الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
BC is now the most common cancer after surpassing lung cancer worldwide in 2020. The prevalence of patients living with MBC has been steadily rising, therefore, it is important to be able to counsel MBC patients on the association between MFI and prognosis. Furthermore, the use of MFI as a surrogate end point in breast cancer clinical trials was not tested before, yet if the correlation is proven and validated, we might have a trusted endpoint that facilitate trial designation and provide patient’s population with beneficial drugs in a feasible process in shorter duration.
As stated by the ASCO, active cancer management should achieve the goal of improving quality of life or extending overall survival. The FDA considers OS benefit as the foundation for the approval of new antineoplastic therapeutics.
Nevertheless, the increasing number of effective treatments available in many types of tumors as well as the understanding of the heterogenous nature of a single tumor type have resulted in the need for a larger number of intent to treat patients to be included in clinical trials as well as more prolonged follow up period to attain sufficient events that can achieve planned significant statistical power; this however leads to an increase in the financial cost of clinical trials and requires a more prolonged duration to obtain valid results.
As a result, the FDA has permitted the use of clinical trial’s intermediate endpoint that is considered a substitute or an alternative for the outcome they want to study and name it a surrogate endpoint. Both prospective and retrospective research are needed to show that the surrogate endpoint can be relied upon to predict or correlate with the clinical benefit before using it.
In breast cancer, surrogate end points, such as pCR, DFS and PFS have been widely used as primary end points in phase III trials.(25) Nevertheless, the evidence behind the validation of these intermediate end points as surrogate end points for OS is weak and still may trials are doubting and questioning their validation. Meanwhile, MFS has been proven to be a Strong statistically significant OS Surrogate in Localized Prostate Cancer.(25, 35) However, this surrogacy has not been studied or put in a research context in breast cancer or any other solid tumor except for prostate cancer.
Between December 2009 and 2019, we conducted a retrospective study at Medical Research Institute, and we found two thousand one hundred and twenty-nine BC patients in total. Out of these, 1704 didn’t develop any distant metastasis and hence were excluded from the study, remaining with 425 metastatic breast cancer female patients. Among them, 93 patients presented with de novo stage IV and were as well excluded according to the eligibility criteria. our analysis was focused on patients with upfront stage I-III disease and furtherly turned metastatic who were 332 in number. Out of these 332 breast cancer female patients, 186 patients (56%) had a short MFI ( < 3 years), 80 patients (24.1%) had an intermediate MFI (3-5 years), and 66 patients (19.9%) had a long MFI ( > 5years).
At the end of the study, the mean overall survival time for patients was 102.3 months and the median duration of MFS was 31.4 months. The mean OS for patients having Short, Intermediate and Long MFS was 72.8, 84.9 and 124.9 months respectively and that was statistically significant.
Regarding the correlation between the MFS and OS, in the whole study population, the MFS was very strongly correlated with the OS with a pearson coefficient of 0.855 and a p value <0.001. In the MFS interval subgroups, in Patients with short MFS, the MFS was moderately correlated to OS, while in patients with Long MFS, the MFS was strongly correlated to OS, However, in patients with intermediate MFS, There was a weak non statistically significant correlation between MFS and OS, Longer confirmatory follow up is needed for that subgroup.
MFI was significantly different among different breast cancer subtypes; the duration of MFI was longest in the ER+ve, PR+ve Her2-ve with a median of 41.60 months followed by ER+ve, PR+ve HER2+ve with a median MFI of 34.37 months. On the other hand, ER-ve, PR–ve HER2 +ve and TNBC had roughly equal median duration of MFI of 19.15 and 19.20 respectively.
After adjusting for confounders by Cox regression, patients age at diagnosis, tumors size, N-status, breast cancer subtype and targeted therapy administration were independent predictors for MFS.
Patient’s age at diagnosis was a significant predictor of MFI with young patients aged <40 years had a shorter median MFI of 23.6 months in comparison to that of 40 years or older who had longer median MFI of 54.1 months. MFI is significantly influenced by pathological tumor size (p <0.001), Patients with T1 tumors had a median MFI of 34.3 months followed by T2 tumors with a median MFI of 31.4 months then T4 tumor with a median MFI of 24.5 months while T3 tumors had the least median MFI of 7.8 months . Regarding the correlation between MFI and pathological LN status, MFI was significantly the longest in No patients with a median duration of 67 months followed by N1, N3, N2 status with a median MFI of 32.4 months, 24.3 months, and 30.9 months respectively. There was a clear significant difference in MFI among tumor subtypes. (p<0.001). ER+ve, PR+ve Her2-ve had the highest MFI with a median of 41.6 months followed by ER+ve, PR+ve HER2+ve who had a median MFI of 34.4 months. ER-ve, PR–ve HER2: +ve and TNBC had a nearly equal MFI with a median of 19.1 months and 19.2 months respectively. Receival of targeted therapy significantly impacted the MFI (p value=0.002); Patients who received targeted therapy had a higher median MFI of 34.4 months in comparison to median of 24.3 months in those who didn’t receive targeted therapy.
The investigation of the univariate effect of Treatment modalities on both MFS and OS. It was found that MFS was significantly influenced by Chemotherapy, adjuvant hormonal therapy and targeted therapy administration while on the other hand OS was significantly influenced by Targeted Therapy administration.
Therefore, MFS was found to be significantly and strongly correlated to OS in the whole sample population with significant differences among different breast cancer subtypes. Multivariate analysis showed that patient’s age at diagnosis, tumors size, N-status, breast cancer subtype and targeted therapy administration were independent predictors for MFS validating its use as a prognostic marker. Regarding the effect of treatment modalities on both, MFS was significantly influenced by Chemotherapy, adjuvant hormonal therapy and targeted therapy administration while on the other hand OS was significantly influenced by Targeted Therapy administration.