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Association of Age with Response to Preoperative Chemotherapy in Patients with Muscle-Invasive Bladder Cancer - Beyond the Abstract

Cisplatin-based neoadjuvant chemotherapy (NAC) has been shown to significantly improve survival in patients with clinically non-metastatic bladder cancer (cT2-4N0M0 MIBC).1–3 However, not every patient is likely to respond to NAC and is, therefore at risk for progression and delay of radical cystectomy (RC).4 Identification of patients who are unlikely to respond to NAC is of paramount importance for clinical decision making and patient counseling in order to avoid overtreatment and minimize unnecessary adverse events. A recent analysis of The Cancer Genome Atlas (TCGA) showed an age-related distribution of total mutational burden, neoantigen load, molecular subtypes, and intra-tumoral immune signaling in MIBC.5 Based on these findings, we hypothesize that there might be an age-dependent response to NAC.

In this study, we analyzed the data originating from a large multicenter cooperation project. We evaluated the association of patient age with pathologic response using univariable and multivariable logistic regression modeling. We used two different approaches for the time-to-event analysis. First, we used the Cox regression analysis to investigate the association of age with OS and CSS. Second, we estimated the marginal probability of death from BC using competing risk analysis where death of other cause was considered the competing event.

We identified 1,105 patients with MIBC treated with cisplatin-based NAC. Overall, 437 (40%) patients had a pathologic objective response (≤ypT1N0, pOR) and 234 (21%) had pathologic complete response (ypT0N0, pCR). The population was stratified based on age quartiles. There was no difference in clinicopathologic features, distribution in pOR or pCR between age quartiles. On logistic regression analyses, age evaluated as a continuous variable or stratified in quartiles was not associated with pathologic response (all p > 0.7). Overall, 139 patients had an insufficient follow-up, leaving 966 patients for survival analyses.

During a median follow-up for alive patients of 18 months (IQR 6 – 37), 303 (31%) died of any cause and 250 (21%) died of MIBC. On Cox regression analysis, age evaluated as continuous variable or stratified in quartiles was not associated with cancer-specific survival or overall survival (all p > 0.2). Similarly, on competing risk regression analysis age was not associated with cancer-specific death (all p > 0.052).

In a second step, we used data from 395 TCGA patients6 to investigate the prevalence of TCGA molecular subtypes (luminal papillary, luminal infiltrated, luminal, basal squamous, and neuronal) and DNA damage repair (DDR) gene alterations according to patient age.

When age was analyzed as a continuous variable, we found an association of ERCC2 mutations with older age. There was no difference in the distribution of age according to overall gene mutation (p = 0.13). Finally, we found older age distribution in patients with luminal (p < 0.001) and luminal infiltrated (p = 0.002) compared to those with luminal papillary molecular subtype.

In our analysis, we failed to prove an association of age with response to preoperative chemotherapy and survival in patients treated with RC. Our findings support the administration of preoperative chemotherapy, in patients who can tolerate it, regardless of their age.

Written by: David D'Andrea, MD,1 Shahrokh F. Shariat, MD,1,2,3,4,5

  1. Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
  2. Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA
  3. Departments of Urology, Weill Cornell Medical College, New York, New York, USA
  4. Department of Urology, Second Faculty of Medicine, Charles University, Prag, Czech Republic
  5. Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
References:

  1. Vale CL. Neoadjuvant Chemotherapy in Invasive Bladder Cancer: Update of a Systematic Review and Meta-Analysis of Individual Patient Data Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Eur Urol 2005;48:202–6. https://doi.org/10.1016/j.eururo.2005.04.006.
  2. Yin M, Joshi M, Meijer RP, Glantz M, Holder S, Harvey HA, et al. Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: A Systematic Review and Two-Step Meta-Analysis. Oncol 2016;21:708–15. https://doi.org/10.1634/theoncologist.2015-0440.
  3. Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, et al. Neoadjuvant Chemotherapy plus Cystectomy Compared with Cystectomy Alone for Locally Advanced Bladder Cancer. New Engl J Medicine 2003;349:859–66. https://doi.org/10.1056/nejmoa022148.
  4. Zargar H, Espiritu PN, Fairey AS, Mertens LS, Dinney CP, Mir MC, et al. Multicenter Assessment of Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer. Eur Urol 2015;67:241–9. https://doi.org/10.1016/j.eururo.2014.09.007.
  5. Seiler R, Wyatt AW, Black PC. Molecular landscape of carcinoma invading bladder muscle: does patient age matter?: Comment. Bju Int 2019;124:719–21. https://doi.org/10.1111/bju.14802.
  6. Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, et al. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell 2017;171:540-556.e25. https://doi.org/10.1016/j.cell.2017.09.007.

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