Impact of HPV-16 lineages infection on response to radio-chemotherapy in cervical cancer

doi:10.21203/rs.3.rs-2626331/v1

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Impact of HPV-16 lineages infection on response to radio-chemotherapy in cervical cancer

https://doi.org/10.21203/rs.3.rs-2626331/v1

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Aim

Estimate the frequency of Human papilloma virus (HPV) 16 lineages in specimens of cervical cancer, relate the pathological factors in those variants and assess the response to treatment with radical chemoradiotherapy.

Methods

Samples of cervical cancer were collected from women referred to reference cancer hospital to test the presence of Human papilloma virus types DNA. The standard protocol of the service consisted of cisplatin based chemotherapy 40 mg/m² plus conventional pelvic irradiation in the dosis of 45-50.4 Gy and high dose rate brachytherapy of 28–30 Gy to Point A. The response to chemotherapy was avaliated after three months in those patients with HPV − 16 lineage.

Results

HPV DNA was detected in out 104 (88.1%) of the 118 patients. HPV-16 present in 63 patients (53%). Lineages of HPV 16 identified in 57 patients being: 33 (57.8%) lineage A, 2 lineage B (3.5%), 2 lineage C (3.5%) and 20 (35.0%) lineage D. The median age of the patients was 48.4 years (range 25–85 years). Squamous cell carcinoma was detected 48 times (84.2%). Adenocarcinoma were more likely to occur in lineage D, as three of the four cases occurred in this lineage. A total of 11patientes with HPV-16 variant were treated with chemoradiotherapy. After three months, was observed that nine of the eleven patients (81.8%) achieved complete response: five of the lineage A, two of the lineage C and two of the lineage D. The cases of partial response and progression of disease, one each, occurred in the lineage A.

Conclusion

Besides the small number of patients and HPV variants, we notice better response in patients with HPV 16 lineage A. Increasing the sample could be helpful to better associate the impact of HPV variants on cervical cancer treatment.

Cervical cancer

HPV 16 variants

Radiotherapy

follow-up

Among women are estimated 8.6 million new cases of cancer and 4.2 million deaths for 2018. Cervical cancer occupies the fourth position in incidence and mortality, with 569,847 new cases (6.6%) and 311,365 deaths (7.5%). Its frequency relates to Human Development Index (HDI), although its frequency is declining in developed countries, we observe a burden of new cases in regions less developed. Are expected 710,249 new cases in the world so soon as 2030 (Bray et al. 2018). High-risk human papillomavirus (HPV) infection is supposed to be the main cause of cervical carcinoma (zur Hausen, 2002). Its presence is considered necessary, but nor sufficient for the progress of this type of tumorr (Bosch et al., 1995). Among the high-risk types HPV with oncogenic potential, the HPV 16 is responsible for half of the cases of cervical cancer (American College of Obstetricians and Gynecologists, 2002).

In addition to the classification of HPV types, we can analyze in terms of variants. A variants lineage must show a difference between 1% and 10% in the nucleotide sequences of the protein L1. Since 2013 the classification of HPV16 variants utilizes a numerical alpha pattern, they were grouped in four main strains: A, B, C and D. Lineage A includes the sublineages before known as European (A1, A2, A3) and Asian (A4). Lineage B comprisses the sublineages African 1a and African 1b (B1, B2). Lineage C encompasses the old African branch 2. Lineage D includes the sublineages North American (D1), Asian American (D2, D3)(Yamada et al., 1975; Burk et al., 2013).Several studies suggested that this genetic variability between the HPV16 variants could influence the potential for infection, viral persistence and development of invasive cervical cancer (Villa et al., 2000; Bernard et al., 2006; Gheit et al., 2011).

Remains controversial the role of genotyping HPV to determine better outcome in cervical cancer treatment. Some studies proposed that the determination of HPV type has no prognostic consequence in cervical cancer (Kristensen et al., 1996) and others demonstrated worse response to radiation registered in the patients HPV16 infected (Ferdousi et al., 2010). It was hypothesized that this phylogenetic single-nucleotide polymorphism among HPV 16 lineages and sublineages could provide difference in the response to cancer treatment with radiotherapy and chemotherapy depending of the detected HPV variant (Hang et al., 2014) and thus serve as a prognostic factor in the treatment of cervical tumor. Nevertheless the function of HPV variants as a modulator factor on response to treatment in carcinoma of the cervix still uncertain.

2.1 Sample

Patients with proven cervical carcinoma were requested to join this study, conducted between April 2016 and April 2018 at the Aldenora Bello Cancer Hospital and Tarquinio Lopes Filho Cancer Hospital, located in São Luis – Maranhão (Brazil).

Samples of tumor material were collected from 125 women with cervical cancer, with follow-up being carried out women, recording the oncological treatment, according to the protocol of the hospitals, until the when they returned for a consultation to evaluate the treatment performed.

The study was accepted by the Institutional Ethical Committee. All patients were informed and signed permission to participate before trial initiation.

2.2 Epidemiological data

Patients referred for outpatient care at the Gynecology Service Oncologists in these hospitals were invited to participate in this study, and the objectives of the study, if they accepted, they signed the Informe Consent Form (ICF) and were submitted to a questionnaire to collect the socio-demographic data.

The patients in whom the presence of a tumor was demonstrated in the biopsy of the uterine cervix and that met the inclusion criteria, were followed up after diagnosis, and collected treatment data in a Clinical Questionnaire recording performed oncological procedures (Surgery, Radiotherapy, Chemotherapy or otherwise performance), until your first follow-up return with tests to assess the response to the treatment performed.

2.3 Inclusion and exclusion criteria

The inclusion criteria was to be women over 18 years of age diagnosed with cervical cancer who agreed to participate in the research by signing an informed consent form.

The exclusion criteria were: Women with small lesions, in which the performance of the biopsy could interfere with the staging, women undergoing psychiatric treatment and women that refused to sign the informed consent form.

2.4 Experimental procedures

The collected samples containing tumor fragments were placed in microtubes, containing one ml of RNA Later and transported in thermal boxes at 4°C and sent to the Multiuser Laboratory located in the Biobank of Tumors and DNA of the Maranhão following registration and storage protocols. After 24 hours, the sample was RNA was removed later and stored in a freezer at -80°C until the procedures were performed laboratory.

Extraction of genomic DNA from frozen samples was performed as per protocol described by the Dneasy Blood and Tissue kit user manual.

For the identification of HPV DNA in samples of cervical tumors, it was PCR Nested amplification technique was used, according to Vidal et al (2016).

The determination of HPV genotypes was performed by automated sequencing of the PCR product using the MegaBACE 1000 sequencer (GE Healthcare, UK). At reactions were carried out at the Molecular Biology Laboratory of the State University of Maranhão located at the Center for Higher Studies in Caxias (CESC - UEMA). The sequencing was performed with the BigDye™ Terminator v3.1 Cycle Sequencing kit (Thermo Fisher Scientific), according to the manufacturer's protocol.

For the analysis and alignment of the nucleotide sequences obtained in the sequencing, the Chromas program was used, obtaining electropherograms of the HPV DNA sequences present in the samples. For confirmation and identification of type of HPV, the comparison of the nucleotide sequences of the samples was performed sequenced, submitting them to the World Nucleotide Database – Gene Bank, using the BLAST program (NCBI).

2.4 HPV variants

After identifying the types of HPV present, the samples infected by HPV16 were submitted to a new PCR amplification protocol of regions of the viral genome, capable of identifying the variant to which that type of HPV detected belongs.

Two pairs of primers were used, which amplify the entire LCR region and the E6 gene.

The PCR product was further purified and sequenced according to afore mentioned protocol. Consensus sequences were joined using the software Geneious (Biomatters Ltd.) and all generated sequences were aligned according to the specific strains for HPV 16, using reference sequences proposed by Burk et al (2013) using MEGA software (version 6.0, www.megasoftware.net). The analysis ofvariants of HPV 16 and the construction of the phylogenetic tree was carried out at the National Institute of Cancer, under the supervision of Dr. Miguel Angelo Martins Moreira.

2.6 Clinical data

The International Federation of Gynecology and Oncology (FIGO) staging system was used to classify all patients. Contrast enhanced computadorized tomography (CT) of abdomen and pelvis performed to access lymph node involvement. Pathological features as tumor size, histological type, grade of differentiation, hemoglobin level and parametrial and vaginal were recorded. We included patients treated with concurrent chemotherapy radiotherapy treatment (CCRT) for the purpose of cure.

Patients treated according to the department protocol. The external beam radiotherapy (EBRT) were performed with 4-field box procedure to whole pelvis, protecting organs at risk, being prescript 45-50.4 Gy dosis, daily fractions of 1.8 Gy, five fractions treated weekly. Additional parametrial boost until 54 Gy, protecting the midline, was realized with dose planned according to the stage. External beam irradiation executed by Cobalt-60 or 6 MV linear accelerator (Siemens). The patients given treatment with CCRT, received cisplatin, 40mg/m² for 6 cycles, weekly, performed with concurrent external radiation. Intracavitary brachytherapy was given employing the high-dose rate (HDR) after loading technique, supplied in four fractions, two times a week, with a dosis of 7-7.5 Gy per session to Point “A” according to clinical stage and tumor volume.

2.6 Local response to treatment

The assessment of local response to treatment was programmed to occur 12 weeks after radiation end, performed with gynecological clinical examination, a cervical cytology, CT in all cases (whenever necessary ultrasound or magnetic resonance imaging) and cervical biopsies in uncertain cases to access absence or presence of the tumor. They were classified ascomplete response (100% decreasing of the original tumor volume without clinical or radiologic presence of disease), partial response (decreasing of the original tumor volume by at least 50%), stable disease (reduction of less than 25% or progression up to 10% of the initial volume) and progression of disease (increase of more than 25% of the initial volume).

2.7 Ethical aspects

This study complied with all the principles set out in the Declaration of Helsinki and Resolution 466 of December 2012 of the National Health Council of Ministry of Health, guaranteeing the secrecy, reliability and dignity of the subjects of the research, as well as guaranteeing their autonomy and defense of their vulnerability.

The study project was previously approved by the Research Ethics Committee of the Federal University of Maranhão (CEP-UFMA), under Consolidated Opinion No.1.289.419/2015.

2.8 Statistical analysis

Descriptive statistical analysis was performed using the Stata program (version 14.0), data being presented in the form of figures and tables. To check association between the HPV and sociodemographic and clinical variables, the x 2 (square) test was used, with p values ≤ 0.05 were considered statistically significant.

The values referring to not knows/did not answer were excluded from the association analysis.

3.1 Sociodemographic data

The study population consisted of 118 women diagnosed with cancer cervical cancer treated at the Aldenora Bello Cancer Hospital and Tarquínio Cancer Hospital Lopes Filho.

The age range varied between 25 and 89 years, with an average age at diagnosis of 50.6 years old. Most of the cases, around 75 (63.5%) occurred between 30 and 59 years of age. Most women declared themselves to be brown (69.5%). Married or in a stable union predominated (51.7%)

Smoking was a reported habit by about 50 women (42.4%). The largest contingent of women was illiterate (33.0%), only 22 women (18.6%), had 12 or more years of study. The per capita income in the families of 76 women (64.4%) was less than half the minimum wage (corresponding amount of R$ 880.00 at the time). Most of the women, 52 (44.1%) came from municipalities with low human development index (HDI).

3.2 Reproductive data

Evaluating the reproductive history, it was observed that 75 women (63.6%) started sexual activity before age 18, and 63 women (53.4%) reported having had up to 2 lifetime sexual partners. High parity was observed, with 62 women (52.6%) having had more than 5 children. Most women, 87 (73.7%) reported having knowledge of the purpose of the preventive, and about 15 women (12.7%) reported not perform preventive and more 48 women (40.7%) do it with a higher periodicity to 3 years or irregularly (Table 1).

Table 1

Reproductive history and knowledge about cervical cancer prevention of patients with cervical cancer, São Luís – Maranhão, 2016–2018, (n = 118).
Age of onset of sexual activity (years)	N	%
10–15	38	32.2%
16–18	37	31.5%
>= 19	20	16.9%
Don't know/didn't answer	23	19,.5%
Sexual partners
1	37	31.5%
2	26	22.0%
3	18	15.3%
4 ou mais	17	14.4%
Don't know/didn't answer	20	16.9%
Delivery number
0	04	3.4%
1 a 2	21	17.8%
3 a 4	29	24.6%
5 a 6	16	13.6%
7 a 8	22	18.6%
9 or more	24	20.3%
Don't know/didn't answerl	02	1.7%
Knowledge about the purpose of the Pap test
Yes	87	73.7%
No	29	24.6%
Don't know/didn't answer	02	1.7%
Pap test before câncer diagnostic
Yes	102	86.4%
No	15	12.7%
Don't know/didn't answer	01	0.8%
Pap test frequency
Once a year	43	36.4%
Every 2 years	09	7.6%
Every 3 years	02	1.7%
Not regular	48	40.7%
Never	15	12.7%
Don't know/didn't answer	01	0.8%

3.3 Clinical data

There was a high frequency of advanced stages at diagnosis. EC IIB was recorded in 30 women (25.4%) and EC IIIB in 50 women (42.4%). Squamous cell carcinoma was the most frequent, with 94 cases (79.7%), while adenocarcinoma was observed 11 times (9.3%). About 67 patients (56.8%) had a tumor with a diameter greater than 4.0 cm. The presence of lymph node metastasis was observed in 12.7% of cases. (Table 2).

Table 2

Tumor staging and clinical aspects in patients with cervical cancer, São Luís – Maranhão, 2016–2018, (n = 118).
Tumor staging
EC 0	02	1.7%
EC IA1	01	0.8%
EC IB1	18	15.3%
EC IB2	01	0.8%
EC IIA	10	8.5%
EC IIB	30	25.4%
EC IIIB	50	42.4%
EC IVA	04	3.4%
EC IVB	02	1.7%
Hisological type
Squamous cell carcinoma	94	79.7%
Adenocarcinoma	11	9.3%
Carcinoma	08	6.8%
Malignant neoplasm	05	4.2%
Tumor grade
Grade I	12	10.2%
Grade II	41	34.7%
Grade III	36	30.5%
Grade IV	07	5.9%
Not available	22	18.6%
Tumor diameter
>= 4.0 cm	49	41.5%
> 4.0 cm	67	56.8%
Não avaliado	2	1.7%
Lymph node metastasis
Yes	15	12.7%
Not	60	50.8%
Not available	43	36.4%

Regarding the treatment performed, it is observed that Surgery (followed or not by adjuvant with Radiotherapy and/or Chemotherapy) was the procedure performed by 25 women (21.1%), most of whom were in the initial clinical stage. Treatment with Radiotherapy and Chemotherapy, used alone or in combination, was used by 64 women (54.2%), most of whom were in advanced clinical stages. A total of 06 patients (5.0%) underwent treatment in another city and about 20 women (16.9%) did not undergo treatment.

3.4. HPV types and lineages

The HPV test was positive in 104 samples (88.1%). About 98 samples were of oncogenic high risk HPV (HPV 16, HPV 18, HPV 31, HPV 33, HPV 35, HPV 45, HPV 52, HPV 58 and HPV 59), 04 samples were of low risk HPV (HPV 09 and HPV 53) and co-infection was observed in 02 samples. HPV 16 with 63 samples (53.3%) was the most prevalent, followed by HPV 18 with 12 samples (10.2%), HPV 35 with 06 samples (5.1%), HPV 45 with 05 samples (4 .2%), HPV 52 with 04 samples (3.4%), HPV 9 with 03 samples (2.5%), HPV 33 with 03 samples (2.5%), HPV 31 with 02 samples (1.7%), HPV 58 with 02 samples (1.7%), HPV 53 and HPV 59 with 1 sample (0.8%) each.

Squamous cell carcinoma was observed in 53 samples (84.1%) of HPV 16 and in 8 samples (66.7%) of HPV 18. Proportionally, adenocarcinoma was more frequent in HPV 18, where it occurred in 03 samples (25%), than in HPV 16, where it was recorded in 4 samples (6.3%).

Of the total of 63 samples of HPV 16, in six samples it was not possible to identify the intratype variant, leaving 57 samples that could have the variant identified, 33 samples (57.8%) of the A lineage, 02 samples (3, 5%) from lineage B, 02 samples (3.5%) from lineage C and 20 samples (35.0%) from lineage D.

Regarding age, the average was 48.3 years for A lineage, 58.5 for B lineage, 58.5 for C lineage and 46.4 for D lineage. scaly, with 48 samples (84.2%); followed by adenocarcinoma, with 4 samples (7.0%), of which, three belonged to the D lineage. Lesions larger than 4.0 cm were the majority, with 37 samples (64.9%). Clinical stage III was the most observed, with 28 cases (49.1%) (Table 3).

Table 3

Clinical and pathological characteristics of patients with Human papilloma virus (HPV) 16 lineages identified (n = 57).
HPV 16 lineages	A	B	C	D	n = 57	(%)
N°of patients	33	2	2	20	57	100.0
Mean age (years)	48.3	58.5	58.5	46.4
FIGO stage
IB1	5	0	0	3	8	13.9
IIA	4	0	0	2	6	10.5
IIB	7	0	1	3	11	19.3
IIIB	16	1	1	10	28	49.1
IVA	1	1	0	2	4	7.0
Tumor size
≤ 4.0 cm	10	0	1	9	20	35.1
> 4.0 cm	23	2	1	11	37	64.9
Histological type
Squamous cell carcinoma	30	2	1	15	48	84.2
Adenocarcinoma	1	0	0	3	4	7.0
Carcinoma	1	0	0	1	2	3.5
Malignant neoplasm	1	0	1	1	3	5.2
Grade of differentiation
Well	3	0	0	1	4	7.0
Moderately	10	1	0	8	19	33.3
Poor	12	1	2	6	21	36.8
Not reported	8	0	0	5	13	22.8

FIGO: International Federation of Gynecology and Obstetrics; HPV: Human papillloma virus.

3.5 Treatment and HPV lineages

Of the 57 women who had the HPV 16 variant identified, a total of 11 patients underwent treatment with Chemotherapy, External Radiotherapy and Brachytherapy; seven from the European group, carriers of the A lineage, and four from the non-European group, two from the C lineage and two from the D lineage. The age range varied between 25 and 76 years, with an average age of 46.5 years. Squamous cell carcinoma was the most frequent histological type, being observed in 10 women (90.9%). The tumors were well advanced, in nine women (81.8%), they measured more than 4.0 cm. Clinical stage IIIB was the most frequent, with 07 patients (63.6%). The assessment of response to treatment took place three months after its completion. Complete response occurred in nine patients (81.8%), five of whom were from the A lineage, two from the C lineage and two from the D lineage. Cases of partial response and disease progression occurred, once with patients carrying the lineage A (Table 4).

Tabela 15: Avaliação de resposta ao tratamento com Quimioterapia + Teleterapia + Braquiterapia, em pacientes com câncer de colo do útero e portadoras de variantes do HPV 16, São Luís – Maranhão, 2016–2018, (n = 11).

	HPV 16 lineages
				n = 11	(%)
Age	16 A	16 C	16 D
Medium age (years)	44.4	58.5	42.0
Histological type	16 A	16 C	16 D
Squamous cell carcinoma	7	1	2	10	90,9%
Malignant neoplasm	0	1	0	1	9.1%
Histologic grade	16 A	16 C	16 D
GradeII	2	0	2	4	36.4%
Grade III	1	1	0	2	18.2%
Grade IV	0	1	0	1	9.1%
Not available	4	0	0	4	36.4%
Tumor diameter	16 A	16 C	16 D
Until 4,0 cm	1	1	0	2	18.2%
> 4,0 cm	6	1	2	9	81.8%
Stage	16 A	16 C	16 D
EC IIA	2	0	0	2	18.2%
EC IIB	1	1	0	2	18.2%
EC IIIB	4	1	2	7	63.6%
Response evaluation	16 A	16 C	16 D
Complete	5	2	2	9	81.8%
Partial	1	0	0	1	9.1%
Disease progression	1	0	0	1	9.1%

Cisplatin based chemoradioterapy arise as a cornerstone in treatment of advanced cervical carcinoma at the last two decades. The quasi-simultaneous publication of randomized trials indicated improvement in disease-free survival and overall survival (Morris et al., 1999; Rose et al., 1999; Whitney et al., 1999). Meta-analysesalso observed a better survival when compared to isolated radiotherapy (Green et al., 2005). After a complete curse of radiotherapy, the lower the stage, the more likely to achieve a complete response; Stage I = 94%; Stage II = 86%, Stage III = 62% (Jacobs et al, 1986). The complete response after a complete curse of radiotherapy is a predictor of survival, the 5 years survival rates varies between 76% and 41% when a complete response is achieved or not (Huang et al., 2016).

Since patients with the same pathological factors do not evolve the same way applying the same therapy and the human papillomavirus is the virtually origin of all cervical cancers, it was hypothesized that it types and it variants could be used as a prognostic factor to estimate response to treatment and survival. The use of HPV type as a prognostic factor remains controversial; some studies demonstrated a worse prognostic for HPV 18 infected patients (Lai, et al., 2007), others studies have demonstraded a poorer outcome for HPV 16 detected tumors (Ferdousi et al., 2010, Lau et al., 2015).HPV 16 is the most frequent type of human papillomavirus worldwide, from normal cytology tests, ranging from lesions as different stages of progression to cervical cancer, it counts at least for 50% of the all cervical cancer in the world (de Sanjose, et al., 2007; Gheit et al., 2011; Crow, 2012). The study of variants and lineages of human papillomavirus is concentrated in HPV 16 variants and could be the key to understand how de difference in viral genome influence development of cancer and mediate resistance to oncological treatment.

A few studies address the association of HPV variants and response to chemoradiotherapy. The literature suggests that European human papillomavirus variants would provide the better response to chemoradiotherapy.As Moreno-Acosta (2017) reported in his previous work, out eleven of seventeen patients with European variant, treated with radiotherapy +/- chemotherapy, achieved complete response; and in the non-European variants, the complete response was observed in one of two cases. In our study, out two of the seven patients HPV 16 lineage A evolved with tumor persistence; while in the non-European HPV lineages, two patients with lineage C and two patients with lineage D, was observed complete response within three months after chemo-irradiation.

The small number of patients studied and irregular distribution of lineages evaluated do not permitted stablish association between HPV-16 lineages and response to treatment. A multi-institutional cohort study, with a larger number of patients larger addressing the various HPV 16 intratype variants should answer this question.

Acknowledgements

The authors thank the staff of Postgraduate Program in Adult Health (PPGSAD) (Medicine II/CAPES – MSc Academic) of the Federal University of Maranhao (UFMA) and Genetic Laboratory from State University of Maranhão, Caxias and Genetic Division of National Institute of Cancer.

Funding Statement:

This research was supported by Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Estado do Maranhão (FAPEMA) (BEPP 10/2015) and CAPES FINANCE CODE 001.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests

The authors declare there is no conflict of interests.

Authors' contributions

FVF, GRBS, ZSB, FCBV, RLS and MDSBN participated in interpretation of data, drafted and critically revised the manuscript. MCLB, MSA, ACBNM, MCPS, MACNS and MDSBN contributed to study design, interpretation of data, and critically revised the manuscript. MACNS, FVF, GRBS, RLS analyzed and assisted in interpretation of the data and assisted in drafting the manuscript. All authors read and approved the final manuscript

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Impact of HPV-16 lineages infection on response to radio-chemotherapy in cervical cancer

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Abstract

Aim

Methods

Results

Conclusion

Figures

1. Introduction

2. Materials And Methods

2.1 Sample

2.2 Epidemiological data

2.3 Inclusion and exclusion criteria

2.4 Experimental procedures

2.4 HPV variants

2.6 Clinical data

2.6 Local response to treatment

2.7 Ethical aspects

2.8 Statistical analysis

3. Results

3.1 Sociodemographic data

3.2 Reproductive data

3.3 Clinical data

3.4. HPV types and lineages

3.5 Treatment and HPV lineages

Discussion

Declarations

References

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