- Email: [email protected]
Development and characterization of salivary gland cancer organoid cultures
abstracts
1167P
Classification of esthesioneuroblastoma (ENB) based on chromosome (chr) arm gain and loss (CNA) in the setting of a hypomutated genomic landscape
R. Madison1, D.C. Pavlick2, J.M. Johnson3, S. Khan4, J. Lee1, J.S. Ross5, V.A. Miller1, B.M. Alexander1, J. Chung1, A.B. Schrock1, S.M. Ali1 1 Clinical Development, Foundation Medicine, Cambridge, MA, USA, 2Cancer Genomics, Foundation Medicine, Cambridge, MA, USA, 3Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA, 4Internal Medicine - Hematology/Oncology, UT Southwestern Medical Center, Dallas, TX, USA, 5Pathology, Foundation Medicine, Cambridge, MA, USA Background: ENB is a rare skull base tumor arising from the olfactory neuroepithelium with variable prognosis and no consensus guidelines for treatment. Previous genomic studies (Classe 2018, Capper 2018) have reported scant genomic alterations (GA) in advanced and metastatic ENB (mENB), including mutation of IDH2. Here, we explore the cytogenetic landscape of in 94 cases of mENB as assessed by NGS-based comprehensive genomic profiling (CGP). Methods: Tumour specimens from 94 patients with mENB were assayed using hybrid capture-based CGP to delineate all classes of GA as point mutations, insertions deletions (indels), rearrangements and focal (<20 MB) amplifications or loss. Each chr was assessed for arm wide copy gain, loss of heterozygosity (LOH1, only one allele remaining) and copy neutral loss of heterozygosity (LOHx, 2þ identical alleles). % score by arm was utilized to generate two principal components and analysis was performed using distance based hierarchical clustering. Results: mENB cases had 1 or fewer GA detected in 80% (75/94) of cases with a corresponding median tumor mutational burden of 1.5 mut/mb. TP53 was the most frequently altered gene in the cohort, while IDH2 mutations were found in only 2 cases (2.1%). Focal and homozygous deletions were identified in 11.7% (11/94) and 14.9% (14/94) of cases respectively. We then assessed chr arm gain and LOH1/X and identified a median of 11 events per case. Based on chr arm level changes, we identified 3 distinct subtypes of mENB: type IA (n ¼ 53), defined by wide spread LOHx, type IB (n ¼ 22), defined by wide spread LOH1, and type II (n ¼ 19) generally lacking arm CNA. Type IB lacked chr5 or chr20 gain, which were both seen in 36% of type IA (p ¼ 0.001). Patients with IA/B types were older than type II (mean 54.9 v 46.5 years, p ¼ 0.015) and both IDH2 mutated cases segregated into type II. Conclusions: Given the pauci-mutational genomic landscape of mENB, clustering by chr arm level changes identifies distinct classes of mENB, which were associated with biologic factors including age and IDH2 mutation. Further studies to correlate clinico-pathologic characteristics with the cytogenetic characteristics of these newly defined subtypes of mENB are needed. Legal entity responsible for the study: Foundation Medicine Inc. Funding: Foundation Medicine Inc. Disclosure: R. Madison: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. D.C. Pavlick: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. S. Khan: Honoraria (self): Ariad; Honoraria (self): Genentech; Honoraria (self): Foundation Medicine; Honoraria (self): EMD Serono; Honoraria (self): Genzyme; Honoraria (self): Guardant; Honoraria (self): Takeda; Honoraria (self): Oak Ridge Universities; Honoraria (self): Onyx Pharmaceuticals. J. Lee: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. J.S. Ross: Leadership role, Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche; Officer / Board of Directors: Celcius Therapeutics. V.A. Miller: Leadership role, Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche; Advisory / Consultancy, Scientific Advisory Board: Revolution Medicines. B.M. Alexander: Full / Part-time employment, Officer / Board of Directors: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche; Advisory / Consultancy, Personal Fees: AbbVie; Advisory / Consultancy, Personal Fees: Schlesinger Associates; Advisory / Consultancy, Personal Fees: BristolMyers Squibb; Advisory / Consultancy, Personal Fees: Precision Health Economics; Research grant / Funding (self), grants outside submitted work: Puma Biotechnology; Research grant / Funding (self), grants outside submitted work: Celgene; Research grant / Funding (self), grants outside submitted work: Eli Lily. J. Chung: Full / Part-time employment: Foundation Medicine Inc; Shareholder /
v472 | Head And Neck Cancer, Excluding Thyroid
Stockholder / Stock options: Roche. All other authors have declared no conflicts of interest. A.B. Schrock: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. S.M. Ali: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche.
1168P
Trastuzumab plus docetaxel in patients with advanced HER2-positive salivary duct carcinoma: Exploratory biomarker analyses
H. Takahashi1, D. Kawakita2, C. Fushimi1, T. Nagao3, H. Hirai3, N. Saigusa3, T. Masubuchi1, T. Matsuki1, T. Okada1, D. Baba1, K. Miura1, T. Saotome4, Y. Tada1 1 Department of Head and Neck Oncology and Surgery, International University of Health and Welfare Mita Hospital, Tokyo, Japan, 2Department of Otorhinolaryngology, Head and Neck Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, 3Department of Anatomic Pathology, Tokyo Medical University School of Medicine, Tokyo, Japan, 4Division of Medical Oncology, Matsudo City General Hospital, Matsudo, Japan Background: A phase II trial of trastuzumab plus docetaxel in patients with advanced HER2–positive salivary duct carcinoma (SDC) showed 70% of the overall response rate. However, biomarkers which predict survival in this population remain unknown. Methods: A total of 91 patients with HER2–positive SDC treated with trastuzumab plus docetaxel were included. Age, sex, ECOG performance status (PS), status of visceral metastases, previous treatment, previous docetaxel exposure, previous combined androgen blockade, the best overall response to the treatment, pretreatment serum Creactive protein (CRP) level, modified Glasgow Prognosis Score (mGPS), HER2 status (immunohistochemistry [IHC] score, HER2/CEP17 ratio, HER2 copy number, overall positivity according to ASCO/CAP Guidelines), mutational status of PIK3CA, HRAS, and TP53, IHC score of AR, Ki-67, CK5/6, p53, HER3, Akt, PI3K, FOXA1, adipophilin, mTOR and PTEN were assessed and correlated with progression-free survival (PFS) and overall survival (OS). Results: Treatment response (PR or CR vs. SD or PD) and PTEN IHC score (1þ – 3þ vs. 0) were related with favorable PFS (hazard ratio [HR], 0.25 and 0.39, respectively) and OS (HR, 0.29 and 0.36, respectively). CRP ( 0.50 mg/dL) was related with shorter PFS (HR, 2.28) and OS (HR 4.46). Presence of previous treatment and mTOR IHC (1þ – 3þ vs. 0) had significant predictive value of better PFS (HR 0.47 and 0.22, respectively) but not significantly related with OS. ECOG PS of 1-2 (vs. 0), presence of visceral metastasis, and mGPS of 1-2 (vs. 0) had significant relationship with shorter OS but not with PFS. Neither previous docetaxel exposure nor previous combined androgen blockade did not affect the survival outcome. HER2, PIK3CA, HRAS and TP53 status did not related with survival. Conclusions: Although HER2 status did not correlated with survival, its downstream factors PTEN and mTOR can serve as predictive biomarkers in patients with advanced SDC treated with trastuzumab plus docetaxel. Serum CRP level may predict survival of this population. Clinical trial identification: UMIN000009437, Released on 03/12/2012. Legal entity responsible for the study: The authors. Funding: MEXT/JSPS. Disclosure: All authors have declared no conflicts of interest.
1169P
Development and characterization of salivary gland cancer organoid cultures
W.V. Boxtel1, T.M.W. Aalders2, G. Lassche1, I.C.H. van Engen - van Grunsven3, G.W. Verhaegh2, C. van Herpen1, J. Schalken2 1 Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands, 2Department of Urology, Radboud University Medical Center, Nijmegen, Netherlands, 3Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands Background: Recently 3D organoid cell cultures have been established for a variety of human cancers. Salivary gland cancer (SGC) is a rare cancer with 22 different subtypes and few treatment options. Our aim is to generate a large repertoire of patient-derived SGC organoids with different phenotypes, which will facilitate pre-clinical and pharmacological studies. Methods: Fresh tissues of resected primary tumours and/or metastases of SGC patients were collected. Tissues were minced and digested with collagenase type 2 and TrypLE to generate single cells. After washing, the cells were seeded in growth factor reduced Matrigel. Organoid medium, containing Rho kinase inhibitor Y27632, was refreshed twice a week. Viable organoids were characterized by immunohistochemistry and by DNA/RNA sequencing. Moreover, the organoids were used to evaluate various treatments that are or may be relevant for the treatment of SGC. Results: Between 2016 and 2018 we obtained tissue of 17 SGC patients, of which 16 contained sufficient material for processing: 10 salivary duct carcinoma (SDC), 3 adenoid cystic carcinoma (ACC), 2 muco-epidermoid carcinoma (MEC) and 1 parotid adenocarcinoma not otherwise specified (NOS). For 5 tumors (2 SDC, 2 ACC, 1 adenocarcinoma NOS) viable organoids were established, which could be passaged at least
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[HR], 3.57, 2.01, 1.76, 1.62, and 2.16, respectively) and OS (HR, 4.91, 4.98, 3.10, 2.95, and 1.78, respectively). IHC scores of PTEN (3þ) and adipophilin (5%) were related with favorable PFS (HR, 0.57 and 0.49, respectively) and OS (HR, 0.48 and 0.42, respectively). Age, ECOG PS, CRP, testosterone, AR positive ratio (70% or < 70%), HER2 status, previous treatment with trastuzumab plus docetaxel, FOXA1 immunopositivity, and mutational status of BRAF, PIK3CA, HRAS, and TP53 did not have significant association with survival. Conclusions: Rather than age and PS, sex and higher inflammation-based prognostic scores can serve as predictive biomarkers in patients with advanced SGC treated with CAB. IHC assessment of Ki-67, PTEN, and adipophilin may predict survival of this population. Biological validation of such markers is warranted. Clinical trial identification: UMIN000009437, Released on 03/12/2012. Legal entity responsible for the study: The authors. Funding: MEXT/JSPS. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
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
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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.
1167P
Classification of esthesioneuroblastoma (ENB) based on chromosome (chr) arm gain and loss (CNA) in the setting of a hypomutated genomic landscape
R. Madison1, D.C. Pavlick2, J.M. Johnson3, S. Khan4, J. Lee1, J.S. Ross5, V.A. Miller1, B.M. Alexander1, J. Chung1, A.B. Schrock1, S.M. Ali1 1 Clinical Development, Foundation Medicine, Cambridge, MA, USA, 2Cancer Genomics, Foundation Medicine, Cambridge, MA, USA, 3Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA, 4Internal Medicine - Hematology/Oncology, UT Southwestern Medical Center, Dallas, TX, USA, 5Pathology, Foundation Medicine, Cambridge, MA, USA Background: ENB is a rare skull base tumor arising from the olfactory neuroepithelium with variable prognosis and no consensus guidelines for treatment. Previous genomic studies (Classe 2018, Capper 2018) have reported scant genomic alterations (GA) in advanced and metastatic ENB (mENB), including mutation of IDH2. Here, we explore the cytogenetic landscape of in 94 cases of mENB as assessed by NGS-based comprehensive genomic profiling (CGP). Methods: Tumour specimens from 94 patients with mENB were assayed using hybrid capture-based CGP to delineate all classes of GA as point mutations, insertions deletions (indels), rearrangements and focal (<20 MB) amplifications or loss. Each chr was assessed for arm wide copy gain, loss of heterozygosity (LOH1, only one allele remaining) and copy neutral loss of heterozygosity (LOHx, 2þ identical alleles). % score by arm was utilized to generate two principal components and analysis was performed using distance based hierarchical clustering. Results: mENB cases had 1 or fewer GA detected in 80% (75/94) of cases with a corresponding median tumor mutational burden of 1.5 mut/mb. TP53 was the most frequently altered gene in the cohort, while IDH2 mutations were found in only 2 cases (2.1%). Focal and homozygous deletions were identified in 11.7% (11/94) and 14.9% (14/94) of cases respectively. We then assessed chr arm gain and LOH1/X and identified a median of 11 events per case. Based on chr arm level changes, we identified 3 distinct subtypes of mENB: type IA (n ¼ 53), defined by wide spread LOHx, type IB (n ¼ 22), defined by wide spread LOH1, and type II (n ¼ 19) generally lacking arm CNA. Type IB lacked chr5 or chr20 gain, which were both seen in 36% of type IA (p ¼ 0.001). Patients with IA/B types were older than type II (mean 54.9 v 46.5 years, p ¼ 0.015) and both IDH2 mutated cases segregated into type II. Conclusions: Given the pauci-mutational genomic landscape of mENB, clustering by chr arm level changes identifies distinct classes of mENB, which were associated with biologic factors including age and IDH2 mutation. Further studies to correlate clinico-pathologic characteristics with the cytogenetic characteristics of these newly defined subtypes of mENB are needed. Legal entity responsible for the study: Foundation Medicine Inc. Funding: Foundation Medicine Inc. Disclosure: R. Madison: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. D.C. Pavlick: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. S. Khan: Honoraria (self): Ariad; Honoraria (self): Genentech; Honoraria (self): Foundation Medicine; Honoraria (self): EMD Serono; Honoraria (self): Genzyme; Honoraria (self): Guardant; Honoraria (self): Takeda; Honoraria (self): Oak Ridge Universities; Honoraria (self): Onyx Pharmaceuticals. J. Lee: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. J.S. Ross: Leadership role, Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche; Officer / Board of Directors: Celcius Therapeutics. V.A. Miller: Leadership role, Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche; Advisory / Consultancy, Scientific Advisory Board: Revolution Medicines. B.M. Alexander: Full / Part-time employment, Officer / Board of Directors: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche; Advisory / Consultancy, Personal Fees: AbbVie; Advisory / Consultancy, Personal Fees: Schlesinger Associates; Advisory / Consultancy, Personal Fees: BristolMyers Squibb; Advisory / Consultancy, Personal Fees: Precision Health Economics; Research grant / Funding (self), grants outside submitted work: Puma Biotechnology; Research grant / Funding (self), grants outside submitted work: Celgene; Research grant / Funding (self), grants outside submitted work: Eli Lily. J. Chung: Full / Part-time employment: Foundation Medicine Inc; Shareholder /
v472 | Head And Neck Cancer, Excluding Thyroid
Stockholder / Stock options: Roche. All other authors have declared no conflicts of interest. A.B. Schrock: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. S.M. Ali: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche.
1168P
Trastuzumab plus docetaxel in patients with advanced HER2-positive salivary duct carcinoma: Exploratory biomarker analyses
H. Takahashi1, D. Kawakita2, C. Fushimi1, T. Nagao3, H. Hirai3, N. Saigusa3, T. Masubuchi1, T. Matsuki1, T. Okada1, D. Baba1, K. Miura1, T. Saotome4, Y. Tada1 1 Department of Head and Neck Oncology and Surgery, International University of Health and Welfare Mita Hospital, Tokyo, Japan, 2Department of Otorhinolaryngology, Head and Neck Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, 3Department of Anatomic Pathology, Tokyo Medical University School of Medicine, Tokyo, Japan, 4Division of Medical Oncology, Matsudo City General Hospital, Matsudo, Japan Background: A phase II trial of trastuzumab plus docetaxel in patients with advanced HER2–positive salivary duct carcinoma (SDC) showed 70% of the overall response rate. However, biomarkers which predict survival in this population remain unknown. Methods: A total of 91 patients with HER2–positive SDC treated with trastuzumab plus docetaxel were included. Age, sex, ECOG performance status (PS), status of visceral metastases, previous treatment, previous docetaxel exposure, previous combined androgen blockade, the best overall response to the treatment, pretreatment serum Creactive protein (CRP) level, modified Glasgow Prognosis Score (mGPS), HER2 status (immunohistochemistry [IHC] score, HER2/CEP17 ratio, HER2 copy number, overall positivity according to ASCO/CAP Guidelines), mutational status of PIK3CA, HRAS, and TP53, IHC score of AR, Ki-67, CK5/6, p53, HER3, Akt, PI3K, FOXA1, adipophilin, mTOR and PTEN were assessed and correlated with progression-free survival (PFS) and overall survival (OS). Results: Treatment response (PR or CR vs. SD or PD) and PTEN IHC score (1þ – 3þ vs. 0) were related with favorable PFS (hazard ratio [HR], 0.25 and 0.39, respectively) and OS (HR, 0.29 and 0.36, respectively). CRP ( 0.50 mg/dL) was related with shorter PFS (HR, 2.28) and OS (HR 4.46). Presence of previous treatment and mTOR IHC (1þ – 3þ vs. 0) had significant predictive value of better PFS (HR 0.47 and 0.22, respectively) but not significantly related with OS. ECOG PS of 1-2 (vs. 0), presence of visceral metastasis, and mGPS of 1-2 (vs. 0) had significant relationship with shorter OS but not with PFS. Neither previous docetaxel exposure nor previous combined androgen blockade did not affect the survival outcome. HER2, PIK3CA, HRAS and TP53 status did not related with survival. Conclusions: Although HER2 status did not correlated with survival, its downstream factors PTEN and mTOR can serve as predictive biomarkers in patients with advanced SDC treated with trastuzumab plus docetaxel. Serum CRP level may predict survival of this population. Clinical trial identification: UMIN000009437, Released on 03/12/2012. Legal entity responsible for the study: The authors. Funding: MEXT/JSPS. Disclosure: All authors have declared no conflicts of interest.
1169P
Development and characterization of salivary gland cancer organoid cultures
W.V. Boxtel1, T.M.W. Aalders2, G. Lassche1, I.C.H. van Engen - van Grunsven3, G.W. Verhaegh2, C. van Herpen1, J. Schalken2 1 Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands, 2Department of Urology, Radboud University Medical Center, Nijmegen, Netherlands, 3Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands Background: Recently 3D organoid cell cultures have been established for a variety of human cancers. Salivary gland cancer (SGC) is a rare cancer with 22 different subtypes and few treatment options. Our aim is to generate a large repertoire of patient-derived SGC organoids with different phenotypes, which will facilitate pre-clinical and pharmacological studies. Methods: Fresh tissues of resected primary tumours and/or metastases of SGC patients were collected. Tissues were minced and digested with collagenase type 2 and TrypLE to generate single cells. After washing, the cells were seeded in growth factor reduced Matrigel. Organoid medium, containing Rho kinase inhibitor Y27632, was refreshed twice a week. Viable organoids were characterized by immunohistochemistry and by DNA/RNA sequencing. Moreover, the organoids were used to evaluate various treatments that are or may be relevant for the treatment of SGC. Results: Between 2016 and 2018 we obtained tissue of 17 SGC patients, of which 16 contained sufficient material for processing: 10 salivary duct carcinoma (SDC), 3 adenoid cystic carcinoma (ACC), 2 muco-epidermoid carcinoma (MEC) and 1 parotid adenocarcinoma not otherwise specified (NOS). For 5 tumors (2 SDC, 2 ACC, 1 adenocarcinoma NOS) viable organoids were established, which could be passaged at least
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[HR], 3.57, 2.01, 1.76, 1.62, and 2.16, respectively) and OS (HR, 4.91, 4.98, 3.10, 2.95, and 1.78, respectively). IHC scores of PTEN (3þ) and adipophilin (5%) were related with favorable PFS (HR, 0.57 and 0.49, respectively) and OS (HR, 0.48 and 0.42, respectively). Age, ECOG PS, CRP, testosterone, AR positive ratio (70% or < 70%), HER2 status, previous treatment with trastuzumab plus docetaxel, FOXA1 immunopositivity, and mutational status of BRAF, PIK3CA, HRAS, and TP53 did not have significant association with survival. Conclusions: Rather than age and PS, sex and higher inflammation-based prognostic scores can serve as predictive biomarkers in patients with advanced SGC treated with CAB. IHC assessment of Ki-67, PTEN, and adipophilin may predict survival of this population. Biological validation of such markers is warranted. Clinical trial identification: UMIN000009437, Released on 03/12/2012. Legal entity responsible for the study: The authors. Funding: MEXT/JSPS. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
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
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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.