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. 2024 Jul:8:e2300724.
doi: 10.1200/PO.23.00724.

TOWARDS Study: Patient-Derived Xenograft Engraftment Predicts Poor Survival in Patients With Newly Diagnosed Triple-Negative Breast Cancer

Christos Vaklavas  1 , Cindy B Matsen  2 , Zhengtao Chu  3 , Kenneth M Boucher  4 , Sandra D Scherer  3 , Satya Pathi  3 , Anna Beck  1 , Kirstyn E Brownson  2 , Saundra S Buys  1 , Namita Chittoria  1 , Elyse D'Astous  5 , H Evin Gulbahce  6 , N Lynn Henry  1   7 , Stephen Kimani  1 , Jane Porretta  2 , Regina Rosenthal  2 , John Ward  1 , Mei Wei  1 , Bryan E Welm  2 , Alana L Welm  3
Affiliations

TOWARDS Study: Patient-Derived Xenograft Engraftment Predicts Poor Survival in Patients With Newly Diagnosed Triple-Negative Breast Cancer

Christos Vaklavas et al. JCO Precis Oncol. 2024 Jul.

Abstract

Purpose: Assessing risk of recurrence for nonmetastatic triple-negative breast cancer (TNBC) is a key determinant of therapeutic strategy. The best predictor of recurrence risk is failure to achieve a pathologic complete response after preoperative chemotherapy, but it imperfectly correlates with the definitive end points of relapse-free and overall survival (OS). The inability to accurately predict recurrence has led to increasingly toxic treatment regimens for patients with early-stage TNBC. Better assays for recurrence risk are needed to tailor aggressive therapy for patients who need it and avoid overtreatment and unnecessary toxicity for those at low risk. The purpose of this study was to determine if patient-derived xenograft (PDX) engraftment of newly diagnosed breast tumors can serve as an accurate predictor of recurrence and death from breast cancer.

Methods: This study was a blinded noninterventional trial comprising 80 patients with newly diagnosed, nonmetastatic, estrogen receptor (ER)-negative or ER-low breast cancer.

Results: PDX engraftment was strongly associated with relapse in 1 year: 8 of 18 (44.4%) patients whose tumors engrafted relapsed versus 1 of 62 (1.6%) patients whose tumors did not engraft (P < .0001). Patients whose tumors engrafted had a hazard ratio (HR) for relapse of 17.5. HRs for OS and breast cancer-specific survival in PDX+ patients were 21.1 and 39.5, respectively.

Conclusion: We report that the ability of a tumor to engraft as a PDX predicts early recurrence by serving as a functional readout of aggressiveness and prospectively identifies the most devastating tumors. This provides new opportunity to develop surrogate assays, such as biomarkers of engraftment, which will extend the clinical feasibility of this finding.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Figures

FIG 1.
FIG 1.
Flow diagram for the TOWARDS study. ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; pCR, pathologic complete response; PDX, patient-derived xenograft; PDX+, successful engraftment; PDX–, no engraftment; RD, residual disease; TNBC, triple-negative breast cancer.
FIG 2.
FIG 2.
(A) RFS, (B) OS, and (C) BCSS by pCR (left) versus PDX engraftment (right) in the overall population. BCSS, breast cancer-specific survival; OS, overall survival; pCR, pathologic complete response; PDX, patient-derived xenograft; PDX+, successful engraftment; PDX–, no engraftment; RD, residual disease; RFS, relapse-free survival.
FIG 3.
FIG 3.
(A) RFS, (B) OS, and (C) BCSS by pCR (left) versus PDX engraftment (right) in the ER-low HER2-negative and TNBC subgroup. BCSS, breast cancer-specific survival; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; OS, overall survival; pCR, pathologic complete response; PDX, patient-derived xenograft; PDX+, successful engraftment; PDX–, no engraftment; RD, residual disease; RFS, relapse-free survival; TNBC, triple-negative breast cancer.
FIG 4.
FIG 4.
(A) Overall survival time of the PDX+ patients who relapsed, measured from the time of histologic diagnosis of relapse. (B) Overview of the characteristics and treatment timelines of tumors that relapsed, stratified by PDX engraftment. Time of recurrence was the interval between definitive surgery and histologic diagnosis of recurrence. Patients were treated per physician discretion. The two PDX+ patients for whom PDX-derived organoid-based drug profiling was performed on recurrence for informed treatment selection are highlighted in red boxes on the right. The first patient has been discussed elsewhere; the second patient (marked with a) is shown in detail in (C). (C) Clinical course of a patient with PDX+ metaplastic breast cancer after development of recurrent (metastatic) disease (day 0) where treatment was informed by prospective genomic and PDX-derived organoid-based drug profiling studies. ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; pCR, pathologic complete response; PDX, patient-derived xenograft; PDX+, successful engraftment; PDX–, no engraftment; RD, residual disease; TNBC, triple-negative breast cancer.
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