DAY 4: Circulating Tumor Cells, HDAC Inhibition, and Neoadjuvant Chemotherapy in High-Risk EBC

by Chase Doyle

Day 4 of the 2020 San Antonio Breast Cancer Symposium (SABCS) virtual meeting featured advances in early treatment monitoring, a surprising setback for HDAC inhibition in endocrine-resistant disease, and better selection of patients for neoadjuvant chemotherapy in high-risk early breast cancer (EBC).

Circulating Tumor Cells Predict Overall Survival in Metastatic Breast Cancer

A simple blood test may be enough to predict survival in metastatic breast cancer less than one month after initiating treatment.

Results of a large, pooled analysis confirm that at a median of 29 days after treatment initiation, follow-up circulating tumor cell (CTC) assessments strongly predicted overall survival (OS) in patients with metastatic breast cancer (Abstract GS4-08).

Patients with evidence of CTC response had a significantly increased OS of 32.2 months compared with 17.9 months in patients without a treatment response (hazard ratio [HR] = 0.49).

Furthermore, early treatment monitoring of CTCs, which are shed from the primary tumor into the bloodstream, was predictive of survival in all tumor subtypes.

“With the increasing number of treatment options available to patients with metastatic breast cancer, being able to predict and monitor treatment responses rapidly will be critical to aiding treatment decisions,” said lead study author, Wolfgang Janni, Professor and Director of the Women’s Clinic at Ulm University Hospital, in Germany. “These data indicate that CTC dynamics can predict the trajectory of the disease a little more than four weeks after initiating treatment.”

For this study, the researchers analyzed global pooled datasets from peer-reviewed and published studies of 4,079 patients with metastatic breast cancer who had undergone baseline and follow-up CTC measurements using the CellSearch test.

According to Dr. Janni, “This provides an advantage over conventional imaging methods and can help physicians determine very early on whether a treatment should be continued,” said Dr. Janni. “It is also very reassuring that CTC dynamics predicted outcomes for all breast cancer subtypes.”

As precision medicine approaches continue to evolve, CTC dynamics combined with circulating tumor DNA may also be used to guide initial treatment decisions, concluded Dr. Janni.

Entinostat Disappoints in Endocrine-Resistant Breast Cancer

Despite recent treatment advances, resistance to endocrine therapy remains a significant clinical problem in breast cancer. Results of a randomized Phase 3 trial suggest that histone deacetylase (HDAC) inhibition is unlikely to be the solution (Abstract GS4-02).

Data from the E2112 study, which randomized 608 patients with hormone-receptor positive (HR+), HER2-negative advanced breast cancer to endocrine therapy plus entinostat, an HDAC inhibitor, versus endocrine therapy alone, showed no improvement in survival with the combination of exemestane and entinostat versus control.

“We were very disappointed in these results after so many years of work, but we’ve realized again the importance of confirmation of promising data,” said lead study author, Roisin M. Connolly, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

The findings showed no significant difference in progression-free survival (PFS) with the addition of entinostat to endocrine therapy, and the overall response rate was low in both study arms (4.6% in the entinostat arm and 4.3% in the placebo arm).

With a median OS of 23.4 months in the intervention arm and 21.7 months in the placebo arm, no significant difference in OS was observed.

Subgroup analysis for both progression-free survival (PFS) and OS showed similar results in all subgroups, including prior CDK inhibitor exposure, said Dr. Connolly, who noted that these results differ from those of the multicenter ACE trial where a modest PFS advantage was observed with the addition of an HDAC inhibitor, chidamide or tucidinostat, to exemestane to a Chinese patient population.

“Although robust preclinical and clinical data supported the development of E2112, our results highlight the importance of Phase 3 confirmation of promising Phase 2 data,” said Dr. Connolly. “The short median PFS of approximately 3 months and low overall response rate observed with an endocrine-therapy backbone suggest that improved decision-making tools are required to help determine who may need chemotherapy versus alternative strategies in this setting.”

When asked to speculate on the future of HDAC inhibitors, Dr. Connolly noted several ongoing investigations of HDAC inhibitors in various combinations. After the results of this study, however, HDAC inhibitors “clearly do not have a role in this patient population,” she observed.

“HDAC inhibitors have been combined with chemotherapies and other targeted therapies over the years but have unfortunately not broken into the solid tumor space,” concluded Dr. Connolly. “Ongoing work will be required to see where they may fit in the future.”

Neoadjuvant Nab-Paclitaxel Improves pCR vs Dose-Dense Paclitaxel

Data from a large Phase 3 trial could help select patients for neoadjuvant chemotherapy in high-risk HR+, HER2-negative breast cancer.

Results from the neoadjuvant part of the ADAPT HR+/HER2– trial showed that patients randomized to nab-paclitaxel had improved rates of pathological complete response (pCR) compared with those receiving standard paclitaxel (Abstract GS4-03).

“Use of neoadjuvant nab-paclitaxel appears to be highly effective and well tolerated and was associated with a significantly higher pCR,” said lead study author, Sherko Kuemmel, MD, Director of the Breast Centre of the Essen-Mitte Clinics, in Germany. “We will have to wait for the final analysis of this huge trial to see if there’s a benefit in disease-free survival and overall survival, but these results are very promising.”

Dr. Kuemmel noted that dose-dense chemotherapy is currently the standard of care in high-risk EBC. In some trials of HR+, HER2-negative EBC, however, neoadjuvant nab-paclitaxel has been shown to superior to solvent-based paclitaxel with respect to pCR and survival.

For the neoadjuvant part of this study, a total of 864 high-risk patients were randomized between 8x weekly nab-paclitaxel and a dose-dense regimen of paclitaxel. Results of the primary endpoint showed a pCR of 20.8% in the nab-paclitaxel arm compared with 12.9% in patients receiving paclitaxel (P=.002).

ADAPT is also the first large prospective study confirming recurrence score (RS) >25 as a predictive factor for pCR in patients treated with neoadjuvant chemotherapy, said Dr. Kuemmel, who noted that RS >25 and tumor size (<cT2) were shown to be independent predictive factors for pCR.

Ki67 as an additional dynamic marker further separates the high-risk group and identifies patients who may not benefit from intensive chemotherapy,  reported Dr. Kuemmel.

Optimal therapy for these patients is being investigated in the ongoing ADAPTcYcle trial, which is evaluating a standard endocrine approach together with CDK4/6 inhibition versus chemotherapy in patients who are not candidates for chemotherapy alone in the adjuvant treatment setting.

When asked whether the improvement in pCR would translate into disease-free or OS benefit, Dr. Kuemmel noted results from the recent GeparSept trial.

“The difference in pCR in this subgroup of endocrine-positive disease translated to improved overall survival, so we will have to wait a few months to see just how many patients benefit with nab-paclitaxel instead of paclitaxel,” he concluded.

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