Abstract PD2-01: Personalized serial circulating tumor DNA (ctDNA) analysis in high-risk early stage breast cancer patients to monitor and predict response to neoadjuvant therapy and outcome in the I-SPY 2 TRIAL

Abstract

ctDNA analysis offers a non-invasive approach for monitoring response and resistance to treatment. Serial ctDNA testing during neoadjuvant therapy (NAT) may provide early indicators of emerging resistance and disease progression. In this study, we analyzed ctDNA from high-risk early breast cancer patients who received NAT and definitive surgery in the I-SPY 2 TRIAL (NCT01042379). We hypothesize that (1) assessment of ctDNA levels early in treatment will improve the performance of molecular and imaging-based predictors of pathologic complete response (pCR) to NAT; and (2) levels of ctDNA after NAT are associated with residual cancer burden and recurrence [distant recurrence free survival (DRFS)]. Methods: ctDNA analysis was performed in 84 high-risk stage II and III breast cancer patients randomized to neoadjuvant investigational agent (n=52), AKT inhibitor MK-2206 (M) in combination with paclitaxel (T) followed by doxorubicin and cyclophosphamide (AC) (M+T->AC), or standard-of-care (T->AC) (n=32). HER2+ patients also received trastuzumab (H). Serial plasma was collected before NAT (T0), early treatment (3 weeks, T1), between regimens (12 weeks, T2), and after NAT prior to surgery (T3). Mutational profiles derived from pretreatment tumor biopsy and normal matched DNA whole exome sequencing were used to design personalized assays targeting 16 patient-specific somatic variants to detect ctDNA in serial plasma. Results: Of the 84 patients in this study, 43% were HR-/HER2- (TNBC), 35% HR+/HER2-, and 23% HER2+. In total, 74% (61 of 83), 35% (28 of 79), 14% (9 of 65), and 8% (5 of 61) were positive for ctDNA at timepoints T0, T1, T2, and T3, respectively. At T0, ctDNA positivity and levels (average number of mutant molecules detected per mL) were significantly associated with increased tumor burden (by clinical and MRI examination), more aggressive tumor biology (as reflected in higher Mammaprint scores and grade) and subtype (HER2+ and TNBC). Twenty-seven percent (27%) of the 84 patients achieved a pCR and all patients who were ctDNA-positive at T3 (n=5) did not achieve a pCR. Currently, data are being collected to: (1) assess the relationship of ctDNA and MRI imaging in predicting tumor response to therapy; (2) examine the relationship of ctDNA levels before and after NAT with 3-year DRFS and event-free survival (EFS). The results of these analyses will be presented at the SABCS 2018 meeting. Conclusions: Our study provides a platform to evaluate the clinical significance of ctDNA for serial monitoring of response to NAT. Accurate and early response prediction by highly sensitive ctDNA analysis can facilitate a timely and judicious change in treatment to improve patients' chances of achieving a pCR. Finally, personalized ctDNA testing may complement imaging and pathologic evaluation of tumor response to fine-tune pCR as a surrogate endpoint for improved DRFS and EFS. Citation Format: Magbanua MJM, Brown-Swigart L, Hirst GL, Yau C, Wolf D, Ma AA, Bergin E, Venters S, Sethi H, Wu H-T, Salari R, Tin T, Sawyer S, Louie M, Zimmermann B, Lin C-HJ, Keats J, Liang WS, Cuyugan L, Enriquez D, Tripathy D, Chien AJ, Forero A, DeMichele A, Liu M, Delson AL, Asare S, Esserman L, van't Veer L, I-SPY 2 Consortium. Personalized serial circulating tumor DNA (ctDNA) analysis in high-risk early stage breast cancer patients to monitor and predict response to neoadjuvant therapy and outcome in the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD2-01.

Circulating tumor DNA analysis in breast cancer: Is it ready for prime-time?

“…On the other hand, ctDNA presence was not significantly associated with pCR or EFS neither at 2 weeks after the treatment start, nor before surgery [75]. Consistent results were reported by a translational sub-study of the I-SPY 2 trial, where high ctDNA at the pre-neoadjuvant time point was associated with tumor burden, aggressive biology and subtype, while the presence of ctDNA at post treatment time point was associated with low pCR [76].…”

“…Magbanua et al [76] Retrospective-prospective analysis of the I-SPY 2 trial ctDNA levels and exploratory biomarkers 100% of ctDNA-positive pts. at T3 (n = 5) did not achieve a pCR Sotiriou et al [75] Retrospective analysis of the NeoALTTO trial…”

Personalized circulating tumor DNA analysis to detect residual disease after neoadjuvant therapy in breast cancer

“…At various stages of development, these approaches generally improve on the current limit of detection for ctDNA analysis (~0.1% mutation allele fraction), but each approach has some limitations. Conventional multiplexed PCR-based approaches have been limited by the high background error rates observed (9,22). An alternative is to incorporate UMIs during the first few cycles of PCR to overcome background errors, but this limits molecular conversion because template DNA molecules not incorporated within the first 2-3 cycles are excluded from further analysis (16,25,26).…”

Circulating tumor DNA-based predictive biomarkers in breast cancer clinical trials: a narrative review

“…The translational sub-study of the ongoing I-SPY 2 trial demonstrated the significance of serial monitoring of ctDNA in predicting response to neo-adjuvant treatment (61). ctDNA analysis of the NeoALTTO trial demonstrated that the detection of PIK3CA and/or TP53 mutations, in the baseline (before neo-adjuvant therapy) plasma sample was correlated with lower rates of pathological complete response, whereas persistent ctDNA detection both at baseline and after 14 days of neo-adjuvant therapy was significantly associated with the lowest rate of pathological complete response (71,72).…”

“…ctDNA dynamics could serve as a predictive biomarker independent of the histology. Indeed, the I-SPY 2 trial reported that early ctDNA dynamics could predict response to neo-adjuvant treatment (61), whereas in the basket trial SUMMIT a decrease in ctDNA HER2 mutation variant allele frequency during treatment with the pan-HER inhibitor neratinib was followed by an increase upon radiographically proven progression (59).…”