Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial.
Nicholas C. Turner,Nicholas C. Turner,B Kingston,Lucy Kilburn,Sarah Kernaghan,Andrew M Wardley,Andrew M Wardley,Iain R. Macpherson,Richard D. Baird,Rebecca Roylance,Rebecca Roylance,Peter Stephens,Olga Oikonomidou,Jeremy P Braybrooke,Mark Tuthill,Jacinta Abraham,Matthew C Winter,Hannah Bye,Mike Hubank,Mike Hubank,Heidrun Gevensleben,Ros Cutts,Claire Snowdon,Daniel Rea,David Cameron,Abeer M Shaaban,Katrina Randle,Sue Martin,Katie Wilkinson,Laura Moretti,Judith M Bliss,A Ring +31 more
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The results demonstrate clinically relevant activity of targeted therapies against rare HER2 and AKT1 mutations, and agreement between ctDNA digital PCR and targeted sequencing was 96–99% (n=800, kappa 0·89–0·93).Abstract:
Summary Background Circulating tumour DNA (ctDNA) testing might provide a current assessment of the genomic profile of advanced cancer, without the need to repeat tumour biopsy. We aimed to assess the accuracy of ctDNA testing in advanced breast cancer and the ability of ctDNA testing to select patients for mutation-directed therapy. Methods We did an open-label, multicohort, phase 2a, platform trial of ctDNA testing in 18 UK hospitals. Participants were women (aged ≥18 years) with histologically confirmed advanced breast cancer and an Eastern Cooperative Oncology Group performance status 0–2. Patients had completed at least one previous line of treatment for advanced breast cancer or relapsed within 12 months of neoadjuvant or adjuvant chemotherapy. Patients were recruited into four parallel treatment cohorts matched to mutations identified in ctDNA: cohort A comprised patients with ESR1 mutations (treated with intramuscular extended-dose fulvestrant 500 mg); cohort B comprised patients with HER2 mutations (treated with oral neratinib 240 mg, and if oestrogen receptor-positive with intramuscular standard-dose fulvestrant); cohort C comprised patients with AKT1 mutations and oestrogen receptor-positive cancer (treated with oral capivasertib 400 mg plus intramuscular standard-dose fulvestrant); and cohort D comprised patients with AKT1 mutations and oestrogen receptor-negative cancer or PTEN mutation (treated with oral capivasertib 480 mg). Each cohort had a primary endpoint of confirmed objective response rate. For cohort A, 13 or more responses among 78 evaluable patients were required to infer activity and three or more among 16 were required for cohorts B, C, and D. Recruitment to all cohorts is complete and long-term follow-up is ongoing. This trial is registered with ClinicalTrials.gov , NCT03182634 ; the European Clinical Trials database, EudraCT2015-003735-36; and the ISRCTN registry, ISRCTN16945804. Findings Between Dec 21, 2016, and April 26, 2019, 1051 patients registered for the study, with ctDNA results available for 1034 patients. Agreement between ctDNA digital PCR and targeted sequencing was 96–99% (n=800, kappa 0·89–0·93). Sensitivity of digital PCR ctDNA testing for mutations identified in tissue sequencing was 93% (95% CI 83–98) overall and 98% (87–100) with contemporaneous biopsies. In all cohorts, combined median follow-up was 14·4 months (IQR 7·0–23·7). Cohorts B and C met or exceeded the target number of responses, with five (25% [95% CI 9–49]) of 20 patients in cohort B and four (22% [6–48]) of 18 patients in cohort C having a response. Cohorts A and D did not reach the target number of responses, with six (8% [95% CI 3–17]) of 74 in cohort A and two (11% [1–33]) of 19 patients in cohort D having a response. The most common grade 3–4 adverse events were raised gamma-glutamyltransferase (13 [16%] of 80 patients; cohort A); diarrhoea (four [25%] of 20; cohort B); fatigue (four [22%] of 18; cohort C); and rash (five [26%] of 19; cohort D). 17 serious adverse reactions occurred in 11 patients, and there was one treatment-related death caused by grade 4 dyspnoea (in cohort C). Interpretation ctDNA testing offers accurate, rapid genotyping that enables the selection of mutation-directed therapies for patients with breast cancer, with sufficient clinical validity for adoption into routine clinical practice. Our results demonstrate clinically relevant activity of targeted therapies against rare HER2 and AKT1 mutations, confirming these mutations could be targetable for breast cancer treatment. Funding Cancer Research UK, AstraZeneca, and Puma Biotechnology.read more
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Liquid biopsy enters the clinic - implementation issues and future challenges.
TL;DR: In this article, the authors discuss key issues and gaps in technology, clinical trial methodologies and logistics for the eventual integration of liquid biopsy into the clinical workflow, and discuss the potential applications of this technology in cancer screening and diagnosis.
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ctDNA guiding adjuvant immunotherapy in urothelial carcinoma.
Thomas Powles,Zoe June Assaf,Nicole N. Davarpanah,Romain Banchereau,Bernadett Szabados,Kobe C. Yuen,Petros Grivas,Petros Grivas,Petros Grivas,Maha Hussain,Stéphane Oudard,Jürgen E. Gschwend,Peter Albers,Daniel Castellano,Hiroyuki Nishiyama,Siamak Daneshmand,Shruti Sharma,Bernhard Zimmermann,Himanshu Sethi,Alexey Aleshin,Maurizio Perdicchio,Jingbin Zhang,David S. Shames,Viraj Degaonkar,Xiaodong Shen,Corey Carter,Carlos Bais,Joaquim Bellmunt,Sanjeev Mariathasan +28 more
TL;DR: In this paper, the authors evaluated outcomes in 581 patients who had undergone surgery and were evaluable for ctDNA from a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer.
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Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver
Alice Bertocchi,Sara Carloni,Paola Simona Ravenda,Giovanni Bertalot,Ilaria Spadoni,Antonino Lo Cascio,Sara Gandini,Michela Lizier,Daniele Braga,Francesco Asnicar,Nicola Segata,Chris Klaver,Paola Brescia,Elio Rossi,Achille Anselmo,Silvia Guglietta,Annalisa Maroli,Paola Spaggiari,Noelia Tarazona,Andrés Cervantes,Silvia Marsoni,Luca Lazzari,Maria Giovanna Jodice,Chiara Luise,Marco Erreni,Salvatore Pece,Salvatore Pece,Pier Paolo Di Fiore,Pier Paolo Di Fiore,Giuseppe Viale,Giuseppe Viale,Antonino Spinelli,Chiara Pozzi,Giuseppe Penna,Maria Rescigno +34 more
TL;DR: In this article, the authors show that the premetastatic niche in the liver is induced by bacteria dissemination from primary colorectal cancer (CRC) patients, and that increased levels of PV-1, a marker of impaired Gut vascular barrier (GVB), is associated with liver bacteria dissemination and metachronous distant metastases.
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ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group.
Javier Pascual,Gerhardt Attard,François-Clément Bidard,Giuseppe Curigliano,Leticia De Mattos-Arruda,Maximilian Diehn,Antoine Italiano,Johan Lindberg,Jason D. Merker,Clara Montagut,Nicola Normanno,Klaus Pantel,George Pentheroudakis,Sanjay Popat,Jorge S. Reis-Filho,Jeanne Tie,Joan Seoane,Noelia Tarazona,Takayuki Yoshino,Nicholas C. Turner +19 more
TL;DR: Alix-Panabières et al. as discussed by the authors reviewed analytical and clinical validity and utility of circulating tumour DNA (ctDNA) assays and made recommendations for reporting of results, future development of ctDNA assays, and future clinical research are made.
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Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial
TL;DR: Elacestrant as mentioned in this paper is an oral selective estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer degrader that demonstrated activity in early studies.
References
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Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer
Sarah-Jane Dawson,Dana W.Y. Tsui,Muhammed Murtaza,Heather Biggs,Oscar M. Rueda,Suet-Feung Chin,Mark J Dunning,Davina Gale,Tim Forshew,Betania Mahler-Araujo,Sabrina Rajan,Sean Humphray,Jennifer Becq,David Halsall,Matthew G. Wallis,David Bentley,Carlos Caldas,Nitzan Rosenfeld +17 more
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Garrett M. Frampton,Alex Fichtenholtz,Geoff Otto,Kai Wang,Sean R. Downing,Jie He,Michael Schnall-Levin,Jared White,Eric M. Sanford,Peter An,James Sun,Frank Juhn,Kristina W. Brennan,Kiel Iwanik,Ashley Maillet,Jamie Buell,Emily White,Mandy Zhao,Sohail Balasubramanian,Selmira Terzic,Tina Richards,Vera Banning,Lazaro Garcia,Kristen Mahoney,Zac Zwirko,Amy Donahue,Himisha Beltran,Himisha Beltran,Juan Miguel Mosquera,Juan Miguel Mosquera,Mark A. Rubin,Mark A. Rubin,Snjezana Dogan,Cyrus V. Hedvat,Michael F. Berger,Lajos Pusztai,Matthias Lechner,Chris Boshoff,Mirna Jarosz,Christine Vietz,Alexander N. Parker,Vincent A. Miller,Jeffrey S. Ross,Jeffrey S. Ross,John Curran,Maureen T. Cronin,Philip J. Stephens,Doron Lipson,Roman Yelensky +48 more
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Alpelisib for PIK3CA-Mutated, Hormone Receptor–Positive Advanced Breast Cancer
Fabrice Andre,Eva Ciruelos,G. Rubovszky,Mario Campone,Sibylle Loibl,Hope S. Rugo,H. Iwata,Pierfranco Conte,Ingrid A. Mayer,Bella Kaufman,Toshinari Yamashita,Yen-Shen Lu,Kenichi Inoue,Masato Takahashi,Zsuzsanna Papai,Anne-Sophie Longin,David Mills,Celine Wilke,Samit Hirawat,Dejan Juric +19 more
TL;DR: Treatment with alpelisib–fulvestrant prolonged progression‐free survival among patients with PIK3CA‐mutated, HR‐positive, HER2‐negative advanced breast cancer who had received endocrine therapy previously.
Journal ArticleDOI
Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer
Nicholas C. Turner,Jungsil Ro,Fabrice Andre,Sherene Loi,Sunil Verma,Hiroji Iwata,Nadia Harbeck,Sibylle Loibl,Cynthia Huang Bartlett,Ke Zhang,Carla Giorgetti,Sophia Randolph,Maria Koehler,Massimo Cristofanilli,Massimo Cristofanilli +14 more
TL;DR: Among patients with hormone-receptor-positive metastatic breast cancer who had progression of disease during prior endocrine therapy, palbociclib combined with fulvestrant resulted in longer progression-free survival than fulvestrants alone.
Journal ArticleDOI
ESR1 ligand-binding domain mutations in hormone-resistant breast cancer
Weiyi Toy,Yang Shen,Helen Won,Bradley Green,Rita A. Sakr,Marie Will,Zhiqiang Li,Kinisha Gala,Sean W. Fanning,Tari A. King,Clifford A. Hudis,Clifford A. Hudis,David Chen,Tetiana Taran,Gabriel N. Hortobagyi,Geoffrey L. Greene,Michael F. Berger,José Baselga,José Baselga,Sarat Chandarlapaty,Sarat Chandarlapaty +20 more
TL;DR: A comprehensive genetic analysis of two independent cohorts of metastatic ER-positive breast tumors and identified mutations in ESR1 affecting the ligand-binding domain (LBD) in 14 of 80 cases that implicate LBD-mutant forms of ER in mediating clinical resistance to hormonal therapy and suggest that more potent ER antagonists may be of substantial therapeutic benefit.
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