ena-STUDY-MCGILL UNIVERSITY AND GENOME QUEBECT INNOVATION CENTRE-22-04-2019-19:12:06:646-253
Triple negative breast cancer is treated primarily with chemotherapy, even before surgery (neoadjuvant chemotherapy or NAC). The prognosis and need for adjuvant therapy depends greatly on the tumor response assessed by pathology (pCR). Highly sensitive and specific ctDNA assays have been shown to be of prognostic value in the metastatic setting but not yet in earlier settings. To evaluate the value of ctDNA to predict response to NAC and prognosis we analyzed 149 plasma samples from 26 patients with TNBC. Our results show that ctDNA detection after NAC prior to surgery is strongly predictive of disease-free survival and overall survival and is comparable to RCB as a prognostic factor in our cohort.
Response to neoadjuvant chemotherapy (NAC) in triple negative breast cancer (TNBC) patients is highly prognostic and determines if patients should undergo adjuvant chemotherapy in case of significant residual cancer burden (RCB). To evaluate the value of ctDNA to predict response to NAC and prognosis we analyzed 149 plasma samples from 26 patients with TNBC. Serial bloods and tumor were collected prior to, during and after NAC.  Personalized digital droplet PCR assays for 121 variants (average 5/patient) identified from tumor sequencing analysis were developed with threshold for detection based on normal control samples. At baseline, 96% of patients had detectable ctDNA and mutant allele frequency (MAF) was strongly associated with tumor size, stage, grade and nodal status (p=0. 022). ctDNA levels drastically fell after the first cycle of chemotherapy and only rose before surgery in patients with high RCB (p=0.00014). Detectable ctDNA prior to surgery (T4) was the most predictive of poor response to NAC (PPV=87%, NPV=89%). In contrast, analysis of only TP53 gene variants resulted in poorer overall predictive value (PPV=88%, NPV=50%). Patients with ctDNA detected at T4 had a median RFS of 14 months and OS of 24 months while patients with no ctDNA detection had better clinical outcome (p=0.0047 for RFS and p=0.0025 for OS).  Interestingly, ctDNA detection prior to surgery was better than RCB score at predicting relapse (PPV=73% vs 71% and NPV=89% vs 80%). In conclusion, individualized ctDNA testing results in highly prognostic and predictive assays in early TNBC.
Response to neoadjuvant chemotherapy (NAC) in triple negative breast cancer (TNBC) patients is highly prognostic and determines if patients should undergo adjuvant chemotherapy in case of significant residual cancer burden (RCB). To evaluate the value of ctDNA to predict response to NAC and prognosis we analyzed 149 plasma samples from 26 patients with TNBC. Serial bloods and tumor were collected prior to, during and after NAC.  Personalized digital droplet PCR assays for 121 variants (average 5/patient) identified from tumor sequencing analysis were developed with threshold for detection based on normal control samples. At baseline, 96% of patients had detectable ctDNA and mutant allele frequency (MAF) was strongly associated with tumor size, stage, grade and nodal status (p=0. 022). ctDNA levels drastically fell after the first cycle of chemotherapy and only rose before surgery in patients with high RCB (p=0.00014). Detectable ctDNA prior to surgery (T4) was the most predictive of poor response to NAC (PPV=87%, NPV=89%). In contrast, analysis of only TP53 gene variants resulted in poorer overall predictive value (PPV=88%, NPV=50%). Patients with ctDNA detected at T4 had a median RFS of 14 months and OS of 24 months while patients with no ctDNA detection had better clinical outcome (p=0.0047 for RFS and p=0.0025 for OS).  Interestingly, ctDNA detection prior to surgery was better than RCB score at predicting relapse (PPV=73% vs 71% and NPV=89% vs 80%). In conclusion, individualized ctDNA testing results in highly prognostic and predictive assays in early TNBC.