Combination of Variables May Inform Oncologists on Residual Risk After Adjuvant Therapy for Breast Cancer

Independent variables, such as the burden of disease prior to treatment, molecular prognosis, sensitivity to chemotherapy, sensitivity to endocrine therapy, and sensitivity to other treatments could be effective in predicting risk of recurrence in patients with breast cancer.

Independent variables, such as the burden of disease prior to treatment, molecular prognosis, sensitivity to chemotherapy, sensitivity to endocrine therapy, and sensitivity to other treatments, when combined, could inform residual risk after adjuvant treatments for patients with stage II to III breast cancer, according to W. Fraser Symmans, MD.1

“There are multiple clinical scenarios where the prediction of independent sensitivity would be useful,” Symmans, professor, Departments of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, said during a presentation at the 38th Annual Miami Breast Cancer Conference®.

“The following variables [are] added together in some complex way to determine prognostic risks, and it’s the sequence of everything that happens to the patient; what strategies to measure or predict these variables could be effective, but maybe we should be breaking them down into modules and reconstructing predictive risk based on what contributes to risk overall,” he added.

Residual Disease and Burden After Chemotherapy

To start, Symmans noted that time is a big factor in trying to understand treatment outcomes, in particular the lack of response to chemotherapy.

For example, a large meta-analysis presented at the 2019 San Antonio Breast Cancer Symposium (SABCS) showed that residual cancer burden after neoadjuvant chemotherapy can be an accurate long-term predictor of recurrence and survival across all breast cancer subtypes.2

“[In the trial data], we can see that about 20% of these patients get a [pathologic complete response; PCR] or [residual cancer burden; RCB]–I at the end of the new age on chemotherapy; and they, of course, do very well with similar outcomes. But the majority of patients have the same protracted risk, which is increasing with increasing burden of risk of residual disease.”

Using the RCB index, the investigators saw an increased risk related to pCR as well as 3-year event rates as RCB increased. “This is where the risk climbs very quickly,” Symmans said, adding that this is something investigators noticed a long time ago. “There was this interplay between the endocrine function in the tumor cell biopsied before treatment, which we were measuring [for] endocrine hormone receptor [HR]–related transcriptional activity, and the response to chemotherapy.”

If the tumor responds to chemotherapy, the next question becomes: How will the tumor be controlled by the long-term integrant therapy, given these sequences of treatments seem to interplay either additively or interactively together?

Response-Guided Neoadjuvant Therapy

In an exploratory analysis of long-term survival data from the GeparTrio trial (NCT00544765), investigators evaluated neoadjuvant therapy in 2072 patients with early breast cancer who were treated with 2 cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC).3 Early responders were randomly assigned to an additional 4 or 6 TAC cycles, and early nonresponders were randomly assigned to 4 more cycles of TAC or 4 cycles of vinorelbine/capecitabine (NX) before surgery.

In turn, they found that response-guided neoadjuvant chemotherapy improved disease-free survival (HR, 0.78; P = .026) and overall survival (HR, 0.76; P = .060), which was most effective in patients with HR–positive disease, “suggesting, perhaps, that if you can improve on the chemotherapy response, it can translate to a survival improvement,” Symmans said.

Induction Therapy Alone

Symmans noted that, while there is prognostic information from contemporary prognostic signatures in breast cancer, in particular the node-positive setting, the effect is lessened. Therefore, it may not be clinically useful in this setting.

This was demonstrated in the phase 3 RxPONDER trial (NCT01272037), where investigators evaluated the use of endocrine therapy versus chemotherapy followed by endocrine therapy in women with HR–positive, HER2-negative, lymph node–positive breast cancer with a recurrence score between 0 and 25.

The study found that postmenopausal women could safely skip adjuvant chemotherapy; however, premenopausal women may derive a benefit from it. “In some ways, these results were a little bit surprising,” Symmans said.

In the phase 3 POETIC trial (NCT02338310), investigators evaluated the long-term outcomes and prognostic value of Ki67 in pre and perioperative aromatase inhibitor therapy in women with operable estrogen receptor–positive primary breast cancer.5 They found that most patients with low Ki67 or low pre and perioperative aromatase inhibitor–induced Ki67 did well with adjuvant standard endocrine therapy. However, patients with pre and perioperative aromatase inhibitor–induced Ki67 remained high, and therefore might benefit from further adjuvant treatment or trials of new therapies.

“The bottom line is that by the time you get out to about 10 years, you’re still seeing accumulated risk,” Symmans said. “In fact, arguably, probably out to 15 or more [years]. And that associated risk over time is linear. It's like the Duracell bunny of risk, it just keeps on going. And this is what makes this subtype in this stage setting such a problem in terms of optimizing treatment for patients.”


1. Symmans WF. Predicting Sensitivity to Endocrine-Based Therapies. Presented at: 38th Annual Miami Breast Cancer Conference®; March 4-7, 2021; virtual.

2. Yau C, van der Noordaa M, Wei J, et al. Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: A multi-center pooled analysis. Presented at: San Antonio Breast Cancer Symposium; December 13, 2019; San Antonio, Texas. Abstract GS5-01.

3. von Minckwitz G, Blohmer JU, Costa SD, et al. Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol. 2013;31(29):3623-3630. doi:10.1200/JCO.2012.45.0940

4. Cosgrove NS, Vareslija D, Keelan S, et al. Homologous recombination deficiency represents a new therapeutic strategy for breast cancer brain metastases. Presented at: San Antonio Breast Cancer Symposium; December 8-12, 2020; virtual. Abstract PD13-01.

5. Smith I, Robertson J, Kilburn L, et al. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. doi:10.1016/S1470-2045(20)30458-7