - ET combination, aromatase inhibitor versus fulvestrant. Results Time to treatment failure of capecitabine after combination of CDKi - ET was 6.1 months (IC95% 1.3-17.4). Six patients discontinued capecitabine due to toxicity. Median PFS and OS were respectively 7.1 and 13.4 months. Outcomes were not significantly different regardless of age, hormone receptor status, metastases localization, line of CDKi and ET class, (Table 1). Conclusion In comparison with capecitabine efficacy after ET progression without CDKi in BOLERO-6 trial (TTF = 6,2 months and PFS = 9,6 months), our results suggest that capecitabine efficacy is maintained after progression on combination of ET - CDKi. This efficacy is independent of metastatic sites, and previous ET - CDKi line setting. Table 1.Univariate analysis considering factors of capecitabine time to treatment failureUnivariate analysisVariablesEvent (n)No event (n)pAge (years)0.6Hormone-receptor status n (%)0.3PR+/ER+2917PR-/ER+ or PR+/ER-82Metastasis localisation n (%)Bone metastasis only1690.2Visceral metastasis only71Endocrine therapy n (%)Aromatase inhibitor1240.3Fulvestrant2415CDK 4/6 inhibitor n (%)Palbociclib33160.6Ribociclib/Abemaciclib43CDK 4/6 inhibitor plus ET n (%)First line1790.9≥ 2 lines2010 Citation Format: Capecitabine efficacy after progression on endocrine treatment and cycline-dependant-kinase 4/6 inhibitor combination in metastatic hormone-receptor positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-16-04.

Background: The cyclin dependent kinases (CDK) along with their partners, the cyclins, have a crucial role in regulation of the cell cycle. Several CDK-targeted agents have been employed in hormone receptor positive metastatic breast cancer (MBC) with noteworthy safety concerns. Nevertheless, the impact of this agent on risk of venous thromboembolism (VTE) remains uncertain. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of VTE among patients with hormone receptor-positive HER2-negative MBC treated with CDK 4/6 inhibitors. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts through June 2017. Trials that mention deep vein thrombosis and pulmonary embolism as adverse effects were incorporated in the analysis. The primary meta- analytic approach was a fixed effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Pooled VTE rates were estimated as follows: we multiplied the median follow-up duration by the sample size. Crude study-specific VTE rates were then calculated by dividing the number of incident VTE cases by the total number of person-months follow-up. Results: A total of 2671 patients with hormone receptor-positive HER2-negative MBC from four phase 3 studies and one phase 2 study were eligible for analysis. The study arm used palbociclib-letrozole, palbociclib-fulvestrant, ribociclib-letrozole and abemaciclib-fulvestrant while the control arm utilized placebo in combination with letrozole or fulvestrant. The I2 statistic for heterogeneity was 13.6, and the heterogeneity X2 (Cochran's Q) was 4.6 (P= 0.3), suggesting homogeneity of results among the randomized trials. The VTE incidence was 24 (1.46%) in CDK 4/6 group vs 4 (0.39%) in control group. The pooled RR for VTE was 2.736 (95% CI: 1.115 – 6.714, P = 0.028) and the absolute RD was 0.010 (95% CI: 0.002 – 0.018, P = 0.010) according to the fixed effects model. By the random effects model, the pooled RR was 2.411 (95% CI: 0.809 – 7.181, P = 0.114) and RD was 0.009 (95% CI: 0.0 – 0.019, P = 0.048). Over median follow up of 36 months, the RR for VTE was 3.792 (95% CI: 1.838 – 7.822, P < 0.0001) and RD was 0.024 (95% CI: 0.014 – 0.034, P < 0.0001) with the fixed effects model. By the random effects model, the pooled RR for VTE was 4.248 (95% CI: 0.952- 18.959, P = 0.058) and RD was 0.026 (95% CI: 0.004 – 0.021, P < 0.0001). The pooled rate of VTE among CDK 4/6 group was 2.99 per person years compared to 0.50 per person years among control arm. Conclusion: Approximately 1% of patients on letrozole or fulvestrant alone developed VTE in previous studies. Our meta-analysis demonstrated that the addition of CDK 4/6 inhibitors to letrozole or fulvestrant, contribute to higher incidence of VTE. More randomized trials are required to determine the actual relation and definitive incidence of VTE, a major cause of morbidity and mortality among these patients. Citation Format: Thein KZ, Zaw MH, Tun AM, Jones C, Radhi S, Hardwicke F, Oo TH. Incidence of venous thromboembolism in patients with hormone receptor-positive HER2-negative metastatic breast cancer treated with CDK 4/6 inhibitors: A systematic review and meta- analysis of randomized controlled trials [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-02.

Achieving a pathologic complete response as a result of neoadjuvant treatment is associated with improved prognosis in breast cancer. The CREATE-X trial showed a significant survival improvement with capecitabine treatment of patients with residual invasive disease following neoadjuvant chemotherapy, and the KATHERINE trial demonstrated a significant benefit of trastuzumabemtansine (TDM1) in patients with HER2-positive breast cancer who did not achieve a pathologic complete response, so we have a lot of interesting alternatives of post-neoadjuvant treatments for high-risk patients. The discovery of molecular markers of resistance to endocrinotherapy (cyclin-dependent kinases (CDK 4/6), ER mutation (ESR1), mTOR signaling pathway, co-expression of ER+/HER2+) and inhibitors to them expanded the possibilities of endocrinotherapy not only in advanced and metastatic breast cancer, but also in residual ER+ tumors. The pCR rates in hormone receptor-positive breast cancer after neoadjuvant chemotherapy are around 10%, which is much lower than the values observed in HER2-positive and triple negative subtypes, so new strategies are needed to improve pCR rates in this subgroup, even though the adjuvant endocrine therapy impacts significantly the outcomes of this patients. The cyclin-dependent kinases (CDKs) are serine–threonine kinases that regulate cell cycle progression from the G1 to the S-phase during mitosis. CDKs activity can be abnormally increased or dysregulated in breast cancer, leading to a constant stimulus for cell proliferation and survival, which is a known mechanism of resistance to endocrine treatment. The CDK inhibitors act on CDKs and block their activity, thereby restoring the cell cycle regulation. In studies with metastatic hormone receptor-positive breast cancer patients, the combination of a CDKis with first or second-line endocrine therapy showed significant improvements in progression-free survival and response rates. Evolving techniques such as next-generation sequencing and gene expression profiles have improved our understanding of the biology of residual disease and also the mechanisms involved in treatment resistance.

Achieving a pathologic complete response as a result of neoadjuvant treatment is associated with improved prognosis in breast cancer. The CREATE-X trial showed a significant survival improvement with capecitabine treatment of patients with residual invasive disease following neoadjuvant chemotherapy, and the KATHERINE trial demonstrated a significant benefit of trastuzumabemtansine (TDM1) in patients with HER2-positive breast cancer who did not achieve a pathologic complete response, so we have a lot of interesting alternatives of post-neoadjuvant treatments for high-risk patients. The discovery of molecular markers of resistance to endocrinotherapy (cyclin-dependent kinases (CDK 4/6), ER mutation (ESR1), mTOR signaling pathway, co-expression of ER+/HER2+) and inhibitors to them expanded the possibilities of endocrinotherapy not only in advanced and metastatic breast cancer, but also in residual ER+ tumors. The pCR rates in hormone receptor-positive breast cancer after neoadjuvant chemotherapy are around 10%, which is much lower than the values observed in HER2-positive and triple negative subtypes, so new strategies are needed to improve pCR rates in this subgroup, even though the adjuvant endocrine therapy impacts significantly the outcomes of this patients. The cyclin-dependent kinases (CDKs) are serine–threonine kinases that regulate cell cycle progression from the G1 to the S-phase during mitosis. CDKs activity can be abnormally increased or dysregulated in breast cancer, leading to a constant stimulus for cell proliferation and survival, which is a known mechanism of resistance to endocrine treatment. The CDK inhibitors act on CDKs and block their activity, thereby restoring the cell cycle regulation. In studies with metastatic hormone receptor-positive breast cancer patients, the combination of a CDKis with first or second-line endocrine therapy showed significant improvements in progression-free survival and response rates. Evolving techniques such as next-generation sequencing and gene expression profiles have improved our understanding of the biology of residual disease and also the mechanisms involved in treatment resistance.

Background: Fulvestrant is one of the standard treatments for first- and second-line endocrine therapy for hormone receptor (HR)-positive metastatic breast cancer (MBC). Palbociclib inhibits cyclin dependent kinase (CDK) 4 and CDK6 in vitro, resulting in loss of RB1 phosphorylation. Palbociclib has high activity in HR-positive breast cancer cell lines and is synergistic in combination with endocrine therapies. The PALOMA-3 trial enrolled patients with metastatic estrogen receptor (ER)-positive breast cancer with resistance to aromatase inhibitor. The results demonstrated that palbociclib combined with fulvestrant was associated with significantly longer progression-free survival (PFS) than fulvestrant alone. However, patients in the trial reported higher rates of adverse events, such as neutropenia and alopecia, compared with fulvestrant monotherapy. We investigate in this prospective cohort study that the addition of palbociclib to fulvestrant is effective and safe in HR-positive and HER2-negative advanced breast cancers that progressed during fulvestrant monotherapy. Specific Aims: Primary objective: To observe the PFS in patients with resistance to fulvestrant monotherapy who were treated with fulvestrant plus palbociclib. Secondary Objective: To observe the PFS in patients treated with fulvestrant as the first and second line therapy. We also aim to observe overall survival and safety. A prospective translational research is also planned to assess the correlations between biomarkers and response. Trial Design: Single arm exploratory trial Eligibility Criteria: Eligible patients must have historically confirmed ER-positive and HER2-negative MBC who received fulvestrant as first or second line therapy. Prior chemotherapy in the neoadjuvant and adjuvant settings and up to one line of chemotherapy in MBC is permissible. Patients who received CDK4/6 inhibitor as metastatic therapy are excluded. Statistical Design: We aim to set the lowest limit of the therapeutic effect at a median PFS of 5 months, which is the value reported in the PALOMA-3 study. If we assume that the expected median PFS is 8 months, at least 63 patients are required to reject the null hypothesis (5 months) with a power of 80% under a one-sided alpha at 0.05. The length of the accrual period and follow-up period are set at 12 and 18 months, respectively. Target Accrual: First registration: 200 patients with fulvestrant monotherapy as the first and second line setting. Second registration: 70 patients with combined palbociclib and fulvestrant. (UMIN 000029294) Citation Format: Kokoro Kobayashi, Naoki Niikura, Shigehira Saji, Takayuki Iwamoto, Nobutaka Iwakuma, Yuichiro Kikawa, Norikazu Masuda, Kenichi Watanabe, Takashi Takeshita, Mari Oba, Shinji Ohno. Fulvestrant with additional palbociclib in advanced or metastatic hormone receptor-positive HER2-negative breast cancer after progression to fulvestrant monotherapy: JBCRG- M07 (FUTURE trial) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-02-07.