Progression-free Survival In Metastatic Breast Cancer Research Articles

Deep Learning Artificial Intelligence Predicts Homologous Recombination Deficiency and Platinum Response From Histologic Slides.

Cancers with homologous recombination deficiency (HRD) can benefit from platinum salts and poly(ADP-ribose) polymerase inhibitors. Standard diagnostic tests for detecting HRD require molecular profiling, which is not universally available. We trained DeepHRD, a deep learning platform for predicting HRD from hematoxylin and eosin (H&E)-stained histopathological slides, using primary breast (n = 1,008) and ovarian (n = 459) cancers from The Cancer Genome Atlas (TCGA). DeepHRD was compared with four standard HRD molecular tests using breast (n = 349) and ovarian (n = 141) cancers from multiple independent data sets, including platinum-treated clinical cohorts with RECIST progression-free survival (PFS), complete response (CR), and overall survival (OS) endpoints. DeepHRD predicted HRD from held-out H&E-stained breast cancer slides in TCGA with an AUC of 0.81 (95% CI, 0.77 to 0.85). This performance was confirmed in two independent primary breast cancer cohorts (AUC, 0.76 [95% CI, 0.71 to 0.82]). In an external platinum-treated metastatic breast cancer cohort, samples predicted as HRD had higher complete CR (AUC, 0.76 [95% CI, 0.54 to 0.93]) with 3.7-fold increase in median PFS (14.4 v 3.9 months; P = .0019) and hazard ratio (HR) of 0.45 (P = .0047). There were no significant differences in nonplatinum treatment outcome by predicted HRD status in three breast cancer cohorts, including CR (AUC, 0.39) and PFS (HR, 0.98, P = .95) in taxane-treated metastatic breast cancer. Through transfer learning to high-grade serous ovarian cancer, DeepHRD-predicted HRD samples had better OS after first-line (HR, 0.46; P = .030) and neoadjuvant (HR, 0.49; P = .015) platinum therapy in two cohorts. DeepHRD can predict HRD in breast and ovarian cancers directly from routine H&E slides across multiple external cohorts, slide scanners, and tissue fixation variables. When compared with molecular testing, DeepHRD classified 1.8- to 3.1-fold more patients with HRD, which exhibited better OS in high-grade serous ovarian cancer and platinum-specific PFS in metastatic breast cancer.

Abstract P4-01-34: Benefits Provided by Antibody Drug Conjugates in Overall Survival Outweighs those in Progression-free Survival for Metastatic Breast Cancer: A Class Effect

Abstract Background: In metastatic breast cancer (MBC), the benefits of progression-free survival (PFS) and overall survival (OS) is not always proportional. This dissociation is related to the multiple other treatment options such as chemotherapy after disease progression and these treatments would contribute to the long post-progression survival. A constant improvement of PFS that translates into OS has been reported in anti-HER2 antibody containing treatments. In the era of antibody drug conjugates (ADC), we aim to examine the relationship between the increments of PFS and OS in MBC. Methods: We have used “ metastatic breast cancer” and “antibody drug conjugate” to search for clinical trials that report both PFS and OS. Hazard ratios (HR) and median survival were analyzed. Increments in PFS (delta PFS) and increments in OS (delta OS) were compared between studies. Results: A total of 5 trials were identified and summarized in table 1. The target of ADC is HER2 (N=4) or Trop2 (N=1). In DESTINY-Breast 03 trial, the control arm is another ADC (T-DM1). The control arms in all the other 4 trials are chemotherapy. The HR of PFS ranged from 0.28 to 0.65 and the HR of OS ranged from 0.48 to 0.68. The HR of PFS is smaller than HR of OS in all of the 5 trials. The median OS was not reached in 1 of the trials (DB-03) and was thus removed from the analysis for delta PFS and delta OS. In the comparison of delta PFS, the increments of median PFS fell between 2.9 and 4.8 months. The increments of median OS were between 5.4 and 6.6 months. All the delta OS are larger than the delta PFS in the four trials.Conclusion: Regardless of the antibody drug targets, ADC provides consistent improvements in median OS that surpasses the improvements in median PFS in metastatic breast cancer. The mechanism warrants further investigation. Citation Format: I-Chun Chen, Ching-Hung Lin, Yen-Shen Lu. Benefits Provided by Antibody Drug Conjugates in Overall Survival Outweighs those in Progression-free Survival for Metastatic Breast Cancer: A Class Effect [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 P4-01-34.

Palbociclib plus endocrine therapy in hormone receptor-positive and HER2 negative metastatic breast cancer: a multicenter real-world study in the northwest of China

BackgroundReal-world data of Palbociclib are insufficient in China. This study aimed to investigate the treatment pattern and real-world outcomes in hormone receptor positive and human epidermal growth factor 2 receptor negative (HR+/HER2-) metastatic breast cancer (MBC) patients treated with Palbociclib in the northwest of China.MethodsHR+/HER2- MBC patients who received Palbociclib in 8 centers from July 2017 to September 2019 were retrospectively included in this study. Real-world objective response rate (ORR), progression-free survival (PFS) and safety profiles were analyzed. The survival curves were plotted by the Kaplan-Meier method to analyze PFS, which was verified by the log-rank test.ResultsIn total, 211 women were eligible for the analysis. A total of 85 patients (40.3%), 78 (37.0%), and 48 (22.7%) received Palbociclib in the first-, second-, third- or later-line setting, respectively. 46 patients achieved partial response and 145 patients experienced stable disease, with an ORR of 21.8% and a disease control rate of 90.5%. Following a median follow-up period of 14.2 months, the median PFS was 12.2 months (95% confidence interval, 10.1-14.3 m), and the median overall survival was not reached. Early Palbociclib initiation, sensitivity or acquired resistance to endocrine therapy, estrogen receptor and progesterone receptor double positivity, less than 3 metastatic sites, without visceral metastasis, bone metastasis only, without prior chemotherapy or endocrine therapy were associated with a prolonged PFS in MBC (All P < 0.05). The most common grade 3 or 4 adverse events (AE) was neutropenia (36.5%), and the most common nonhematologic AE was fatigue (10.9%). No patient experienced AE leading to treatment discontinuation.ConclusionPalbociclib plus endocrine therapy exhibited favorable effectiveness and manageable toxicities in the real-world setting, supporting their use in Chinese patients with HR+/HER2 − MBC.

Abstract P1-04-10: Assessment of circulating tumor cells (CTC) by RT/PCR as a surrogate marker for PFS in metastatic breast cancer (MBC)

Abstract Background: Despite significant improvements in the treatment of metastatic breast cancer (MBC), it remains an incurable disease. The presence of circulating tumor cells (CTC) predicts for progression free survival (PFS) in (MBC) patients. We hypothesized that the change in level of CTCs can be a good surrogate marker for PFS. Methods: CTC level was determined by flow cytometry (FCM) in the blood of MBC female patients with measurable or non-measurable evaluable disease excluding CNS metastasis 1) before starting taxanes (Docetaxel or Paclitaxel) regimen, 2) after the first cycle, and 3) at assessment of the disease after 3-4 cycles. The breast origin was further confirmed through assessment of CK19, mammaglobin, prolactin inducible peptide (PIP), aldehyde dehydrogenase 1 (ALDH1) and human chorionic gonadotropin (hCG) in the separated CTCs by quantitative real time PCR (QRT-PCR). CTC level and level of these markers were correlated with the clinical features of the patients, response to treatment and PFS. Results: Sixty-six female patients were enrolled between May 2010 and Jan. 2011. The median age was 48.9 years and duct carcinoma was the main pathologic subtype. After a median follow up period of 20 months, median PFS was 6 months. There was a very strong relation between the selection marker CK-19 and the breast cancer markers (p value = 0.0001). Patients with baseline CTC &amp;lt; 4 had significantly higher median, 6 months and 1 year PFS when compared with those with CTC ≥ 4 (p value = 0.03) while CTC levels did not correlate with PFS in the 2nd &amp; 3rd samples respectively (p value = 0.28). Also patients whose CTC level decreased after treatment had significantly prolonged median PFS compared to patients whose CTC level increased (10 versus 4 months, p = 0.007). Conclusions: CTCs; measured by RT-PCR were strongly predictive of PFS in MBC. CTC also could be of a great potential value in early assessment of response to chemotherapy after the 1st cycle especially in non-measurable lesions. Key Words: Circulating tumor cells, metastatic breast cancer, progression free survival and RT-PCR. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-04-10.

Abstract P4-09-09: Circulating HER2 extracellular domain (ECD) levels are associated with progression-free survival in metastatic breast cancer patients

Abstract Background: The human epidermal growth factor (HER2/neu) oncoprotein is composed of an intracellular tyrosine kinase portion, a short transmembrane section, and an extracellular ligand-binding domain (ECD). The latter is frequently cleaved from the surface of breast cancer cells and the serum HER2 ECD levels can be detected by enzyme-linked immunosorbent assay (ELISA). Consistent with majority of reports, our prior study showed that high circulating levels of the HER2 ECD indicates poor prognosis in 207 patients with metastatic breast cancer. In the present study, we aimed to elucidate whether serum HER2 ECD levels would predict the clinical outcome of metastatic breast cancer patients. Methods: Till May 19, 2012, one hundred ninty metastatic breast cancer patients were followed up. Serum was available from 190 patients at baseline, 46 patients in the assessment of time. Serum HER2 ECD levels were measured by ELISA. Disease state was assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Progression-free survival (PFS) was defined as the interval from the time of randomization until the first documentation of disease progression or death due to any cause. PFS and median PFS were generated by Kaplan-Meier spots. Results: Elevated baseline HER2 ECD levels (bECD) (≥15 ng/ml) were observed in 40% (40/100) of patients with HER2-amplified tumors and 21.8% (19/87) of patients with HER2-negative tumors. Patients with bECD-elevated disease had a median PFS of 356 days compared with 229 days for patients with bECD-low disease(P = 0.001). In HER2-amplified cohort, median PFS for patients with low bECD levels was longer than those with bECD-elevated disease (391 days v 226 days, P = 0.005). And patients with low bECD levels treated with Herceptin-based regimen (n = 36) had a trend of longer PFS than patients(n = 24) treated with non-Herceptin regimen(447 days v 298 days, P = 0.227). Moreover, bECD-low patients (n = 36) showed a significantly longer median PFS than bECD-elevated patients(n = 22) when treated with Herceptin-based scheme (447 days v 229 days, P = 0.004). While, in patients with increased bECD levels, there was no statistical difference between Herceptin-treated groups (n = 22) and non-Herceptin-treated groups (n = 14) (229 days v 173 days, P = 0.761). In the HER2-negative group, patients with bECD-low disease had a median PFS of 313 days compared with 206 days for patients with bECD-elevated disease (P = 0.02). In a cohort of 46 patients whose HER2 ECD levels were monitored during treatment, 29 patients remains low ECD levels, 12 patients convert from elevated to low, 2 patients convert from low to high, and 3 patients remains elevated HER2 ECD levels. The patients who remained low ECD levels or achieved low ECD leves have significantly longer PFS than those whose levels remained above 15ng/mL or converted from low to high regardless of treatment given (440 days v 192days, P = 0.019). Conclusion: Elevated HER2 bECD predicts poor median PFS irrespective of HER2 status. HER2-amplified patients with low-HER2 ECD levels may get more benefit from Herceptin-based scheme. Remained low-HER2 ECD levels or decreases in serum HER2 ECD levels during treatment were associated with longer median PFS in metastatic breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-09-09.

Relationship between OS and PFS in metastatic breast cancer (MBC): Review of FDA submission data.

1035 Background: An improvement in overall survival (OS) in a randomized controlled study is the gold standard endpoint for the regular approval of new treatments in MBC. Progression-free survival (PFS) has been used for approval of second and third-line indications or accelerated approval of first-line indications. We have further explored the relationship between OS and PFS in MBC. Methods: We reviewed 12 randomized clinical trials in 8,431 patients with MBC. The trials led to new drug approvals or were presented at an ODAC meeting. All of these trials had PFS as a primary or secondary endpoint. Due to important limitations (e.g., lack of endpoint definitions, inconsistent PFS definitions, or insufficient information on trial statistical design) with some published trials, we limited our evaluation and endpoints correlation to data reviewed by the FDA. The relationship between PFS and OS in MBC was investigated using a weighted linear regression model, where each trial was weighted by the sample size. T...