PDX engraftment predicts high recurrence and poor survival in triple-negative breast cancer

By Dr. Liji Thomas, MDReviewed by Benedette Cuffari, M.Sc.Sep 11 2024

Patient-derived xenografts (PDX) may accurately predict early recurrence and survival outcomes in triple negative breast cancer (TNBC), offering a potential tool for tailoring treatment strategies to reduce relapse risk.

Study: TOWARDS Study: Patient-Derived Xenograft Engraftment Predicts Poor Survival in Patients With Newly Diagnosed Triple-Negative Breast Cancer. Image Credit: Design_Cells / Shutterstock.com

A recent study published in JCO Precision Oncology examines the association between patient-derived xenograft (PDX) with recurrence and survival rates in triple negative breast cancer (TNBC) patients.

Strategies to reduce TNBC recurrence risk

Currently, recurrence risk in TNBC is predicted by failure to obtain a pathologic complete response (pCR) to preoperative chemotherapy. Thus, pCR is used to obtain a long-term prognosis and monitor the effectiveness of preoperative treatment.

However, pCR fails to correlate well with relapse-free survival or overall survival (OS). The use of adjuvant chemotherapy to reduce recurrence risk has also produced mixed results in previous trials.

The inability to accurately identify patients at high risk of recurrence has led to the potential overtreatment of patients with early-stage TNBC with more toxic chemotherapy regimens. As a result, this intensive approach increases the risk of drug adverse effects without improving patient prognoses.

About the study

PDX looks and behaves like the tumor of origin, thus making it easier to predict how new drugs may act on the patient with this type of tumor. Although PDX engravement often correlates with a more aggressive phenotype, the rate of engraftment can be unpredictable and changes with tumor subtype.

The current study was a blinded trial on 80 patients with newly diagnosed TNBC, as well as tumors with low hormone receptors and negative human epidermal growth factor receptor-2 status. No intervention was provided to the patients during the trial. Tumors from these patients were removed and subsequently engrafted operatively into young female mice with severe combined immunodeficiency (SCID).

The aim of the current study was to establish more reliable risk markers for determining recurrence and breast cancer-related mortality risk based on the rate of successful engraftment of PDX from nonmetastatic TNBC.

The primary endpoint of the trial is three-year disease-free survival, with follow-up still ongoing. Thus, the current study reports disease-free OS at one year and pathologic response to neoadjuvant chemotherapy.

Engraftment and recurrence rates

The median follow-up for the current study was 2.6 years. Overall, relapse occurred in 16% of patients, nine within one year of follow-up. Ten deaths were reported, nine of which were due to metastatic recurrent breast cancer. Eight of these nine patients were PDX-engraftment-positive.

Among 18 patients who were positive for PDX engraftment, eight had a year-one relapse for a relapse rate of 44.4%.

Even after definitive surgery, eight of 17 patients with successful engraftment relapsed within a year. Conversely, only one of 45 non-engraftment patients relapsed.

TNBC recurred within one year of definitive surgery in 80% of PDX-engraftment patients. The median survival in these patients was 0.55 years from the diagnosis of recurrence, whereas the postoperative relapse risk was 21.1 times higher in the engraftment group.

One relapse was reported among 62 non-engraftment patients for a relapse rate of 1.6%. Thus, the overall risk of relapse in the engraftment group was 17.5 times higher than in the non-engraftment group.

Conversely, three non-engraftment patients relapsed and none died within the period of follow-up to date. The median OS and breast cancer-specific survival (BCSS) were both 1.8 years in the engraftment group with hazard ratios of 21.1 and 39.5, respectively.

The pCR was not significantly associated with one-year relapse rates. Three patients achieved pCR but relapsed within the first year, all three of whom had successful PDX engraftment. All three patients died due to metastatic breast cancer within one year of biopsy-diagnosed relapse.

Conclusions

The study findings indicate the potential of PDX engraftment to clearly, strongly, and independently predict early tumor recurrence in nonmetastatic TNBC. Successful engraftment reflects the aggressive behavior of the tumor cells, thereby revealing which tumors are likely to recur and metastasize with an exceptionally poor prognosis.

These patients could be given additional treatment to reduce recurrence rates, while simultaneously limiting unnecessary chemotherapy treatment for individuals at a low risk of recurrence. Moreover, high-risk patients could be administered therapies that act more effectively in relapse-prone cases to eliminate the disease altogether.

Although the current study is ongoing, these findings do not reveal correlations between engraftment and outcomes in patients with hormone receptor-positive tumors.

PDX engraftment is not a feasible clinical method. Thus, future research could focus on identifying biomarkers of engraftment to provide a clinically useful and viable surrogate for PDX engraftment in TNBC patients.