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A parent-of-origin effect of the RB1 mutations in retinoblastoma with low penetrance and variable expressivity
abstracts
Annals of Oncology
1170P
A parent-of-origin effect of the RB1 mutations in retinoblastoma with low penetrance and variable expressivity
E.A. Alekseeva1, O.V. Babenko1, V.M. Kozlova2, T.L. Ushakova2, T.P. Kazubskaya2, S.V. Sahakyan3, A.S. Tanas1, D.V. Zaletaev4, V.V. Strelnikov1 1 Epigenetics, Federal State Budgetary Scientific Institution "Research Center for Medical Genetics", Moscow, Russian Federation, 2Institute of Pediatric Oncology and Hematology, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» jf the Ministry of Health of the Russian Federation, Moscow, Russian Federation, 3Clinical Center, Federal State Budgetary Institution «Helmholtz Moscow Research Institute of Eye Diseases», Moscow, Russian Federation, 4 Medical Genetics, Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russian Federation Background: Retinoblastoma (RB) is the most common pediatric intraocular neoplasm caused by the biallelic inactivation of the RB1 tumor suppressor gene. In 40% of cases, the development of RB is mediated by a germline mutation in one of the alleles of RB1. Patients with germline mutation develop bilateral tumor with penetrance of more than 90%. However, some families demonstrate cases of RB with low penetrance (unaffected carries) and variable expressivity (carries develop either bi- or uni- RB). It is believed that the phenotypic manifestation of hereditary retinoblastoma depends on the functional type of the germinal mutation in the RB1. The molecular mechanisms underlying the variable phenotypic manifestation of the same mutation in different family members are currently explained by the parent-of-origin effect of RB1 mutation. Methods: Using NGS of the RB1 we have analyzed DNA from blood of 331 unrelated patients with RB (226 patients with uni- RB and 105 with bi- RB). DNA samples of available family members were also examined for the presence of an identified mutation using Sanger sequencing. Results: We identified 11 germline mutations in the RB1 that led to the RB with low penetrance and/or variable expressivity in 12 families. Among the identified mutations:, 25.0% - are missense mutations, 58.3% - are splice mutations and 16.7% - are frame shift mutations. In 91,7% of cases, probands inherited the mutant allele from their fathers, who were either clinically healthy carriers (7 families) or had the uni-/bilateral form of RB (3 families).
Table: 1170P Mutations
Carrier (Proband, P) Form (uni, U; bi-lateral, B; no symptoms, -)
c.1364G>C; c.1573G>A; c.1981C>T; P # c.607 þ 1G-T (2 families); c.45_76del; c.83del c.861G>C P$ c.939G>A P # Grandfather Uncle c.380 þ 1G-A; c.1695 þ 5G-T; P# c.1696-2A-G
U-
UU--U BU
Conclusions: The identification of mutations in the RB1 leading to the development of RB with low penetrance and variable expressivity, is necessary for adequate treatment and competent determination of the risk of developing the disease in other family members. Legal entity responsible for the study: State assignment of Ministry of Science and Higher Education of the Russian Federation.
Volume 30 | Supplement 5 | September 2019
Funding: The state assignment of Ministry of Science and Higher Education of the Russian Federation. Disclosure: All authors have declared no conflicts of interest.
1171P
The humanistic burden reported by patients diagnosed with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) in Europe
P. Singh1, B. Bennett2, T. Bailey3, G. Taylor-Stokes3, L. Hennessy3, I. Rajkovic3, M.C. Contente2 1 WWHEOR, Bristol-Myers Squibb, Lawrence, NJ, USA, 2WWHEOR, Bristol-Myers Squibb, Uxbridge, UK, 3Bespoke Team, Adelphi Real World, Macclesfield, UK Background: R/M SCCHN is associated with poor prognosis and low survival rate. Further, there is a lack of evidence of how the disease impacts patients’ quality of life (QoL) and ability to perform activities of daily living (ADL). This study examines patients’ experience of living with R/M SCCHN. Methods: A cross-sectional study was conducted in the EU5 from Jan to May 2019. Medical oncologists recruited patients to complete a survey, including the Functional Assessment of Cancer Therapy – Head and Neck Cancer (FACT-H&N), a 39-item instrument evaluating patients’ QoL (score range 0-148; higher scores indicating better QoL), the European Quality of Life – 5 Dimension Questionnaire (EQ-5D-3L; utility scores range -0.59-1, VAS scores 0-100; with higher scores indicating better health status) and questions on daily life impact using a 7-point scale (7¼ extremely high impact). Physicians also completed a case report form (CRF) for each patient. This analysis is based on interim data. Results: 191 patients completed the survey. Median age was 66 years (45% < 65, 55% 65), 77% were male, the majority (82%) had an ECOG score 0-1 and 39% required caregiver support for daily needs (mean 32.7 hours per week). At data capture, 9% of patients were in paid work, 21% on sick leave and 48% retired. Most patients (93%) received at least one therapy line following R/M. Patients reported diminished health status, with a mean EQ-5D utility score of 0.62 and a mean VAS score of 58. Mean FACT-H&N score was low at 74.0. Almost half of patients reported high impact (score 5-7) on ADL and family/social life (43% and 46%, respectively). For patients with a lower FACT-H&N score (lowest score quartile [26–60.2]), 75% reported high impact on ADL, versus 15% patients in the highest FACT-H&N score quartile (87.5–120). 81% patients in the lowest FACT-H&N quartile reported high family/social life impact, versus 15% patients in the highest quartile. Conclusions: In addition to considerable impact on health status and QoL, patients report high impact on ability to perform ADL, with a high caregiving burden. There is a clear relationship between reduced QoL and restricted ADL and social life, highlighting the need to consider novel approaches to improve QoL in R/M SCCHN. Legal entity responsible for the study: Bristol-Myers Squibb. Funding: Bristol-Myers Squibb. Disclosure: P. Singh: Full / Part-time employment: Bristol-Myers Squibb. B. Bennett: Full / Parttime employment: Bristol-Myers Squibb. M.C. Contente: Full / Part-time employment: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.
1172TiP
Concurrent chemotherapy and external radiation therapy: An open label non-inferiority phase III randomized controlled trial of weekly versus three weekly cisplatin and radical radiotherapy in locally advanced head and neck squamous cell carcinoma: CONCERT trial
A. Sharma1, M.K. Chaudhary2, A. Thakar3, S. Bhaskar4, K. Sikka3, R. Pramanik1, A. Biswas4, C.A. Singh3, R.K. Sahoo5, S. Deo6, R. Kumar3, S. Thulkar7, A. Kakkar8, S. Seth9, V. Sreenivas10 1 Medical Oncology, B.R. Ambedkar Institute Rotary Cancer Hospital (AIIMS), Delhi, India, 2 Research and Referral, Army Hospital, New Delhi, India, 3Oto-Laryngology and Head & Neck Surgery, B.R. Ambedkar Institute Rotary Cancer Hospital (AIIMS), Delhi, India, 4 Radiation Oncology, B.R. Ambedkar Institute Rotary Cancer Hospital (AIIMS), Delhi, India, 5Medical Oncology, B.R. Ambedkar Institute Rotary Cancer Hospital (AIIMS), New Delhi, India, 6Surgical Oncology, B.R. Ambedkar Institute Rotary Cancer Hospital (AIIMS), New Delhi, India, 7Radiology, B.R. Ambedkar Institute Rotary Cancer Hospital (AIIMS), Delhi, India, 8Pathology, All India Institute of Medical Sciences, Delhi, India, 9Cardiology, All India Institute of Medical Sciences, Delhi, India, 10Biostatistics, B.R. Ambedkar Institute Rotary Cancer Hospital (AIMS), New Delhi, India Background: LA-HNSCC is treated with concurrent chemo-radiation. Majority of guidelines recommend bolus Cisplatin in the dose of 100 mg/m2 (on days 1, 22, and 43). The meta-analysis reported by MACH-NC group found a greater benefit for platinum-based chemotherapy as compared with other protocols. Multiple studies back this notion. Other options are weekly cisplatin (30-40 mg/m2) or split course radiation and combination of DDPþ5FU. Alternative dosing schedules (e.g., 30 to 40 mg/m2 weekly, 6 mg/m2 daily, or 20 mg/m2 daily for five days weeks 1 and 5) are used because of improved patient tolerance and ease of administration. 30 mg/m2 of weekly cisplatin has found to be inferior to 3 weekly 100 mg/m2. Three weekly schedules is the benchmark for further trials. In practice many of physicians alternatively, use low dose. 40 mg/m2 has been found superior to RT alone in a phase II randomized study. Whether 40 mg/m2 weekly cisplatin is inferior to 100 mg/m2 is not known. Based on
doi:10.1093/annonc/mdz252 | v473
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz252.062/5576601 by guest on 26 October 2019
three times. Organoids cultures derived from the other tumours stopped growing after the first passage. Viable organoids showed resemblance with the original primary tumour, based on morphology, protein expression, and growth pattern. Various drugs were tested at a single dose, and showed reduced organoid cell growth compared to untreated controls. Moreover, a dose-response relationship was established for an ALK-positive MEC organoid that was treated with crizotinib. Finally, epithelial-mesenchymal transition was shown in SDC organoids of a primary tumour and a lymph node metastasis of the same patient. Conclusions: We are the first that have successfully developed and characterized longterm organoid cultures for ACC and SDC. These organoid cell lines will facilitate preclinical and pharmacological studies. Other SGC organoid cultures do not grow infinitely, but do provide an in vitro model to study different treatments during initial growth. Legal entity responsible for the study: Radboud University Medical Center. Funding: Dutch Salivary Gland Cancer Patient Platform. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
1170P
A parent-of-origin effect of the RB1 mutations in retinoblastoma with low penetrance and variable expressivity
E.A. Alekseeva1, O.V. Babenko1, V.M. Kozlova2, T.L. Ushakova2, T.P. Kazubskaya2, S.V. Sahakyan3, A.S. Tanas1, D.V. Zaletaev4, V.V. Strelnikov1 1 Epigenetics, Federal State Budgetary Scientific Institution "Research Center for Medical Genetics", Moscow, Russian Federation, 2Institute of Pediatric Oncology and Hematology, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» jf the Ministry of Health of the Russian Federation, Moscow, Russian Federation, 3Clinical Center, Federal State Budgetary Institution «Helmholtz Moscow Research Institute of Eye Diseases», Moscow, Russian Federation, 4 Medical Genetics, Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russian Federation Background: Retinoblastoma (RB) is the most common pediatric intraocular neoplasm caused by the biallelic inactivation of the RB1 tumor suppressor gene. In 40% of cases, the development of RB is mediated by a germline mutation in one of the alleles of RB1. Patients with germline mutation develop bilateral tumor with penetrance of more than 90%. However, some families demonstrate cases of RB with low penetrance (unaffected carries) and variable expressivity (carries develop either bi- or uni- RB). It is believed that the phenotypic manifestation of hereditary retinoblastoma depends on the functional type of the germinal mutation in the RB1. The molecular mechanisms underlying the variable phenotypic manifestation of the same mutation in different family members are currently explained by the parent-of-origin effect of RB1 mutation. Methods: Using NGS of the RB1 we have analyzed DNA from blood of 331 unrelated patients with RB (226 patients with uni- RB and 105 with bi- RB). DNA samples of available family members were also examined for the presence of an identified mutation using Sanger sequencing. Results: We identified 11 germline mutations in the RB1 that led to the RB with low penetrance and/or variable expressivity in 12 families. Among the identified mutations:, 25.0% - are missense mutations, 58.3% - are splice mutations and 16.7% - are frame shift mutations. In 91,7% of cases, probands inherited the mutant allele from their fathers, who were either clinically healthy carriers (7 families) or had the uni-/bilateral form of RB (3 families).
Table: 1170P Mutations
Carrier (Proband, P) Form (uni, U; bi-lateral, B; no symptoms, -)
c.1364G>C; c.1573G>A; c.1981C>T; P # c.607 þ 1G-T (2 families); c.45_76del; c.83del c.861G>C P$ c.939G>A P # Grandfather Uncle c.380 þ 1G-A; c.1695 þ 5G-T; P# c.1696-2A-G
U-
UU--U BU
Conclusions: The identification of mutations in the RB1 leading to the development of RB with low penetrance and variable expressivity, is necessary for adequate treatment and competent determination of the risk of developing the disease in other family members. Legal entity responsible for the study: State assignment of Ministry of Science and Higher Education of the Russian Federation.
Volume 30 | Supplement 5 | September 2019
Funding: The state assignment of Ministry of Science and Higher Education of the Russian Federation. Disclosure: All authors have declared no conflicts of interest.
1171P
The humanistic burden reported by patients diagnosed with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) in Europe
P. Singh1, B. Bennett2, T. Bailey3, G. Taylor-Stokes3, L. Hennessy3, I. Rajkovic3, M.C. Contente2 1 WWHEOR, Bristol-Myers Squibb, Lawrence, NJ, USA, 2WWHEOR, Bristol-Myers Squibb, Uxbridge, UK, 3Bespoke Team, Adelphi Real World, Macclesfield, UK Background: R/M SCCHN is associated with poor prognosis and low survival rate. Further, there is a lack of evidence of how the disease impacts patients’ quality of life (QoL) and ability to perform activities of daily living (ADL). This study examines patients’ experience of living with R/M SCCHN. Methods: A cross-sectional study was conducted in the EU5 from Jan to May 2019. Medical oncologists recruited patients to complete a survey, including the Functional Assessment of Cancer Therapy – Head and Neck Cancer (FACT-H&N), a 39-item instrument evaluating patients’ QoL (score range 0-148; higher scores indicating better QoL), the European Quality of Life – 5 Dimension Questionnaire (EQ-5D-3L; utility scores range -0.59-1, VAS scores 0-100; with higher scores indicating better health status) and questions on daily life impact using a 7-point scale (7¼ extremely high impact). Physicians also completed a case report form (CRF) for each patient. This analysis is based on interim data. Results: 191 patients completed the survey. Median age was 66 years (45% < 65, 55% 65), 77% were male, the majority (82%) had an ECOG score 0-1 and 39% required caregiver support for daily needs (mean 32.7 hours per week). At data capture, 9% of patients were in paid work, 21% on sick leave and 48% retired. Most patients (93%) received at least one therapy line following R/M. Patients reported diminished health status, with a mean EQ-5D utility score of 0.62 and a mean VAS score of 58. Mean FACT-H&N score was low at 74.0. Almost half of patients reported high impact (score 5-7) on ADL and family/social life (43% and 46%, respectively). For patients with a lower FACT-H&N score (lowest score quartile [26–60.2]), 75% reported high impact on ADL, versus 15% patients in the highest FACT-H&N score quartile (87.5–120). 81% patients in the lowest FACT-H&N quartile reported high family/social life impact, versus 15% patients in the highest quartile. Conclusions: In addition to considerable impact on health status and QoL, patients report high impact on ability to perform ADL, with a high caregiving burden. There is a clear relationship between reduced QoL and restricted ADL and social life, highlighting the need to consider novel approaches to improve QoL in R/M SCCHN. Legal entity responsible for the study: Bristol-Myers Squibb. Funding: Bristol-Myers Squibb. Disclosure: P. Singh: Full / Part-time employment: Bristol-Myers Squibb. B. Bennett: Full / Parttime employment: Bristol-Myers Squibb. M.C. Contente: Full / Part-time employment: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.
1172TiP
Concurrent chemotherapy and external radiation therapy: An open label non-inferiority phase III randomized controlled trial of weekly versus three weekly cisplatin and radical radiotherapy in locally advanced head and neck squamous cell carcinoma: CONCERT trial
A. Sharma1, M.K. Chaudhary2, A. Thakar3, S. Bhaskar4, K. Sikka3, R. Pramanik1, A. Biswas4, C.A. Singh3, R.K. Sahoo5, S. Deo6, R. Kumar3, S. Thulkar7, A. Kakkar8, S. Seth9, V. Sreenivas10 1 Medical Oncology, B.R. Ambedkar Institute Rotary Cancer Hospital (AIIMS), Delhi, India, 2 Research and Referral, Army Hospital, New Delhi, India, 3Oto-Laryngology and Head & Neck Surgery, B.R. Ambedkar Institute Rotary Cancer Hospital (AIIMS), Delhi, India, 4 Radiation Oncology, B.R. Ambedkar Institute Rotary Cancer Hospital (AIIMS), Delhi, India, 5Medical Oncology, B.R. Ambedkar Institute Rotary Cancer Hospital (AIIMS), New Delhi, India, 6Surgical Oncology, B.R. Ambedkar Institute Rotary Cancer Hospital (AIIMS), New Delhi, India, 7Radiology, B.R. Ambedkar Institute Rotary Cancer Hospital (AIIMS), Delhi, India, 8Pathology, All India Institute of Medical Sciences, Delhi, India, 9Cardiology, All India Institute of Medical Sciences, Delhi, India, 10Biostatistics, B.R. Ambedkar Institute Rotary Cancer Hospital (AIMS), New Delhi, India Background: LA-HNSCC is treated with concurrent chemo-radiation. Majority of guidelines recommend bolus Cisplatin in the dose of 100 mg/m2 (on days 1, 22, and 43). The meta-analysis reported by MACH-NC group found a greater benefit for platinum-based chemotherapy as compared with other protocols. Multiple studies back this notion. Other options are weekly cisplatin (30-40 mg/m2) or split course radiation and combination of DDPþ5FU. Alternative dosing schedules (e.g., 30 to 40 mg/m2 weekly, 6 mg/m2 daily, or 20 mg/m2 daily for five days weeks 1 and 5) are used because of improved patient tolerance and ease of administration. 30 mg/m2 of weekly cisplatin has found to be inferior to 3 weekly 100 mg/m2. Three weekly schedules is the benchmark for further trials. In practice many of physicians alternatively, use low dose. 40 mg/m2 has been found superior to RT alone in a phase II randomized study. Whether 40 mg/m2 weekly cisplatin is inferior to 100 mg/m2 is not known. Based on
doi:10.1093/annonc/mdz252 | v473
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz252.062/5576601 by guest on 26 October 2019
three times. Organoids cultures derived from the other tumours stopped growing after the first passage. Viable organoids showed resemblance with the original primary tumour, based on morphology, protein expression, and growth pattern. Various drugs were tested at a single dose, and showed reduced organoid cell growth compared to untreated controls. Moreover, a dose-response relationship was established for an ALK-positive MEC organoid that was treated with crizotinib. Finally, epithelial-mesenchymal transition was shown in SDC organoids of a primary tumour and a lymph node metastasis of the same patient. Conclusions: We are the first that have successfully developed and characterized longterm organoid cultures for ACC and SDC. These organoid cell lines will facilitate preclinical and pharmacological studies. Other SGC organoid cultures do not grow infinitely, but do provide an in vitro model to study different treatments during initial growth. Legal entity responsible for the study: Radboud University Medical Center. Funding: Dutch Salivary Gland Cancer Patient Platform. Disclosure: All authors have declared no conflicts of interest.