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Het meten van in bloed circulerend DNA - ctDNA geeft betere voorspellingen dan complete remissies op zowel effectiviteit van behandelingen zoals bv. een operatie of chemotherapie als de noodzaak van het wel of niet inzetten van T-DM1 - Trastuzumab - Deruxtecan Enhertu na de eerste behandelingen bij patiënten met borstkanker met type HER2-positief. Dat toont een studie bestaande uit verschillende groepen aan met totaal 117 deelnemende patiënten. En de verschillen zijn behoorlijk groot tussen de verschillende groepen.
Hier het abstract vrij vertaald in het Nederlands. De deeplinks in het abstract heb ik zelf aangebracht:
In bloed circulerend DNA - ctDNA) is eerder gerapporteerd als een voorspeller van de progressie van uitgezaaide borstkankeren een recidief bij borstkanker in een vroeg stadium van de ziekte. Deze studie onderzocht of de aanwezigheid van in bloed circulerend DNA - ctDNA bij patiënten met HER2-positieve (HER2+) borstkanker die een pathologisch complete respons (pCR) bereikten na neoadjuvante therapie (NAT) wijst op een slechte prognose en de noodzaak van aanvullende T-DM1 - Trastuzumab - Deruxtecan Enhertu-therapie. Van de 117 deelnemende patiënten bereikten 25 patiënten een pCR = complete remissies na NAT = neoadjuvante therapie en 92 patiënten niet. Zes van de 25 patiënten met een pathologische pCR = complete remissie vertoonden een positieve ctDNA na neoadjuvante therapie (NAT), terwijl 26 van de 92 patiënten zonder pCRctDNApositief waren. Achttien patiënten kregen adjuvante T-DM1, terwijl 99 patiënten dit niet kregen. Binnen de groep zonder T-DM1 voorspelde ctDNA-positiviteit na NAT onafhankelijk een optredend recidief (HR, 5,505; 95% betrouwbaarheidsinterval, 1,950–15,540; P = 0,001). Patiënten met een pCR en ctDNA-positiviteit hadden een kortere recidiefvrije overleving vergeleken met patiënten met een pCR en ctDNA-negatieve tumoren na NAT (P = 0,008), terwijl patiënten zonder pCR met ctDNA-negatieve tumoren een betere recidiefvrije overleving hadden vergeleken met patiënten zonder pCR met ctDNA-positieve tumoren (P = 0,001). Bij de 79 patiënten die vóór NAT ctDNA-positief waren, was klaring van ctDNA door neoadjuvante therapie (NAT) geassocieerd met een significant betere recidiefvrije overleving dan niet-klaring (P < 0,001). Adjuvante T-DM1 verbeterde de ctDNA-klaring ook significant (P = 0,035) vergeleken met therapie zonder T-DM1 bij patiënten met ctDNA-positiviteit na NAT tijdens seriële testen. We classificeerden de 117 patiënten als T-DM1/niet-T-DM1 en ctDNA-positief/negatief, en er werd een significant kortere zioektevrije overleving waargenomen bij patiënten met ctDNA-positief/niet-T-DM1 (P = 0,029) dan in de andere drie patiëntengroepen.
Hier de resultaten uit de verschillende groepen grafisch weergegeven:
Illustration of RFS in the non–T-DM1 cohort (n = 99). RFS was estimated using the Kaplan–Meier method for the entire cohort according to (A) ctDNA after NAT and (B) pCR status. C, Among patients with pCR after NAT, ctDNA-positive results were associated with inferior survival (P = 0.008). D, ctDNA levels after NAT are associated with better survival, even in patients who did not achieve pCR (P = 0.001). E, When patients were stratified according to pCR and ctDNA status, HER2 patients with ctDNA-negative had a better RFS despite pCR status, whereas patients with ctDNA positivity had an inferior RFS. F, Among the 79 patients who were ctDNA-positive before NAT, those with ctDNA clearance had a significantly better RFS (P = 0.001).
In onderstaande grafiek staan de karakteristieken van de deelnemende patiënten:
Table 1.
Patient and tumor characteristics according to the postsurgery anti-Her2 therapy.
Het volledige studierapport is gratis in te zien. In het studierapport staan nog veel meer grafische afbeeldingen met gedetailleerde uitleg hoe de onderzoekers te werk zijn gegaan en wat ze hebben gevonden. Klik daarvoor op de titel van het abstract:
ctDNA has been reported as a predictor of the progression of metastatic breast cancer and recurrence in early breast cancer (EBC). This study explored whether ctDNA persistence in patients with HER2-positive (HER2+) EBC who achieved pathologic complete response (pCR) after neoadjuvant therapy (NAT) indicates a poor prognosis and the need for adjuvant T-DM1. Of the 117 patients enrolled, 25 patients achieved pCR after NAT and 92 patients did not. Six of the 25 pCR patients showed positive ctDNA after NAT, whereas 26 of the 92 non-pCR patients were ctDNA-positive. Eighteen patients received adjuvant T-DM1, whereas 99 patients did not. Among the non–T-DM1 group, ctDNA positivity after NAT independently predicted recurrence (HR, 5.505; 95% confidence interval, 1.950–15.540; P = 0.001). pCR patients with ctDNA positivity experienced a shorter recurrence-free survival (RFS) compared with pCR and ctDNA-negative patients after NAT(P = 0.008), whereas non-pCR patients with ctDNA-negative tumors had a better RFS compared with non-pCR patients with ctDNA-positive status (P = 0.001). In the 79 patients who were ctDNA-positive before NAT, clearance of ctDNA by NAT was associated with significantly better RFS than nonclearance (P < 0.001). Adjuvant T-DM1 also significantly improved the ctDNA clearance rate (P = 0.035) compared with non–T-DM1 therapy in patients with ctDNA positivity after NAT during serial tests. We classified the 117 patients as T-DM1/non–T-DM1 and ctDNA-positive/negative, and a significantly shorter RFS was observed in patients with ctDNA-positive/non–T-DM1 (P = 0.029) than in the other three patient groups. In conclusion, the presence of ctDNA after NAT in patients with HER2+ EBC is associated with a poor prognosis and may indicate adjuvant T-DM1.
Significance:
Adjuvant T-DM1 can improve the survival of HER2+ EBC patients who don’t achieve pCR. Our study showed that ctDNA positivity after NAT was associated with decreased RFS. ctDNA-positive status after NAT can be switched to ctDNA-negative status in patients treated with T-DM1. Patients who were ctDNA-positive and treated with T-DM1 had a similar RFS to those who were ctDNA-negative, indicating that “ctDNA positivity” could be a marker determining adjuvant T-DM1 therapy.
We thank the patients, physicians, and research assistants who participated in the study. We also thank the National Applied Research Laboratories for providing access to high-performance computers for analyzing the post-NGS data. P.-H. Lin was supported by grants NSTC 113-2314-B-002-096 from the National Science and Technology Council (Taiwan) and NTUH 110-005105 from the National Taiwan University Hospital. C.-S. Huang was supported by the grant NSTC 113-2314-B-002-006 from the National Science and Technology Council (Taiwan) and a research fund (the development of molecular pathology model and recurrence prediction tool for the Taiwanese breast cancer population) from the Yonglin Foundation. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
Information on individual ctDNA mutations, disease status, and survival time is listed in Supplementary Table S1. The sequencing data (BAM files) of the ctDNA in this study are submitted to NCBI BioProject number SUB15705997. Other information in this study is available upon the request to the corresponding author.
Authors’ Disclosures
No disclosures were reported. P.-H. Lin reports grants from the National Science and Technology Council (Taiwan) during the conduct of the study. C.-S. Huang reports grants from the YongLin Foundation during the conduct of the study, as well as grants and personal fees from Novartis, Daiichi Sankyo, AstraZeneca, EirGenix, and Eli Lilly, grants, personal fees, and nonfinancial support from Gilead, Pfizer and Roche, and grants from Seagen, MSD, OBI Pharma, and Aston Sci outside the submitted work. No disclosures were reported by the other authors.
Authors’ Contributions
P.-H. Lin: Conceptualization, resources, data curation, software, formal analysis, funding acquisition, investigation, methodology, writing–original draft, writing–review and editing. L.-W. Tsai: Resources, data curation, formal analysis. C. Lo: Resources, investigation. S.-H. Kuo: Resources, data curation, investigation. C.-C. Ni: Software, formal analysis, methodology. C.-H. Yu: Investigation, methodology. C.-S. Huang: Conceptualization, resources, data curation, supervision, funding acquisition, investigation, project administration, writing–review and editing.
Ethics Approval and Consent to Participate
This study was conducted in accordance with the Declaration of Helsinki and its later amendments or comparable ethical standards. This study was approved by the Medical Ethics Committee of the National Taiwan University Hospital (201809075RSD), and all patients had written the informed consent.
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