Search

Background The hormone receptor (HR)-positive metastatic breast cancer (MBC) patients show a diverse range of tumor mutational burden (TMB), but its biological and clinical implication has been largely unrevealed. Here we report genomic landscape of 117 HR+ MBC patients who were included in the pre-screening tissue genomic analysis of MUTATION-1 study (SABCS 2021; Abs P1-19-03) according to TMB of tumors. Patients and method The MUTATION-1 study (NCT03608865) enrolled HR-positive MBC patients who received prior ≥ 1 line of systemic therapy, and performed prescreening with whole exome sequencing (WES) and RNA-seq of fresh-frozen tissue of metastatic or recurred tumors. Patients who met upper 30% of TMB were eligible for treatment phase and received durvalumab plus tremelimumab. This study analyzed 117 prescreening tissues of MUTATION-1 study patients for mutation and transcriptomic landscape analysis. (WES, n=117; RNA-seq, n=107) Results The 117 patients showed diverse TMB (range 0~21.7 mut/Mb, median 2.0 mut/Mb) and genomic alterations. The most frequently mutated gene included PIK3CA (29.1%), TP53 (27.4%), ESR1 (23.9%), GATA3 (19.7%), and MAP3K1 (12.0%). There was no association between patient survival and TMB. We estimated single base substitution (SBS) mutational signature of patients with SigMA algorithm. The patients were classified according to their dominant mutational signatures: APOBEC (25.6%), HRD (41.0%), clockwise (28.2%), SBS8, and SBS17. The APOBEC patients showed higher TMB (median 3.47 mut/Mb) and higher mutation prevalence in PIK3CA (63.3% vs. 29.1%), ARID1A (16.7% vs. 6.0%), and NF1 (16.7% vs. 6.8%) compared with other patients. The high TMB positively correlated with time from MBC diagnosis to biopsy. Tumors with TMB ≥ 5 mut/Mb were exclusively found in patients diagnosed as MBC ≥ 36 months before the timing of biopsy. In the matched RNA-seq analysis, TMB was higher in luminal B and HER2-enriched intrinsic subtype patients than basal or luminal A subtype. The high TMB (≥ 3.16 mut/Mb, cutoff used for treatment phase patient selection) patients showed upregulation of G2/M checkpoint, MYC, E2F1, and MTORC1 signature compared to low TMB patients. In the tumor microenvironment analysis by CIBESORT, PIK3CA mutant patients showed lower score of cytotoxic T cell than others. Conclusions The high TMB in HR+ breast cancer was associated with longer time duration from MBC diagnosis to biopsy, high APOBEC signature, and cell cycle/MYC signature gene upregulation. Further therapeutic targeting of high TMB patients is warranted based on their genomic and immunologic characteristics. Citation Format: Min Hwan Kim, Yohan Yang, Eunyoung Kim, Yong Wha Moon, Gun Min Kim, Seul-Gi Kim, Yee Soo 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, Sangwoo Kim, Joo Hyuk Sohn. Genomic characterization of hormone receptor-positive advanced breast cancer with high tumor mutational burden: fresh-frozen tissue genomic analysis from MUTATION-1 study (KCSG BR17-04) [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 P5-14-04.

To evaluate the feasibility of syngeneic mouse models of breast cancer by analyzing the efficacy of immune checkpoint inhibitors (ICIs) and potential predictive biomarkers.To establish the murine triple-negative breast cancer (TNBC) models, JC, 4T1, EMT6, and E0771 cells were subcutaneously implanted into female syngeneic mice. When the tumor reached 50-100 mmThe EMT6 model showed the highest tumor response rate (54%, 6/11) of the syngeneic models: 4T1 (45%, 5/11), JC (40%, 4/10), or E0771 (23%, 3/13). Early changes in tumor size at 7 days post-PD-1 inhibitor treatment predicted the final efficacy of the PD-1 inhibitor. Peripheral blood CD8+ and CD4+ T cells with or without Ki67 expression at 7 days post-PD-1 inhibitor treatment were higher in the finally designated responder group than in the non-responder group. At the time of sacrifice, analyses of tumor infiltrating lymphocytes consistently supported these results. We also demonstrated that retro-orbital blood sampling procedures (baseline, 7 days post-treatment, time of sacrifice) were safe for serum cytokine analyses, suggesting that our preclinical platform may be used for biomarker research using serum cytokines.Our syngeneic mouse model of TNBC is a feasible preclinical platform to evaluate ICI efficacy combined with other drugs and predictive biomarkers in the screening process of immune-oncology drug development.

Backgrounds Low-pass whole-genome sequencing (LP-WGS)-based circulating tumor DNA (ctDNA) analysis is a versatile tool for somatic copy number aberration (CNA) detection, and this study aims to explore its clinical implication in breast cancer. Methods We analyzed LP-WGS ctDNA data from 207 metastatic breast cancer (MBC) patients to explore prognostic value of ctDNA CNA burden, and validated it in 465 stage II-III triple-negative breast cancer (TNBC) patients who received neoadjuvant chemotherapy in phase III PEARLY trial (NCT02441933). The clinical implication of locus-level LP-WGS ctDNA profiling was further evaluated. Results We found that a high baseline ctDNA CNA burden predicts poor overall survival and progression-free survival of MBC patients. The post-hoc analysis of PEARLY trial showed that a high baseline ctDNA CNA burden predicted poor disease-free survival independent from pathologic complete response (pCR), validating its robust prognostic significance. The 24-month disease-free survival rate was 96.9% and 55.9% in pCR (+)/Low I-score and non-pCR/High I-score patients, respectively. The locus-level ctDNA CNA profile classified MBC patients into five molecular clusters and revealed targetable oncogenic CNAs. LP-WGS ctDNA and in vitro analysis identified the BCL6 amplification as a resistance factor for CDK4/6 inhibitors. We estimated ctDNA-based homologous recombination deficiency (HRD) status of patients by shallowHRD algorithm, which was highest in the TNBC and correlated with platinum-based chemotherapy response. Conclusions These results demonstrate LP-WGS ctDNA CNA analysis as an essential tool for prognosis prediction and molecular profiling. Particularly, ctDNA CNA burden can serve as a useful determinant for escalating or de-escalating (neo)adjuvant strategy in TNBC patients.

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 The real-world risk of disease recurrence in patients with HER2-positive early breast cancer who achieved pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) and/or HER2-targeted therapy is unclear. This study aims to identify the patterns and risk factors of disease recurrence after NAC in patients with HER2-positive early breast cancer who achieved a pCR or not. Methods 930 HER2 positive early breast cancer patients who received NAC were identified in the Severance Breast Cancer Registry at the Yonsei Cancer Center and Gangnam Severance Hospital in Seoul, Republic of Korea, between 2006 and 2020. NAC included 3 regimens: only chemotherapy. (CTx), chemotherapy plus trastuzumab (CTx+H), and chemotherapy plus dual anti-HER2 therapy (TCHP). The pCR was defined as the absence of residual invasive cancer in the resected breast specimen and the axillary lymph nodes (ypT0/TisN0) after neoadjuvant systemic therapy. Recurrence of disease was defined as recurrence of ipsilateral locoregional invasive breast cancer, distant disease recurrence, or death. Results The median follow-up duration was 42.0 months (range 4-171), and median age was 51 years old (range 22-80). The rate of pCR was 52.2% (485/930). Depending on the achieved a pCR, the loco-regional recurrence rate was 4.0% (18/445) vs 1.0% (5/485), and the distant recurrence rate was 11.0% (49/445) vs 3.9% (19/445). Of the 79 patients who relapsed, 30.4% (n=24) had achieved a pCR and 69.6% (n=55) had residual disease. The 4-year recurrence risk was 6.9% for patients who achieved pCR versus 12.8% for those who did not (p Citation Format: Jee Hung Kim, Jii Bum Lee, Soong Joon Bae, Sung Gwe Ahn, Joon Jeong, Min Hwan Kim, Seul-Gi Kim, Gun Min Kim, Jee Ye Kim, Hyung Seok Park, Seho Park, Byeong Woo Park, Seung Il Kim, Joohyuk Sohn. Pattern of recurrence after pathologic complete response after neoadjuvant chemotherapy in patients with early HER2-positive breast cancer: Real-world evidence [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 P2-13-14.

Purpose In the patients treated with neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) regimen, grade 3-4 anemia occurs frequently during the treatment course. Anemia develops mainly by cytotoxic drug including carboplatin. By contrast, dose reduction of carboplatin could raise concerns about the oncologic outcome. We compared the pathologic complete response (pCR) rate and grade 3-4 anemia/transfusion rate according to the dose of carboplatin among the patients undergoing neoadjuvant TCHP. Method We retrospectively analyzed 294 patients who treated with neoadjuvant TCHP between Apr 1, 2015 and Dec 31, 2020. Clinicopathological features were collected by electronic medical record review. Hemoglobin levels were measured at baseline, before each cycle of chemotherapy, and after the chemotherapy completion. Multivariable binary logistic regression analysis was performed to identify predictive factors for grade 3-4 anemia and transfusion event. Result In a total of 294 patients, neoadjuvant TCHP with carboplatin AUC6 were initiated in 234 (79.6%, 234 of 294), whereas upfront carboplatin AUC5 were concurrently administered in 60 (20.4%, 60 of 294). There was no statistical difference in the pCR rate between the two groups (70.9% in the AUC6, 80.0% in the AUC5; p=0.159). In the both ER+ and ER-, there were no significant differences between the AUC6 and AUC5 (54.3% and 50.0% in the ER+; 81.7% and 86.0% in the ER-). Tumor and nodal stage were not different between the two groups. The AUC5 group had less grade 3-4 anemia (18.3%, 11 of 60 vs 34.2%, 80 of 234) and transfusion event (10.0%, 6 of 60 vs 21.8%, 51 of 234) compared with the AUC6 group. Multivariable analysis demonstrated that baseline hemoglobin level under 12g/dL and ≥2g/dL hemoglobin down after first chemotherapy are independent risk factors for grade3-4 anemia or blood transfusion before surgery. Conclusion The pCR rate was not different according to the initial carboplatin dose in the HER2+ breast cancer treated with neoadjuvant TCHP. We suggest that the dose of carboplatin could be optimized as AUC5 to reduce TCHP-induced anemia and transfusion rate among Asian HER2-positive breast cancer patients treated with TCHP. Baseline low hemoglobin level under 12 g/dL or rapid hemoglobin down after first cycle are risk factors for TCHP-induced anemia. Table 1.The pathologic complete response (pCR) rate, distribution of anemia grade and transfusion rate according to AUCVariablesAUC6AUC5TotalP-valueOverall (N=294)0.159pCR166 (70.9%)48 (80.0%)214 (72.8%)Non-pCR68 (29.1%)12 (20.0%)80 (27.2%)Total234 (100.0%)60 (100.0%)294 (100.0%)ER-positive (N=102)0.793pCR50 (54.3%)5 (50.0%)55 (53.9%)Non-pCR42 (45.7%)5 (50.0%)47 (16.1%)Total92 (100.0%)10 (100.0%)102 (100.0%)ER-negative (N=192)0.487pCR116 (81.7%)43 (86.0%)159 (82.8%)Non-pCR26 (18.3%)7 (14.0%)33 (17.2%)Total142 (100.0%)50 (100.0%)192 (100.0%)Anemia grade (N=294)0.0181 or 2154 (65.8%)49 (81.7%)203 (69.0%)3 or 480 (34.2%)11 (18.3%)91 (31.0%)Transfusion (N=294)0.039No183 (78.2%)54 (90.0%)237 (80.6%)Yes51 (21.8%)6 (10.0%)57 (19.4%) Citation Format: Jung Hwan Ji, Soong June Bae, Seul-Gi Kim, Min Hwan Kim, Gun-Min Kim, Joohyuk Sohn, Jee Hung Kim, Sung Gwe Ahn, Joon Jeong. Pathologic complete response rate according to the carboplatin dose in patients with non-metastatic HER2+ breast cancer treated with neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) [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 P2-12-13.

Background. Endocrine therapy plus CDK 4/6 inhibitors is the foremost treatment for hormone receptor (HR) positive metastatic breast cancers (mBC). Previously, we reported safety profiles of palbociclib use with grade 3 neutropenia in HR-positive mBC. Here, we investigated two cohorts’ patients who had received palbociclib with or without dose interruptions and/or reductions on afebrile grade 3 neutropenia in terms of efficacy outcomes. Patients and methods. The combined cohort of consecutive mBC patients who received palbociclib with letrozole in 1st line setting (in four major cancer centers in Republic of Korea) was reviewed. We classified patients into 4 groups: Group 1 (patients who maintained palbociclib dose on afebrile grade 3 neutropenia, representing limited dose modification scheme), Group 2 (patients who experienced any dose modification on afebrile grade 3 neutropenia, representing conventional dose modification scheme), Group 3 (patients without the event of afebrile grade 3 neutropenia), and Group 4 (patients who experienced only grade 4 neutropenia) within the first 5 cycles. The primary endpoint was PFS difference between Group 1 and Group 2, and secondary endpoints included PFS and overall survival difference in all groups, and safety profiles of each group. Results. A total of 434 eligible patients recruited from Jan 2017 to Sep 2020 were allocated into 4 groups; Group 1 (n=172, 40.1%), Group 2 (n=128, 29.5%), Group 3 (n=102, 23.5%), and Group 4 (n=30, 6.9%). The overall incidence of palbociclib dose reductions was 272 (62.7%) and dosing delay was 181 (42.2%) in all groups. The median time to first dose reduction for all eligible patients was 3 months (2-5 months) and the median time to second dose reduction was 9 months (2-30 months). At the 12th cycle of treatment, 70.5% (105/at-risk patients of 149) of Group 1 patients still remained on 125mg of palbociclib, whereas no patient was on 125mg dose level but 66.3% patients (65/at-risk patients of 98) were on 100mg in Group 2. At the median follow-up of 23.7 months (95% CI: 21.6-25.8), Group 1 patients showed significantly longer PFS than Group 2 patients (P-value = 0.036, 2-year PFS rate: 67.9% in Group 1 and 55.3% in Group 2). The OS between Group 1 and 2 was not significantly different. The favorable PFS trend of Group 1 over Group 2 was observed across all subgroups. The overall toxicity profiles were not significantly different between Group 1 and Group 2. Conclusion. Our study demonstrates that the clinical practice of limited dose modifications for palbociclib-related grade 3 neutropenia might have more therapeutic benefits than the conventional dose scheme without increasing toxicities. Permissive approach to afebrile grade 3 neutropenia and prospective clinical trials for this new dose scheme are warranted. Funding: This study was supported by a grant from Pfizer. Citation Format: Seul-Gi Kim, Min Hwan Kim, Sejung Park, Gun Min Kim, Jee Hung Kim, Jee Ye Kim, Hyung Seok Park, Seho Park, Byeong Woo Park, Seung Il Kim, Jung Hwan Ji, Joon Jeong, Kabsoo Shin, Jieun Lee, Hyung-Don Kim, Kyung Hae Jung, Joohyuk Sohn. Efficacy of limited dose modifications for palbociclib-related grade 3 neutropenia in hormone receptor positive metastatic 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 P1-17-09.

Objectives: Various sensory symptoms have been recognized after COVID-19 vaccination. Here, we aimed to explore the association between the suggestive symptom of restless legs syndrome (RLSss) and COVID-19 vaccination using an online survey.Methods: We prospectively studied participants who were working in our hospital after at least the first dose of the ChAdOx1 or BNT162b2 mRNA vaccine. The participants were invited via smartphone messages and voluntarily filled out an online questionnaire that included adverse events after vaccination. We considered the participants as having RLSss if they reported that they had three or more symptoms in the restless legs syndrome (RLS) diagnostic criteria.Results: A total of 628 participants (506 female; mean age, 37.7±12.4 years) responded fully to our online survey. 588 participants (93.6%) received the first dose of the ChAdOx1 vaccine (BNT162b2 mRNA vaccine for 40 participants). A total of 44 out of the 628 participants (7.0%) reported that they had RLSss. Myalgia was more common in participants with RLSss than in those without RLSss (97.7% vs. 67.3%, p

The indications for immune checkpoint inhibitors (ICIs) are expanding for various cancers because of their durable responses and tolerable safety profiles. Immune-related adverse events (irAEs), including neurological adverse events (nAEs), are associated with ICIs therapy. However, there have been few studies on whether re-challenge with ICIs can be clinically acceptable after neurological AE has improved.A 69-year-old woman with recurrent ovarian cancer undergoing palliative chemotherapy was admitted to our hospital with sudden development of diplopia, dizziness, and gait instability. The patient was administered ICI therapy with anti-angiogenic agents for 9 weeks for 3 cycles.We performed neurological examination, brain imaging, nerve conduction studies, and serology tests. The patient was diagnosed with Guillain-Barré syndrome variant, an immune-mediated polyneuropathy characterized by a triad of ataxia, areflexia, and ophthalmoplegia.After prompt discontinuation of pembrolizumab, the patient was taken intravenous methylprednisolone (2 mg/kg) was administered for 5 days, and her symptoms were partially resolved. With the addition of immunoglobulin 0.4 g/kg for 5 days, her symptoms gradually improved.The patient's neurological symptoms improved after immunosuppressive therapy, without sequelae. The NCV showed normal nerve conduction. Unfortunately, because there was little evidence for pembrolizumab rechallenge, pembrolizumab therapy was permanently discontinued, and the tumors eventually progressed.

Purpose To evaluate the feasibility of syngeneic mouse models of breast cancer by analyzing the efficacy of immune checkpoint inhibitors (ICIs) and potential predictive biomarkers. Methods Four syngeneic mouse models of triple-negative breast cancer (TNBC) JC, 4T1, EMT6 and E0771 cells were injected subcutaneously. When the tumor reached 50–100 mm3, each mouse model was divided into treatment (murine PD-1 antibody) and no-treatment control. Treatment group is further divided into the responder and nonresponder groups. Potential predictive biomarkers were evaluated by analyzing serum cytokines, peripheral blood T cells and tumor infiltrating immune cells. Results The JC model showed the highest tumor response rate (40%, 4/10) of syngeneic models: 4T1 (36%, 4/11), EMT6 (36%, 4/11), or E0771 model (23%, 3/13). Early change of tumor size at 7 days post PD-1 inhibitor treatment predicted the final efficacy of PD-1 inhibitor. Peripheral blood CD8 + and CD4 + T cells with or without Ki67 expression at 7 days post-PD-1 inhibitor treatment were higher in the finally designated responder group than in the nonresponder group. At the time of sacrifice, analyses of tumor infiltrating lymphocytes consistently supported these results. Furthermore, serum IFN-γ at 7 days post-PD-1 inhibitor treatment was also higher in responders than in nonresponders, suggesting that early changes of these markers could be predictive biomarkers of the final efficacy of ICIs. Conclusions Our syngeneic mouse model of TNBC is a feasible preclinical platform to evaluate ICI efficacies combined with other drugs and predictive biomarkers in the screening period of immune-oncology drug development.

Enhancing therapeutic efficacy of drugs from reactive oxygen species (ROS) and glutathione (GSH)-responsive matrix and minimizing toxic effects on normal cells remains a challenge in programmable anticancer drug delivery. Herein, ROS- and GSH-responsive paclitaxel (PTX)-loaded polymer dot (PD) with mitochondria-targeting capability was designed by constructing diselenide linkage and triphenylphosphonium (TPP) for tunable PTX release and fluorescence for cancer theranostics. PD-TPP nanocarrier could improve the PTX stability after loading (PD-TPP(PTX)), and the cleavage of diselenide bond in the presence of H2O2 and GSH triggered the controllable PTX release, providing higher fluorescence intensity. As the levels of H2O2 and GSH are higher in cancer cells compared to normal cells, PTX was selectively released from PD-TPP in cancer cells, reducing cell viability (∼25%) and causing enhanced apoptosis of cancer cells compared to normal cells. The PD-TPP(PTX) selectivity was also reflected by distinct fluorescence intensity in HeLa and PC-3 cells (cancer) compared to CHO-K1 cells (normal). Furthermore, conjugated TPP promoted the PD-TPP(PTX) accumulation in mitochondria due to specific targeting of TPP towards mitochondria, allowing PTX release in mitochondria of cancer cells. Hence, this approach could be a potential strategy to enhance therapeutic efficacy of cancer drugs and minimize the side effects on normal cells.

In situ wireless monitoring for cell proliferation and detachment kinetics was conducted using pH-responsive zwitterionic polymer dots (Z-PDs), based on changes in electrochemical signals derived from Z-PD-coated substrates via the interaction of charges transferred between Z-PDs and cells. Z-PD-coated substrates were found to be a potent means to monitor and manipulate cell adhesion and detachment because of their high sensitivity over a wide range of pH conditions, and modification of the coated substrates was confirmed using a wireless system. At neutral pH, Z-PD-coated wireless sensors exhibited π-π stacking involving aromatic rings with hydrophobic interactions, thereby promoting cell proliferation; consequently, an increase in the measured resistance was observed. In contrast, Z-PD-coated substrates triggered by acidic and basic conditions promoted cell detachment, which induced an increase in the resistance compared with Z-PD substrates at pH 6.8, as a result of charges transferred to support Z-PD internalization through cell membranes after detachment. Therefore, as a wireless biosensor with excellent pH responsiveness that facilitates cell proliferation and detachment and whose electrochemical signals could be additionally acquired via a smartphone, Z-PD biosensors demonstrated a more favorable approach for monitoring cell-surface interactions than conventional optically based methods.

Grade 3/4 anaemia, which is mainly induced by carboplatin, frequently occurs in patients treated with neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP). However, dose reduction of carboplatin may raise concerns about the oncological outcome. This study investigated the pathologic complete response (pCR) rate, occurrence of grade 3/4 anaemia, and transfusion rate according to carboplatin dose in patients treated with neoadjuvant TCHP. We retrospectively analysed 294 patients treated with neoadjuvant TCHP between April 2015 and December 2020. Case matching was performed using propensity score matching. Among patients treated with neoadjuvant TCHP, carboplatin area under the plasma concentration-time curve 6 (AUC6) was used in 234 patients (79.6%) and upfront carboplatin AUC5 was used in 60 patients (20.4%). No significant difference in pCR rate was found between the two groups (AUC6: 70.9%, AUC5: 80.0%). In both oestrogen receptor-positive (ER+) and ER- patients, no significant differences were observed between the AUC6 and AUC5 groups (ER+: 54.3% vs. 50.0%, ER-: 81.7% vs. 86.0%). The case-matched cohort showed consistent findings. The AUC5 group had lower frequencies of grade 3/4 anaemia (18.3% vs. 34.2%) and transfusion events (10.0% vs. 21.8%) than the AUC6 group. Compared with AUC5, carboplatin at AUC6 would associate with a 2.7-fold increased risk of grade 3 or 4 chemotherapy-induced anaemia. Carboplatin AUC5 has comparable cytotoxic effects to carboplatin AUC6 in patients with HER2+ breast cancer treated with six cycles of neoadjuvant TCHP, with fewer complications associated with clinically meaningful anaemia. AUC5 may be the optimal carboplatin dose to reduce TCHP-induced anaemia in patients with HER2+ breast cancer treated with TCHP.

PARP inhibitors have prolonged the survival of various cancer patients with homologous recombination (HR) deficiencies. However, most patients eternally acquire resistance. Many attempts have been made, but there are no clear strategies to overcome resistance. We evaluated the efficacy and mechanism of JPI-547, a novel dual inhibitor of PARP1/2 and tankyrase1/2, in olaparib resistant breast and ovary preclinical cancer models. We established olaparib resistance models using mammalian cancer cell lines and patient-derived tumor xenografts (PDTXs). Two olaparib-resistant cells cell lines (BT474-OR/SNU251-OR) were established by exposing parent BRCA1/2 mutation carrying BT474 and SNU251 (breast and ovary cancer) to gradually increasing the concentration of olaparib for 8 months. An olaparib-resistant PDTX model [WJO-003(O2)], the parent BRCA1 mutation carrying ovary cancer PDTX was engrafted and treated with olaparib in 75mg/kg twice daily for 1 month and then 100mg/kg twice daily for 3 months. Using established olaparib resistance models, the anti-tumor efficacy of JPI-547 was compared with olaparib, niraparib, and talazoparib. IC50 of BT474-OR and SNU251-OR cell lines showed 5.5 and 6.7 fold increase compared to those of parent cell lines, respectively. While JPI-547 treatment in BT474-OR and SNU251-OR showed similar IC50 to the matching parent cells. In the PARPi-sensitive PDTX model, CPDX-013, JPI-547 inhibited tumor growth the greatest among other PARP inhibitors. Remarkably, 4 of 7 mice showed complete regression of the tumors. In the olaparib-resistant PDTX model, WJO-003(O2), JPI-547 inhibited tumor growth the most effectively compared to other PARP inhibitors (at day 60, the mean tumor volume: 2539, 1319, 871, 601, and 29 mm3 in control, niraparib, olaparib, talazoparib, and JPI-547, respectively; p Citation Format: Min Sil Kang, Nar Katuwal, Mithun Ghosh, Young kyu Jeong, Sa deok Hong, Sung Min Park, John Kim, Hyunju Cha, Banyoon Cheon, Seul-Gi Kim, Yong Wha Moon. JPI-547, a novel dual inhibitor of PARP 1/2 and tankyrase 1/2 overcomes olaparib resistance in BRCA 1/2 mutant ovary and breast cancer preclinical model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4485.

Background The most effective agent for the third-line treatment of advanced/metastatic gastric cancer (AGC) has not yet been determined. The aim of this network meta-analysis is to compare the relative efficacy and tolerability of third-line treatments for AGC. Materials and methods We conducted a comprehensive literature review of randomised clinical trials (RCTs) using four electronic databases. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and adverse events (AEs) were used as efficacy or tolerability outcomes. A Bayesian network meta-analysis with a random-effects model was used. Results Seven RCTs involving 2601 patients and nine treatments were included. The results suggested that 1 mg/kg nivolumab (nivolumab1) + 3 mg/kg ipilimumab (ipilimumab3) (hazard ratio [HR] 0.59, 95% credible interval [Crl] 0.38–0.91) was the most effective treatment, followed by nivolumab (HR 0.63, 95% Crl 0.50–0.79), for prolonging OS. Regorafenib (HR 0.40, 95% Crl 0.28–0.58) was most likely to improve PFS, followed by apatinib (HR 0.45, 95% Crl 0.33–0.60). Nivolumab1 + ipilimumab3 and nivolumab were better at improving ORR, whereas nivolumab1 + ipilimumab3 had the highest toxicity based on the AEs. For benefit-risk ratio, nivolumab, apatinib or regorafenib appeared to be the best options. Chemotherapy or two different dose combinations of nivolumab and ipilimumab were ranked as the next options because of poor tolerability, despite good efficacy. Conclusion Immunotherapy (nivolumab) or antiangiogenic agents (regorafenib and apatinib) are associated with benefits for benefit-risk ratio as third-line monotherapy. This study might serve as a guideline to aid in the selection of third-line treatments for AGC.

The endoplasmic reticulum (ER) apparatus is a part of the secretory pathway that transports proteins to the plasma membrane through vesicle trafficking, enabling post-translational modification of the newly synthesized proteins. Several diseases such as inflammation, neurodegenerative disorder, and bipolar disorder are closely associated with dysfunction of the ER stress response. Herein, we present an ER-targeting, intracellular delivery approach that utilized cell-penetrating peptide (CPP)-conjugated lipid/polymer hybrid nanovehicles (LPNVs). For this, we patched Penetratin, a type of CPP, onto the LPNVs with vesicular membranes formulated with poly(ethylene oxide)-b-poly(ε-caprolactone)-b-poly(ethylene oxide) (PEO-b-PCL-b-PEO) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). We found that the Penetratin-conjugated LPNV (LPNVPnt) was readily taken up by cells and showed specific ER-targeting ability, which was comparable to that of LPNVs conjugated with other types of CPPs. Moreover, we observed that remarkable lysosomal escape of the LPNVs occurred due to effective pH buffering with the aid of PEO-b-PCL-b-PEO. These results highlighted that our LPNVPnt system could pave the way for the development of an elaborate drug delivery technology for ER-targeting at the intracellular level.