Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival

Magbanua, Mark Jesus M.; Swigart, Lamorna Brown; Wu, Hsin-Ta; Hirst, Gillian L.; Yau, Christina; Wolf, Denise M.; Tin, Aung Soe; Salari, Raheleh; Shchegrova, Svetlana; Pawar, Hemant; Delson, Amy L.; DeMichele, Angela; Liu, M.C.; Chien, Amy Jo; Tripathy, Debu; Asare, Smita; Lin, C.-H.J.; Billings, Paul R.; Aleshin, Alexey; Sethi, Himanshu; Louie, Maggie C.; Zimmermann, Bernhard; Esserman, Laura J.; Veer, Laura J. van ’t

doi:10.1016/j.annonc.2020.11.007

Cited by 253 publications

(220 citation statements)

References 51 publications

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“…We have previously shown that pretreatment ctDNA (as binary or continuous variable) was associated with subtype, clinical T stage, and MammaPrint score (as risk categories MammaPrint high 1 and high 2) 16 . Here, we examined associations between pretreatment FTV and clinicopathologic variables.…”

Section: Ctdna Ftv and Clinicopathologic Variablesmentioning

confidence: 99%

“…Hormone receptor (estrogen and progesterone) and HER2 status, and MammaPrint risk classification (MammaPrint high 1 and high 2) based on a 70-gene signature test were assessed at pretreatment. ctDNA was detected using a personalized and a tumor-informed multiplex PCR next generation sequencing platform (Signatera TM bespoke mPCR-NGS assay) as previously described 16 . Briefly, the test's tumorinformed approach allowed for the detection of ctDNA by tracking up to 16 clonal variants (i.e., targets) in plasma.…”

Section: Data Acquisitionmentioning

confidence: 99%

“…In addition to imaging, the I-SPY 2 TRIAL has actively examined molecular biomarkers as predictors of response and recurrence 14,15 , including circulating tumor DNA (ctDNA) 16 . Clinical studies have shown that ctDNA analysis in blood offers a promising minimally invasive approach for real-time disease monitoring and evaluation of response to treatment 17,18 .…”

Section: Introductionmentioning

confidence: 99%

“…Clinical studies have shown that ctDNA analysis in blood offers a promising minimally invasive approach for real-time disease monitoring and evaluation of response to treatment 17,18 . For example, in I-SPY 2, we recently reported on a serial analysis of ctDNA and demonstrated that among patients who were ctDNApositive at baseline, those who cleared ctDNA early during treatment (3 weeks after initiation of treatment) were more likely to achieve pCR than patients who remained ctDNA-positive 16 . We also showed that residual ctDNA after NAC but before surgery was strongly associated with poor DRFS 16 .…”

Section: Introductionmentioning

confidence: 99%

“…For example, in I-SPY 2, we recently reported on a serial analysis of ctDNA and demonstrated that among patients who were ctDNApositive at baseline, those who cleared ctDNA early during treatment (3 weeks after initiation of treatment) were more likely to achieve pCR than patients who remained ctDNA-positive 16 . We also showed that residual ctDNA after NAC but before surgery was strongly associated with poor DRFS 16 . Other ctDNA studies in the neoadjuvant setting in breast cancer have revealed that ctDNApositivity before NAC was associated with a decreased likelihood of achieving a pCR and increased ctDNA levels after NAC was correlated with poor response [19][20][21] .…”

Section: Introductionmentioning

confidence: 99%

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Circulating tumor DNA and magnetic resonance imaging to predict neoadjuvant chemotherapy response and recurrence risk

Magbanua

Wolf

et al. 2021

npj Breast Cancer

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We investigated whether serial measurements of circulating tumor DNA (ctDNA) and functional tumor volume (FTV) by magnetic resonance imaging (MRI) can be combined to improve prediction of pathologic complete response (pCR) and estimation of recurrence risk in early breast cancer patients treated with neoadjuvant chemotherapy (NAC). We examined correlations between ctDNA and FTV, evaluated the additive value of ctDNA to FTV-based predictors of pCR using area under the curve (AUC) analysis, and analyzed the impact of FTV and ctDNA on distant recurrence-free survival (DRFS) using Cox regressions. The levels of ctDNA (mean tumor molecules/mL plasma) were significantly correlated with FTV at all time points (p < 0.05). Median FTV in ctDNA-positive patients was significantly higher compared to those who were ctDNA-negative (p < 0.05). FTV and ctDNA trajectories in individual patients showed a general decrease during NAC. Exploratory analysis showed that adding ctDNA information early during treatment to FTV-based predictors resulted in numerical but not statistically significant improvements in performance for pCR prediction (e.g., AUC 0.59 vs. 0.69, p = 0.25). In contrast, ctDNA-positivity after NAC provided significant additive value to FTV in identifying patients with increased risk of metastatic recurrence and death (p = 0.004). In this pilot study, we demonstrate that ctDNA and FTV were correlated measures of tumor burden. Our preliminary findings based on a limited cohort suggest that ctDNA at surgery improves FTV as a predictor of metastatic recurrence and death. Validation in larger studies is warranted.

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Section: Ctdna Ftv and Clinicopathologic Variablesmentioning

confidence: 99%

Section: Data Acquisitionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Circulating tumor DNA and magnetic resonance imaging to predict neoadjuvant chemotherapy response and recurrence risk

Magbanua

Wolf

et al. 2021

npj Breast Cancer

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Adjuvant Capecitabine in Triple-Negative Breast Cancer

Parsons

Burstein

2021

JAMA

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Surrogacy of Pathologic Complete Response in Trials of Neoadjuvant Therapy for Early Breast Cancer

et al. 2022

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ImportanceThe pathologic complete response (pCR) is supported by regulatory agencies as a surrogate end point for long-term patients’ clinical outcomes in the accelerated approval process of new drugs tested in neoadjuvant randomized clinical trials (RCTs) for early breast cancer (BC). However, a meaningful association between pCR and patients’ survival has been proven only at the patient level (ie, significantly better survival of patients who achieved pCR compared with those who did not), but not at trial level (ie, poor association between degree of improvement in pCR rate and survival reported across trials).ObservationsWe critically discuss the potential reasons of such discrepancy between pCR surrogacy value at the patient and trial level, as well as the relevant implications for both clinical research and drug regulatory policy. We also describe alternative surrogate end points, including combined end points that jointly analyzed pathological response and event-free survival data, or the assessment of circulating tumor DNA (ctDNA). Such proposed surrogate end points could overcome limits of pCR and provide a reasonable trade-off between the 2 conflicting needs to have access to effective therapies rapidly, and to reliably assess patients’ clinical benefit.Conclusions and RelevanceUsing surrogate end points to grant drug approvals is justified only when they can provide accurate prediction of a drug’s effect on the long-term patient outcomes. Evidence currently available does not support pCR used alone as a reliable surrogate end point in regulatory neoadjuvant RCTs for BC. The surrogacy value at trial level of potentially more robust surrogate end points needs to be urgently tested.

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Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival

Cited by 253 publications

References 51 publications

Circulating tumor DNA and magnetic resonance imaging to predict neoadjuvant chemotherapy response and recurrence risk

Circulating tumor DNA and magnetic resonance imaging to predict neoadjuvant chemotherapy response and recurrence risk

Adjuvant Capecitabine in Triple-Negative Breast Cancer

Surrogacy of Pathologic Complete Response in Trials of Neoadjuvant Therapy for Early Breast Cancer

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