Tumores de cabeza y cuello HPV+, una entidad diferente con tratamiento diferente?

Transcription

1 Tumores de cabeza y cuello HPV+, una entidad diferente con tratamiento diferente? Coordinador Científico: Dr. Fernando Rivera Hospital Universitario Marqués de Valdecilla, Santander Organizado por: Fundación para el progreso de la oncología en Cantabria, FUPOCAN Neus Basté Rotllan Hospital Univ. Vall d Hebron nbaste@vhio.net

2 OUTLINE 1. INTRODUCTION 2. EPIDEMIOLOGY 3. ROLE OF HPV 4. MOLECULAR BIOLOGY 5. PROGNOSIS RISK GROUP 6. TNM STAGING 8TH EDITION 7. TREATMENT MODALITIES 8. CONCLUSIONS

3 1. INTRODUCTION Head and neck cancer accounts: Worldwide: > cases and deaths annually Europe: > cases (4% of cancer incidence) and deaths in 2012 Spain: 33 cases/100000/year (incidence) and 11.7 cases/100,000/year (mortality rate) Squamous cell carcinoma of the head and neck (SCCHN) represent >90% of head and neck tumors. 10% Staging at Diagnosis 50% 40% Local Locoregional Metastatic Despite aggressive up-front treatment, about 50% will develop locoregional or distant recurrences within the first 2 years. Zibelman M et al. Am J Clin Oncol Ries LG et al. SEER Cancer Statistics Reviews National Cancer Institute NIH Pub. Updated September 12, 2016

4 1. INTRODUCTION HPV (+) HPV (-) Young Adults White race Others High Social/Economic status Low Social/Economic status Sexual habits Tobacco- Alcohol habits = > Oropharyngeal Higher advanced stage Non mutations (p53,prb) Others locations Lower advanced stage Mutations Incidence GOOD PROGNOSIS Incidence POOR PROGNOSIS Leemans CR et al. Nat Reviews 2011; Fakhry C et al. Oral Oncology 2014

5 2. EPIDEMIOLOGY A meta-analysis of populations from USA and Europe showed an increase in HPV prevalence in oropharyngeal cancer: 40% (1990s) 70% (late 2000s). Kreimer AR et al. Cancer Epidemiol Biomarkers Prev Chaturvedi AK et al. Head and Neck Pathol (2012). Gillison ML et al Vaccine Gillison ML et al. J Clin Oncol 2015

6 3. ROLE OF HPV HPV is a epitheliotropic, circular double-stranded DNA virus. > 100 subtypes of HPV: oncogenic, non-oncogenic. 2 oncoproteins (E6/E7) -> inactivates p53 and prb -> cell cycle regulation -> onset of HPV-mediated carcinogenesis. Stubenrauch F et al. Cancer Biology 1999; Psyrri A et al. Anti-Cancer Drugs 2011; Leemans CR et al. Nat Reviews 2011; Tommasino M. Semin Cancer Biol 2014

7 4. MOLECULAR BIOLOGY 85% HPV (-) N= % HPV (+) TCGA Nature 2015; Seiwert T et al. Clin Cancer Res 2014; Hayes N et al. J Clin Oncol 2015; Keck MK et al. Clin Cancer Res 2015; Zhang Y et al. Clin Cancer Res 2016

8 5. PROGNOSIS RISK GROUP Human papillomavirus associated oropharynx cancer present specific epidemiologic, molecular and biologic characteristics with better prognosis. Risk of morbidity in young patients which live longer with functional impairment or medical burden. Treatment deintensification trials attempt to decrease treatment-related morbidity without compromising efficacy. Defining prognostic risk groups to avoid undertreatment and validation of biomarkers are needed to identify patients with the best prognosis. HPV status is a strong and independent predictor of OS, even after local or distant disease progression (ECOG 1395, ECOG 3301, Bonner trial, RTOG 0129, RTOG 0522, TROG 02.02, ECOG 2399). Which patients present the best prognosis? Bhatia A et al. J Clin Oncol 2015

9 Which patients have the best prognosis? 1- Reliable testing for oncogenic HPV for future studies designs and validation inferences from them. HPV-16 (most common) in Europe, USA, Asia and Australia Others HPV subtypes identified: 18, 52, 58, 61. Tecniques: Immunohistochemistry (IHC) p16 In situ hybridization for high-risk HPV (HPV ISH) Quantitative polymerase chain reaction (qpcr) for viral E6 mrna (RNA qpcr) and viral E6 DNA (DNA qpcr). Limitations: 25% concordance: p16-hpv ISH 15-20% p16 positive are HPV16 negative (qpcr/ish) Risk undertreating patients p16 IHC/DNA qpcr 97% Sensitivity / 94% Specificity. p16 IHC/HPV ISH 88% Sensitivity / 90 % Specificity. 2- Smoking history Risk of progression or death increased by 1% per pack-year. Number of pack-years of smoking ( 10 vs >10) second determinant of OS. Ang KK et al. N Engl J Med 2010; Kreimer AR et al. Cancer Epidemiol Biomarkers Prev.; Ndiaye C et al. Lancet Oncol. 2014; Bhatia A et al. J Clin Oncol 2015; Castellsagué X et al. JNCI J Natl Cancer Inst 2016.

10 Prognostic risk groups in HPV-positive OP (I) Acording to the risk of distant metastasis in HPV positive oropharyngeal cancer, we could select suitable patients for deintensified therapy. 3-y OS:93% 3-y OS:71% 3-y OS:46% 3-y Risk DM:7% 3-y Risk DM: 24% Ang KK et al. N Engl J Med 2010; O Sullivan B et al. J Clin Oncol 2013; Bhatia A et al. J Clin Oncol 2015

11 Prognostic risk groups in HPV-positive OP (II) N=1907 pts 82% 76% 54% Huang SH et al. J Clin Oncol 2015; O Sullivan B et al. Lancet Oncol 2016

12 6. TNM STAGING 8TH EDITION Lydiatt WM et al. Ca cancer J Clin 2017

13 7. TREATMENT MODALITIES In order to reduce long-term toxicites (as mucositis, dysphagia, xerostomia, dental complications, hypothyroidism, fibrosis, renal impairment, late swallowing and vascular complications) treatment deintensification have been planned. Preclinical data have demonstrated that HPV+ oropharyngeal cell lines exhibit greater radiosensitivity, due to higher levels of double-strand breaks DNA and G2-arrest. Rieckmann et al. Radio ther Oncol (2013); Bhatia A et al. J Clin Oncol 2015

14 N= 27 patients 54Gy (non-t4, non-n2c, <10 pack-year smokers) March 2010 until October 2011 N=51patients (54Gy) Resectable, stage III/IV OPSCC HPV positive (p16 and/or HPV16 ISH) IC (CDDP 75 mg/m2 D1, paclitaxel 90 mg/m2 D1-8-15, cetuximab 400/250 mg/m2 weekly)/3w x 3cycles IMRT /Cetuximab ccr: 54 Gy (27fractions) No-cCR: 69.3 Gy (33 fractions) N= % T % N0-N2b. 84% No current smokers. IC compliance: 77pts

15 7.1 Radiation de-escalation trials R R ECOG 3311 (NCT ) Goal to avoid consequences of chemoradiation in patients with low risk disease TRANSORAL RESECTION N=377 III-IVa OP HPV-related 2-year PFS Low risk (negative margins, 0-1 N) High risk (positive margins, ECE, 5N) Intermediate risk (multiple N) RT 50Gy / RT 60Gy Observation CRT

16 7.2 Others de-escalation trials ECE RT 60Gy +/- CDDP 40mg/m2 2-y LRC Masterson L et al. EJC 2014; Bhatia A et al. J Clin Oncol 2015; Mirghani H et al Int. J. Cancer:2015

17 7.3 Chemotherapy de-escalation trials 5-y OS TROG Masterson L et al. EJC 2014; Bhatia A et al. J Clin Oncol 2015; Mirghani H et al Int. J. Cancer:2015

18 7.4 Novel Therapeutic Targets PI3K pathway inhibitors Therapeutic Vaccines Adoptive T-cell therapy Immunotherapy based on immune-checkpoints

19 PI3K pathway inhibitors 4.6 m sv 3.5 m HR 0 65 [95% CI ] Mutational landscape of HNSCC reported differents frequencies of genetic alterations: PIK3CA alterations: 34% HPV(-) vs 56% HPV (+) (hotspot mutations) PTEN alterations: 12% HPV (-) vs 6% HPV (+). PIK3R1 alterations: 1% HPV (-) vs 3% HPV (+). HPV (+) had higher PTEN expression (30%) and AKT amplification (5%) PI3K pathway activation is associated with chemotherapy and targeted agents resistance. There are many clinical trials evaluating PI3K inhibitors in R/M HNSCC resistant : BERIL-1: BKM-120 in combination with paclitaxel. HPV (-) sub-group benefit. NCT (I/II): Pan-class PI3K Inhibitor (BKM120) and Cetuximab. NCT (Ib/II): Alpelisib (BYL719) in combination with cetuximab. NCT (I): Alpelisib (BYL719)with paclitaxel is also ongoing. Bhatia A et al. J Clin Oncol 2015; Mirghani H et al Int. J. Cancer:2015; TCGA Nature 2015; LoRusso PM et al. J Clin Oncol 2016; Massacesi et al OncoTargets and Therapy 2016 Soulières D et al. Lancet Oncol 2017; Felice F et al. Oral Oncology 2017

20 Therapeutic Vaccines Therapeutic HPV vaccines are able to eliminate pre-existing lesions by generating cellular immunity against HPV-infected cells. Based on encouraging preclinical data, several strategies are under development, including vector-based, peptide-based, protein-based, nucleic acid-based, dendritic vaccines and RNA replicon approaches. DNA vaccines do not elicit antivector immune responses. DNA vaccines have the capacity for the repeated administrations that may be required to achieve and maintain target immune responses. Mirghani H et al Int. J. Cancer:2015; Aggarwal C et al. Immunotherapy 2016

21 Adoptive T-cell therapy This approach have already shown striking efficacy in hematologic malignancies and melanoma. T cells from a patient are genetically modified and then reintroduced into the patient with the goal of improving the immune system s anticancer response. Mirghani H et al Int. J. Cancer:2015; Aggarwal C et al. Immunotherapy 2016

22 PD-1 and PD-L1 in tumor immunity Role in the tumor microenvironment: Functional anergy or apoptosis of effector T cell Immune Tolerance on Treg Reverse apoptosis signaling through PD-L1 Inhibition of immune response (PD-L1 / CD80) Biologic implication on HNSCC tumor cells: Higher PD-L1 expression in HPV positive tumors 70% vs. 29% [Lyford-Pike S et al. Cancer Res 2013] 49.2% vs. 34.1% [Ukpo et al. Head Neck Pathol 2013] 62.5% vs. 40% [Badoual C et al. Cancer Res 2013] PD-L1 expression contribute to immune resistance in HPV positive tumors [Lyford-Pike S et al. Cancer Res 2013] PD-1+ CD8+ T cells may be a favorable prognostic biomarker in HPV+ [Badoual C et al. Cancer Res 2013] Regulation of PD-L1 expression in tumor cells: EXTRINSIC MECHANISM: driven by NK / CD8 TILs (IFN Gamma secreting TILs) INTRINSIC MECHANISM: driven by constitutive oncogenic signaling pathways (EGFR-mediated JAK2/STAT1 dependent) PD-L1 expression in tumor cells: Correlated with EGFR, JAK2, STAT1 and IFN Gamma expression regardless HPV status High TILs levels in HPV related correlated with clinical response. Allen CT et al. Laryngoscope 2012; 122(1):144-57; Lyford-Pike S et al. Cancer Res 2013; 15;73(6): ; Zandberg DP et al. Oral Oncology 2014 Ukpo et al. Head Neck Pathol 2013; 7(2): ; Badoual C et al. Cancer Res 2013; 1;73(1):128-38; Jie HB et al Br J Cancer 2013; 12;109(10): ; Concha-Benavente et al. Cancer Res 2016; 76(5): ; Ward MJ et al. British Journal of Cancer 2014; Aggarwal C et al. Immunotherapy 2016

23 Immune-checkpoints Ferris R et al. N Engl J Med2016; Chow L et al. J Clin Oncol 2016; Bauml JM et al. J Clin Oncol 2016

24 8. CONCLUSIONS HPV-associated squamous cell carcinoma arises predominantly in oropharynx which present better prognosis. Increasing incidence worldwide. Molecular profiles of HPV-positive tumors are distinct from HPV-negative (TP53 WT, downregulation p53, upregulation p16, higher PI3KCA alterations). E6/E7 (viral oncoproteins) are responsible for oncogenesis. Moving to TNM Staging 8 th Edition based on Prognostic risk groups. In order to reduce treatment induced-morbility, De-escalation trials are ongoing. Others treatment strategies are been evaluated focused on tumor immunity and mutational landscape.

25 Muchas gracias! Coordinador Científico: Dr. Fernando Rivera Hospital Universitario Marqués de Valdecilla, Santander Organizado por: Fundación para el progreso de la oncología en Cantabria, FUPOCAN Neus Basté Rotllan Hospital Univ. Vall d Hebron nbaste@vhio.net