Faculty Profiles - HIRASAWA Akira

Papers - HIRASAWA Akira

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When and how to enlighten citizens on genetics and hereditary cancer: a web survey of online video viewers. International journal

Reimi Sogawa, Takahito Wada, Noriyuki Yamashita, Mariko Kochi, Mashu Futagawa, Fumino Kato, Yusaku Urakawa, Yayoi Tanimura, Hideki Yamamoto, Shuta Tomida, Shinji Kosugi, Akira Hirasawa

Journal of community genetics 14 ( 6 ) 575 - 581 2023.9

Language：English Publishing type：Research paper (scientific journal)

With the rapid expansion of genomic medicine, more citizens are compelled to think about genetics in their daily lives. This study aims to explore appropriate types of educational media and methods to enlighten activities for genetics and hereditary cancer. We presented an 18-min YouTube video on genetics and hereditary cancer to participants at a scientific event, Science Agora 2020, and administered a web questionnaire to investigate their opinions about when and how citizens should start learning about genetics and hereditary cancer. We recruited 133 participants who watched the video, and 26.3% (35/133) responded to the questionnaire. Most of them were evaluated to understand and appreciate the contents of the video. They identified websites, or videos as suitable learning media, irrespective of their sex, age, or profession. They highlighted upper elementary school or junior high school as appropriate educational stages to start learning about genetics and hereditary cancer to facilitate collecting their own genetic information by themselves. Our findings show that educational institutions should provide opportunities to learn about genetics and hereditary cancers, especially for upper elementary school and junior high school students, using learning media, such as videos, depending on their level or demand.

DOI： 10.1007/s12687-023-00663-x

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Comprehensive genomic profiling of Japanese patients with thoracic malignancies: A single-center retrospective study. International journal

Tetsu Hirakawa, Mihoko Doi, Kosuke Hamai, Ryo Katsura, Shinya Miyake, Suguru Fujita, Sayaka Ueno, Ken Masuda, Takuya Tanimoto, Takashi Nishisaka, Takao Hinoi, Akira Hirasawa, Nobuhisa Ishikawa

Respiratory investigation 61 ( 6 ) 746 - 754 2023.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Few studies have been conducted on comprehensive genomic profiling (CGP) panels in Japanese patients with thoracic malignancies after completing standard treatment. Consequently, its value in clinical practice remains unclear. METHODS: We conducted a retrospective study of Japanese patients with thoracic malignancies who underwent CGP between June 2019 and November 2022 at our hospital. We evaluated the detection rate of actionable genetic alterations and percentage of patients who received genomically-matched therapy. Furthermore, we examined the value of the CGP panel in patients who underwent multiplex gene-panel testing prior to their initial treatment. This study was performed in accordance with the principles of the Declaration of Helsinki. RESULTS: The study included 56 patients, of whom 47 (83.9%) had actionable genetic alterations and 8 (14.3%) received genomically-matched therapy. Of these, four patients were treated with approved drugs and three patients were treated with investigational agents. In addition, one patient was treated with approved drugs using the patient-directed care system. Of the 17 patients who had multiplex gene-panel testing performed at the start of their initial therapy, two (11.8%) were newly identified by the CGP panel and subsequently received genomically-matched therapy. EGFR L718Q and MET amplification were observed in two of the seven patients with epidermal growth factor receptor-tyrosine kinase inhibitor resistance. CONCLUSIONS: The CGP panel could identify genetic alterations, thereby facilitating genomically-matched therapy, even in patients with thoracic malignancies who could not be identified using multiplex gene-panel testing.

DOI： 10.1016/j.resinv.2023.08.005

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Proposal for combined macroscopic and microscopic on-site evaluation (cMOSES) of fresh tissue from liver tumor biopsies for histopathological diagnosis and comprehensive genomic panel testing. International journal

Tami Nagatani, Yoji Wani, Soichiro Fushimi, Yu Matsuo, Shiho Murakami, Toshifumi Tada, Shinichiro Nakamura, Hirofumi Inoue, Maki Tanioka, Hiroyuki Okada, Akira Hirasawa

Pathology international 73 ( 12 ) 612 - 614 2023.9

網羅的がんゲノム医療時代の遺伝性腫瘍診療と遺伝カウンセリング遺伝性腫瘍のリスク評価・診断のための多遺伝子パネル検査受検例の施設横断的な検討(Hereditary tumor syndromes and genetic counseling in the era of cancer genomic medicine Cross-institutional case review of multi-gene panel testing for risk assessments and diagnosis of hereditary tumors)

山本英喜, 藤田裕子, 田村和朗, 浦川優作, 二川摩周, 十川麗美, 加藤芙美乃, 植野さやか, 重安邦俊, 原賀順子, 小川千加子, 河内麻里子, 深野智華, 甲斐恭平, 塩崎滋弘, 平沢晃

日本癌学会総会記事 82回 821 - 821 2023.9

Japanese Society of Medical Oncology/Japan Society of Clinical Oncology/Japanese Society of Pediatric Hematology/Oncology-led clinical recommendations on the diagnosis and use of immunotherapy in patients with DNA mismatch repair deficient (dMMR) tumors, third edition.

Saori Mishima, Yoichi Naito, Kiwamu Akagi, Naomi Hayashi, Akira Hirasawa, Tomoro Hishiki, Ataru Igarashi, Masafumi Ikeda, Shigenori Kadowaki, Hiroaki Kajiyama, Motohiro Kato, Hirotsugu Kenmotsu, Yasuhiro Kodera, Keigo Komine, Takafumi Koyama, Osamu Maeda, Mitsuru Miyachi, Hiroshi Nishihara, Hiroyuki Nishiyama, Shouichi Ohga, Wataru Okamoto, Eiji Oki, Shigeru Ono, Masashi Sanada, Ikuo Sekine, Tadao Takano, Kayoko Tao, Keita Terashima, Katsuya Tsuchihara, Yasushi Yatabe, Takayuki Yoshino, Eishi Baba

International journal of clinical oncology 28 ( 10 ) 1237 - 1258 2023.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. The accumulated evidence of tumor agnostic agent has been made since PD-1 inhibitor was approved and used in clinical practice. Therefore, we have revised the guideline "Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition". METHODS: Clinical questions regarding medical care were formulated for patients with dMMR advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO), Japanese Society of Medical Oncology (JSMO), and Japanese society of pediatric hematology/oncology (JSPHO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO and the public comments among all societies' members were done. RESULTS: The current guideline describes two clinical questions and eight recommendations for whom, when, and how MMR status should be tested. CONCLUSION: In this guideline, the committee proposed eight recommendations for performing MMR testing properly to select patients who are likely to benefit from immunotherapy.

DOI： 10.1007/s10147-023-02397-9

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International journal of clinical oncology 28 ( 8 ) 941 - 955 2023.8

Language：English Publishing type：Research paper (scientific journal)

The development of novel antitumor agents and accompanying biomarkers has improved survival across several tumor types. Previously, we developed recommendations for tumor-agnostic treatments in patients with solid tumors with DNA mismatch repair deficient or neurotrophic receptor tyrosine kinase fusions. Recently, immune checkpoint inhibitors have shown efficacy in patient with tumor mutation burden-high (TMB-H) solid tumors and have been established as a third tumor-agnostic agent, making it necessary to develop the guideline prioritized for these patients. Clinical questions regarding medical care were formulated for patients with TMB-H advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO), Japanese Society of Medical Oncology (JSMO), and Japanese society of pediatric hematology/oncology (JSPHO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. The current guideline describes three clinical questions and seven recommendations for whom, when, and how TMB should be tested, and what is recommended for patients with TMB-H advanced solid tumors. In this guideline, the committee proposed seven recommendations for performing TMB testing properly to select patients who are likely to benefit from immunotherapy.

DOI： 10.1007/s10147-023-02360-8

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肉腫診療におけるがん遺伝子パネルの有用性

中田英二, 藤原智洋, 国定俊之, 遠西大輔, 山本英喜, 二宮貴一朗, 冨田秀太, 二川摩周, 平沢晃, 豊岡伸一, 尾崎敏文

日本整形外科学会雑誌 97 ( 8 ) S1894 - S1894 2023.8

A case of ovarian carcinosarcoma with a germline pathogenic variant of BRCA2 involving a perforated appendix with an abscess. International journal

Ayaka Saito, Eiko Yamashita, Urara Sakurai, Akira Hirasawa, Maki Tanioka, Kazuya Tamura, Satoshi Umezawa

The journal of obstetrics and gynaecology research 49 ( 10 ) 2553 - 2557 2023.7

Language：English Publishing type：Research paper (scientific journal)

We report a case of rare and aggressive ovarian carcinosarcoma with a germline pathogenic BRCA2 variant. A patient with a history of breast cancer who developed an inflammatory ovarian tumor with peritonitis carcinomatosis involving the appendix suffered from cachexia. Following three cycles of weekly paclitaxel and carboplatin chemotherapy, emergency surgery was required owing to sepsis. Bilateral salpingo-oophorectomy, total hysterectomy, appendectomy, and small intestine adhesiolysis were performed. Histologically, the tumor comprised an admixture of carcinomatous and sarcomatous components, with involvement of the appendix, which had caused perforation and abscess formation. The final diagnosis was ovarian carcinosarcoma with a germline pathogenic BRCA2 variant, c.658_659del (p.Val220fs). The patient responded completely to adjuvant chemotherapy. A combination of chemotherapy and surgery might be beneficial to patients with ovarian carcinosarcoma and germline pathogenic BRCA2 variants with a poor general condition. This is the first report of ovarian carcinosarcoma with a germline pathogenic BRCA2 variant that responded favorably to chemotherapy.

DOI： 10.1111/jog.15736

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Japanese Society of Medical Oncology/Japan Society of Clinical Oncology/Japanese Society of Pediatric Hematology/Oncology-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors.

Yoichi Naito, Saori Mishima, Kiwamu Akagi, Naomi Hayashi, Akira Hirasawa, Tomoro Hishiki, Ataru Igarashi, Masafumi Ikeda, Shigenori Kadowaki, Hiroaki Kajiyama, Motohiro Kato, Hirotsugu Kenmotsu, Yasuhiro Kodera, Keigo Komine, Takafumi Koyama, Osamu Maeda, Mitsuru Miyachi, Hiroshi Nishihara, Hiroyuki Nishiyama, Shouichi Ohga, Wataru Okamoto, Eiji Oki, Shigeru Ono, Masashi Sanada, Ikuo Sekine, Tadao Takano, Kayoko Tao, Keita Terashima, Katsuya Tsuchihara, Yasushi Yatabe, Takayuki Yoshino, Eishi Baba

International journal of clinical oncology 28 ( 7 ) 827 - 840 2023.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Clinical trials have reported the efficacy of tropomyosin receptor kinase (TRK) inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors. The accumulated evidence of tumor-agnostic agent has made since TRK inhibitors were approved and used in clinical practice. Therefore, we have revised the 'Japan Society of Clinical Oncology (JSCO)/Japanese Society of Medical Oncology (JSMO)-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors, cooperated by the Japanese Society of Pediatric Hematology/Oncology (JSPHO)'. METHODS: Clinical questions regarding medical care were formulated for patients with NTRK fusion-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by JSCO, JSMO, and JSPHO voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. RESULTS: The current guideline describes 3 clinical questions and 14 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors. CONCLUSION: The committee proposed 14 recommendations for performing NTRK testing properly to select patients who are likely to benefit from TRK inhibitors.

DOI： 10.1007/s10147-023-02345-7

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婦人科遺伝性腫瘍とデータシェアリング Invited

平沢晃

HORMONE FRONTIER IN GYNECOLOGY 30 ( 2 ) 45 - 52 2023.6

Survey of the Current Status of the Secondary Findings Disclosure Process for Tumor Genomic Profiling: A Multicenter Questionnaire Survey

島田咲, 島田咲, 山田崇弘, 山田崇弘, 山田崇弘, 源明理, 松川愛未, 松川愛未, 矢部一郎, 青木洋子, 織田克利, 植木有紗, 東川智美, 森川真紀, 佐藤友紀, 平沢晃, 小川昌宣, 小川昌宣, 近藤知大, 吉岡正博, 金井雅史, 武藤学, 小杉眞司, 松川愛未, 矢部一郎, 青木洋子, 織田克利, 植木有紗, 東川智美, 森川真紀, 佐藤友紀, 平沢晃, 小川昌宣, 近藤知大, 吉岡正博, 金井雅史, 小杉眞司

日本遺伝カウンセリング学会誌 44 ( 2 ) 92 - 92 2023.6

Human resources for administrative work to carry out a comprehensive genomic profiling test in Japan. International journal

Hidenori Kage, Katsutoshi Oda, Manabu Muto, Katsuya Tsuchihara, Natsuko Okita, Yusuke Okuma, Junko Kikuchi, Hidekazu Shirota, Hideyuki Hayashi, Toshio Kokuryo, Daisuke Sakai, Akira Hirasawa, Makoto Kubo, Hirotsugu Kenmotsu, Nana Akiyama, Aya Shinozaki-Ushiku, Masahiko Tanabe, Tetsuo Ushiku, Kiyoshi Miyagawa, Yasuyuki Seto

Cancer science 114 ( 7 ) 3041 - 3049 2023.5

Language：English Publishing type：Research paper (scientific journal)

Comprehensive genomic profiling (CGP) tests have been nationally reimbursed in Japan since June 2019 under strict restrictions, and over 46,000 patients have taken the test. Core Hospitals and Designated Hospitals host molecular tumor boards, which is more time-consuming than simply participating in them. We sent a questionnaire to government-designated Cancer Genomic Medicine Hospitals, including all 12 Core Hospitals, all 33 Designated Hospitals, and 117 of 188 Cooperative Hospitals. The questionnaire asked how much time physicians and nonphysicians spent on administrative work for cancer genomic medicine. For every CGP test, 7.6 h of administrative work was needed. Physicians spent 2.7 h/patient, while nonphysicians spent 4.9 h/patient. Time spent preparing for molecular tumor boards, called Expert Panels, was the longest, followed by time spent participating in Expert Panels. Assuming an hourly wage of \24,000/h for physicians and \2800/h for nonphysicians, mean labor cost was \78,071/patient. On a monthly basis, more time was spent on administrative work at Core Hospitals compared with Designated Hospitals and Cooperative Hospitals (385 vs. 166 vs. 51 h/month, respectively, p < 0.001). Consequently, labor cost per month was higher at Core Hospitals than at Designated Hospitals and Cooperative Hospitals (\3,951,854 vs. \1,687,167 vs. \487,279/month, respectively, p < 0.001). Completing a CGP test for a cancer patient in Japan is associated with significant labor at each hospital, especially at Core Hospitals. Streamlining the exchange of information and simplifying Expert Panels will likely alleviate this burden.

DOI： 10.1111/cas.15833

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今,再考するROSEの意義 EUS-FNA検体のゲノム医療における有用性と限界

井上博文, 松岡博美, 實平悦子, 松岡昌志, 安村早優美, 田中健大, 寺澤裕之, 松本和幸, 加藤博也, 平沢晃

日本臨床細胞学会雑誌 62 ( Suppl.1 ) 187 - 187 2023.5

今,再考するROSEの意義 EUS-FNA検体のゲノム医療における有用性と限界

井上博文, 松岡博美, 實平悦子, 松岡昌志, 安村早優美, 田中健大, 寺澤裕之, 松本和幸, 加藤博也, 平沢晃

日本臨床細胞学会雑誌 62 ( Suppl.1 ) 187 - 187 2023.5

マイクロアレイ染色体検査にてCharcot-Marie-Tooth病責任領域の重複が認められたMiller-Dieker症候群の遺伝カウンセリング

十川麗美, 秋山倫之, 衛藤英理子, 二川摩周, 加藤芙美乃, 山本英喜, 平沢晃, 大守伊織, 小林勝弘

脳と発達 55 ( Suppl. ) S302 - S302 2023.5

The DNA integrity number and concentration are useful parameters for successful comprehensive genomic profiling test for cancer using formalin-fixed paraffin embedded tissue. International journal

Emmy Yanagita, Hiroshi Yamada, Tetsuro Kobayashi, Eriko Aimono, Kohei Nakamura, Akira Hirasawa, Hiroshi Nishihara

Pathology international 73 ( 5 ) 198 - 206 2023.3

Language：English Publishing type：Research paper (scientific journal)

The acquisition of high-quality biospecimens and the appropriate handling of these materials are indispensable for successful clinical sequencing. We developed a cancer clinical sequencing system targeting 160 cancer genes: PleSSision-Rapid. Through the PleSSision-Rapid system, we have analyzed DNA quality evaluated by DIN (DNA integrity number) with 1329 formalin-fixed paraffin embedded (FFPE) samples including 477 prospectively collected tissues for genomic test (P) and 852 archival samples after routine pathological diagnosis (A1/A2). As a result, the samples with more than DIN 2.1 was 92.0% (439/477) in prospectively collected sample (P), while it was 85.6% (332/388) and 76.7% (356/464) in two types of archival samples (A1/A2). We performed the PleSSision-Rapid sequence using the samples with over DIN 2.1 and DNA concentration >10 ng/μL with which we were able to construct a DNA library, and the probability of sequence success was almost equivalent during all types of specimen processing, at 90.7% (398/439) in (P), 92.5% (307/332) in (A1) and 90.2% (321/356) in (A2), respectively. Our result indicated the clinical benefit to prepare the prospective collection of FFPE materials for indisputable clinical sequence, and that DIN ≥ 2.1 would be a solid parameter for sample preparation of comprehensive genomic profiling tests.

DOI： 10.1111/pin.13318

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[Ⅲ. The Role of Comprehensive Genomic Profiling in Sarcoma].

Eiji Nakata, Tomohiro Fujiwara, Toshiyuki Kunisada, Toshifumi Ozaki, Shinichi Toyooka, Daisuke Ennishi, Hideki Yamamoto, Kiichiro Ninomiya, Shuta Tomida, Akira Hirasawa, Mashu Futagawa, Masahiro Tabata

Gan to kagaku ryoho. Cancer & chemotherapy 50 ( 3 ) 314 - 320 2023.3

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study. International journal

Eun-Young Kang, Ashley Weir, Nicola S Meagher, Kyo Farrington, Gregg S Nelson, Prafull Ghatage, Cheng-Han Lee, Marjorie J Riggan, Adelyn Bolithon, Gordana Popovic, Betty Leung, Katrina Tang, Neil Lambie, Joshua Millstein, Jennifer Alsop, Michael S Anglesio, Beyhan Ataseven, Ellen Barlow, Matthias W Beckmann, Jessica Berger, Christiani Bisinotto, Hans Bösmüller, Jessica Boros, Alison H Brand, Angela Brooks-Wilson, Sara Y Brucker, Michael E Carney, Yovanni Casablanca, Alicia Cazorla-Jiménez, Paul A Cohen, Thomas P Conrads, Linda S Cook, Penny Coulson, Madeleine Courtney-Brooks, Daniel W Cramer, Philip Crowe, Julie M Cunningham, Cezary Cybulski, Kathleen M Darcy, Mona A El-Bahrawy, Esther Elishaev, Ramona Erber, Rhonda Farrell, Sian Fereday, Anna Fischer, María J García, Simon A Gayther, Aleksandra Gentry-Maharaj, C Blake Gilks, Marcel Grube, Paul R Harnett, Shariska Petersen Harrington, Philipp Harter, Arndt Hartmann, Jonathan L Hecht, Sebastian Heikaus, Alexander Hein, Florian Heitz, Joy Hendley, Brenda Y Hernandez, Susanna Hernando Polo, Sabine Heublein, Akira Hirasawa, Estrid Høgdall, Claus K Høgdall, Hugo M Horlings, David G Huntsman, Tomasz Huzarski, Andrea Jewell, Mercedes Jimenez-Linan, Michael E Jones, Scott H Kaufmann, Catherine J Kennedy, Dineo Khabele, Felix K F Kommoss, Roy F P M Kruitwagen, Diether Lambrechts, Nhu D Le, Marcin Lener, Jenny Lester, Yee Leung, Anna Linder, Liselore Loverix, Jan Lubiński, Rashna Madan, G Larry Maxwell, Francesmary Modugno, Susan L Neuhausen, Alexander Olawaiye, Siel Olbrecht, Sandra Orsulic, José Palacios, Celeste Leigh Pearce, Malcolm C Pike, Carmel M Quinn, Ganendra Raj Mohan, Cristina Rodríguez-Antona, Matthias Ruebner, Andy Ryan, Stuart G Salfinger, Naoko Sasamoto, Joellen M Schildkraut, Minouk J Schoemaker, Mitul Shah, Raghwa Sharma, Yurii B Shvetsov, Naveena Singh, Gabe S Sonke, Linda Steele, Colin J R Stewart, Karin Sundfeldt, Anthony J Swerdlow, Aline Talhouk, Adeline Tan, Sarah E Taylor, Kathryn L Terry, Aleksandra Tołoczko, Nadia Traficante, Koen K Van de Vijver, Maaike A van der Aa, Toon Van Gorp, Els Van Nieuwenhuysen, Lilian van-Wagensveld, Ignace Vergote, Robert A Vierkant, Chen Wang, Lynne R Wilkens, Stacey J Winham, Anna H Wu, Javier Benitez, Andrew Berchuck, Francisco J Candido Dos Reis, Anna DeFazio, Peter A Fasching, Ellen L Goode, Marc T Goodman, Jacek Gronwald, Beth Y Karlan, Stefan Kommoss, Usha Menon, Hans-Peter Sinn, Annette Staebler, James D Brenton, David D Bowtell, Paul D P Pharoah, Susan J Ramus, Martin Köbel

Cancer 129 ( 5 ) 697 - 713 2022.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

DOI： 10.1002/cncr.34582

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Drug response profiles in patient-derived cancer cells across histological subtypes of ovarian cancer: real-time therapy tailoring for a patient with low-grade serous carcinoma. International journal

Astrid Murumägi, Daniela Ungureanu, Suleiman Khan, Mariliina Arjama, Katja Välimäki, Aleksandr Ianevski, Philipp Ianevski, Rebecka Bergström, Alice Dini, Anna Kanerva, Riitta Koivisto-Korander, Johanna Tapper, Heini Lassus, Mikko Loukovaara, Andrus Mägi, Akira Hirasawa, Daisuke Aoki, Vilja Pietiäinen, Teijo Pellinen, Ralf Bützow, Tero Aittokallio, Olli Kallioniemi

British journal of cancer 128 ( 4 ) 678 - 690 2022.12

Language：English Publishing type：Research paper (scientific journal)

Many efforts are underway to develop novel therapies against the aggressive high-grade serous ovarian cancers (HGSOCs), while our understanding of treatment options for low-grade (LGSOC) or mucinous (MUCOC) of ovarian malignancies is not developing as well. We describe here a functional precision oncology (fPO) strategy in epithelial ovarian cancers (EOC), which involves high-throughput drug testing of patient-derived ovarian cancer cells (PDCs) with a library of 526 oncology drugs, combined with genomic and transcriptomic profiling. HGSOC, LGSOC and MUCOC PDCs had statistically different overall drug response profiles, with LGSOCs responding better to targeted inhibitors than HGSOCs. We identified several subtype-specific drug responses, such as LGSOC PDCs showing high sensitivity to MDM2, ERBB2/EGFR inhibitors, MUCOC PDCs to MEK inhibitors, whereas HGSOCs showed strongest effects with CHK1 inhibitors and SMAC mimetics. We also explored several drug combinations and found that the dual inhibition of MEK and SHP2 was synergistic in MAPK-driven EOCs. We describe a clinical case study, where real-time fPO analysis of samples from a patient with metastatic, chemorefractory LGSOC with a CLU-NRG1 fusion guided clinical therapy selection. fPO-tailored therapy with afatinib, followed by trastuzumab and pertuzumab, successfully reduced tumour burden and blocked disease progression over a five-year period. In summary, fPO is a powerful approach for the identification of systematic drug response differences across EOC subtypes, as well as to highlight patient-specific drug regimens that could help to optimise therapies to individual patients in the future.

DOI： 10.1038/s41416-022-02067-z

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Handling of Germline Findings in Clinical Comprehensive Cancer Genomic Profiling.

Mika Okazawa-Sakai, Yasuko Yamamoto, Mashu Futagawa, Miki Okamura, Satoko Miyawaki, Tomohiro Nishina, Kazuhiro Takehara, Toshiyuki Kozuki, Shuta Tomida, Ichinosuke Hyodo, Shozo Ohsumi, Akira Hirasawa

Acta medica Okayama 76 ( 6 ) 673 - 678 2022.12

Language：English Publishing type：Research paper (scientific journal)

Patients found to have presumed germline pathogenic variants (PGPVs) during comprehensive genomic profiling (CGP) require genetic counseling (GC) referrals. We retrospectively investigated the outcomes of patients with PGPVs. Among 159 patients who underwent CGP, we recommended GC for the 16 patients with PGPVs (3 with [FG group] and 13 without [G Group] a family/personal history of hereditary cancer) as well as for the 8 patients with no PGPVs, but a history (F group); 2 (67%), 5 (38%), and 3 (38%) patients received GC in the FG, G, and F groups, respectively. Germline testing results were positive in 1 and 2 patients of the FG and G groups, respectively. Among the patients recommended for GC, 58% did not receive GC due to lack of interest, poor performance status, or death. CGP contributes to the identification of germline variants in patients without a history of hereditary cancer. However, the proportion of patients who undergo GC should be improved.

DOI： 10.18926/AMO/64117

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