Impact of HPV 16/18 infection on clinical outcomes in locally advanced cervical cancers treated with radical radio (chemo) therapy - A prospective observational study

Mahantshetty, Umesh; Teni, Tanuja; Naga, Pushpa; Hotwani, C.; Umesh, Sumuki; Kannan, Sadhana; Hande, Vinod; Pawar, Sagar; Chopra, Supriya; Deodhar, Kedar; Maheshwari, Amita; Gurram, Lavanya; Gupta, Sudeep; Shrivastava, Shyam Kishore

doi:10.1016/j.ygyno.2017.11.034

Cited by 20 publications

(24 citation statements)

References 23 publications

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“…E2F binding sites are found in the promoters of genes involved in DNA synthesis, mitosis and cell cycle progression, thus E7 activates host DNA replication machinery, promotes G1 to S phase transition and ultimately results in cellular proliferation. 48,49 Similar results have also been reported for HPV-positive head and neck cancer. Additionally, there is evidence that HPV E6 and E7 promote radioresistance in cervical cancer and that radiation-resistant clones can express higher levels of oncoproteins after sublethal damage, which could confer a growth advantage.…”

Section: Discussionsupporting

confidence: 81%

“…Two such studies have reported that patients with persistent HPV infection after radiotherapy have a significantly increased risk of local recurrence. 48,49 Similar results have also been reported for HPV-positive head and neck cancer. 50 Together with our findings reported here, this suggests that cells harboring HPV may survive CRT, maintain proliferative potential and result in poor patient outcome.…”

Section: Discussionsupporting

confidence: 81%

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Decreased local immune response and retained HPV gene expression during chemoradiotherapy are associated with treatment resistance and death from cervical cancer

Cosper

McNair

González

et al. 2019

Intl Journal of Cancer

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More than one-third of patients with locally advanced cervical cancer do not respond to chemoradiation therapy (CRT). We aimed to characterize the transcriptional landscape of paired human cervical tumors before and during CRT in order to gain insight into the evolution of treatment response and to elucidate mechanisms of treatment resistance. We prospectively collected cervical tumor biopsies from 115 patients both before and 3 weeks into CRT. RNA-sequencing, Gene Set Enrichment Analysis and HPV gene expression were performed on 20 paired samples that had adequate neoplastic tissue mid-treatment. Tumors from patients with no evidence of disease (NED) at last follow-up had enrichment in pathways related to the immune response both pretreatment and mid-treatment, while tumors from patients dead of disease (DOD) demonstrated enrichment in biosynthetic and mitotic pathways but not in immune-related pathways. Patients DOD had decreased expression of T-cell and cytolytic genes and increased expression of PD-L2 mid-treatment compared to patients NED. Histological and immunohistochemical analysis revealed a decrease in tumor-associated lymphocytes (TAL) during CRT in all patients but tumors from patients DOD had a significantly more pronounced decrease in TALs and CD8+ cells mid-treatment, which was validated in a larger mid-treatment cohort. Finally, patients DOD retained more HPV E6/E7 gene expression during CRT and this was associated with increased expression of genes driving mitosis, which was corroborated in vitro. Our results suggest that decreased local immune response and retained HPV gene expression may be acting together to promote treatment resistance during CRT in patients with cervical cancer.Additional Supporting Information may be found in the online version of this article.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 81%

Decreased local immune response and retained HPV gene expression during chemoradiotherapy are associated with treatment resistance and death from cervical cancer

Cosper

McNair

González

et al. 2019

Intl Journal of Cancer

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“…For example, Nagai et al 7 reported a 4 to 5 times higher risk of treatment failure in individuals with persistent HPV expression after radiotherapy alone. However, this number is higher than the 3 times higher risk that we report and is similar to the findings by Mahantshetty et al 12 This difference in outcomes could be due to treatment-related factors, such as the use of chemotherapy, or biological differences, such as subtypes of HPV. In our study, in which 69% of the patients had HPV-16, we found that patients with HR-HPV subtypes other than HPV-16 were more likely to have PE after CRT and experience PD.…”

Section: Discussionsupporting

confidence: 90%

“…Although risks of treatment failure were similar among patients with persistent HPV expression in our study and in Mahantshetty et al's study, 12 2 notable differences between the studies were the rates of HPV clearance (80% and 34%, respectively) and the corresponding incidences of PF among all patients (27 of 97 patients [28%] and 56 of 133 patients [42%], respectively). This finding could be due to many factors, but chief among them could be the use of FDG-PET imaging.…”

Section: Discussionsupporting

confidence: 57%

“…Some studies have documented persistent HPV infection rates as high as 40% to 60% after treatment with corresponding higher rates of treatment failure. 8,11,12 The literature remains sparse, however, and the time points at which HPV clearance has been evaluated may not represent actionable time points for treatment escalation. 13 Moreover, none of these studies have evaluated whether posttherapy HPV expression can serve as a prognostic biomarker independently of posttherapy FDG-PET findings, which have previously been shown to be prognostic.…”

Section: Introductionmentioning

confidence: 99%

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Early posttherapy clearance of human papillomavirus and treatment response in cervical carcinoma

Srivastava

Contreras

Davis

et al. 2020

Cancer

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Background Among patients with cervical cancer, little is known about the significance of persistent human papillomavirus (HPV) expression after chemoradiation (CRT). This study evaluated associations between early posttreatment HPV clearance and patient outcomes with an added focus on the value of posttherapy positron emission tomography (PET) imaging. Methods Included patients underwent pretreatment testing indicating a high‐risk HPV infection and posttreatment testing with a messenger RNA (mRNA)–based genital swab after CRT. Posttherapy responses were stratified on the basis of HPV mRNA detection into an early clearance (EC) group (no mRNA) and a persistent expression (PE) group (detectable mRNA) on the basis of an evaluation at a median of 6 weeks after therapy. The Kaplan‐Meier method was used to compare outcomes, and multivariable analysis was used to identify predictors of outcomes. Results Seventy‐two of the 97 eligible patients (74.2%) had EC. The mean follow‐up time was 25 months (range, 4‐56 months), and 2‐year pelvic control (76.9% vs 50.2%; P = .01) and overall survival (OS; 80.9% vs 52.2%; P < .01) were superior among EC patients. In the multivariable analysis, EC predicted for improved survival (hazard ratio [HR] for mortality, 0.46; 95% confidence interval [CI], 0.21‐0.96; P = .047), as did a complete response (CR) on posttherapy PET (HR for less than a CR on PET, 6.17; 95% CI, 2.58‐14.72; P < .01). In a subset analysis of patients with a posttherapy PET CR, HPV clearance retained prognostic significance (2‐year OS, 95.6% with EC vs 66.7% with PE; P = .04), whereas PE patients without a PET CR had the worst survival (35.9%; P < .01 for trend). Conclusions Early posttherapy clearance of HPV is associated with improved survival in cervical cancer. Evaluating HPV expression at this 6‐week time point provides prognostic information beyond posttherapy PET imaging and may aid in risk stratification and decisions for treatment escalation.

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Gynaecological Oncology in India: Past, Present and Future

Kulkarni

Gupta

2022

Indian J Surg Oncol

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Impact of HPV 16/18 infection on clinical outcomes in locally advanced cervical cancers treated with radical radio (chemo) therapy - A prospective observational study

Cited by 20 publications

References 23 publications

Decreased local immune response and retained HPV gene expression during chemoradiotherapy are associated with treatment resistance and death from cervical cancer

Decreased local immune response and retained HPV gene expression during chemoradiotherapy are associated with treatment resistance and death from cervical cancer

Early posttherapy clearance of human papillomavirus and treatment response in cervical carcinoma

Gynaecological Oncology in India: Past, Present and Future

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