PANTHER 10-year data support tailored dose-dense adjuvant chemo for high-risk early breast cancer

Long-term data from the phase III PANTHER trial demonstrate improved breast cancer recurrence-free survival (BCRFS) with tailored dose-dense adjuvant chemotherapy as opposed to standard adjuvant chemo in individuals with high-risk early breast cancer.

“After a median follow-up of 10.3 years, dose-dense adjuvant chemo improved outcomes when compared to an optimal control containing docetaxel Q3W and background treatment according to contemporary standards,” said Dr Theodoros Foukakis from the Karolinska Comprehensive Cancer Centre, Stockholm, Sweden, during his presentation at ESMO Breast Cancer 2024.

At end of study, the cumulative incidences of BCRFS in the respective tailored dose-dense and standard-interval chemo arms were 18.6 percent and 22.3 percent, yielding an absolute difference of 3.7 percent. The hazard ratio (HR) was 0.80 (95 percent confidence interval [CI], 0.65–0.98; p=0.041). [ESMO Breast Cancer 2024, abstract 111MO]

The tailored dose-dense regimen also trumped standard-interval chemo in terms of distant disease-free survival (17.2 percent vs 20.9 percent; HR, 0.79, 95 percent Ci, 0.64–0.98), but there was no significant between-group difference in terms of overall survival (15.1 percent vs 16.6 percent; HR, 0.82, 95 percent CI, 0.65–1.04; p=0.109).

“The benefit with dose-dense chemo was consistent among all relevant subgroups,” said Foukakis, including patients aged ≥50 years (HR, 0.74, 95 percent CI, 0.56–0.97) and those who had ER-positive disease (HR, 0.78, 95 percent CI, 0.62–0.99).

HER2-positive subgroup

Dose-dense chemo was also clearly superior to standard-interval chemo among those with HER2-positive disease when adjuvant trastuzumab was routinely used (HR, 0.53, 95 percent CI, 0.30–0.93).

According to discussant Associate Professor Elzbieta Senkus-Konefka from the Medical University of Gdansk in Poland, the data in the HER2-positive population is very interesting “because we really do now know whether we should use dose-dense in this subgroup.”

A promising strategy to optimize chemo

Dose-dense adjuvant chemo administered Q2W leads to superior outcomes compared to standard Q3W regimens. [Lancet 2019;393:1440-1452] “Dose-dense adjuvant chemo moderately reduces the 10-year risk of recurrence and death from BC without increasing mortality from other causes,” said Foukakis.

However, most studies used the suboptimal paclitaxel Q3W as control and were carried out before the introduction of adjuvant trastuzumab, gonadotropin-releasing hormone analogues, and extended endocrine therapy. [Lancet 2015;385:1863-1872; J Clin Oncol 2003;21:1431-1439; J Clin Oncol 2015;33:2353-2360] Foukakis noted that paclitaxel Q3W is inferior to alternatives such as weekly paclitaxel or docetaxel Q3W.

In PANTHER, 2,003 patients were randomized 1:1 to tailored dose-dense (four cycles of leukocyte nadir-based tailored and dose-dense adjuvant epirubicin and cyclophosphamide Q2W followed by four cycles of tailored dose-dense docetaxel Q2W) or standard-interval chemo (three courses of fluorouracil and epirubicin-cyclophosphamide Q3W followed by three courses of docetaxel Q3W). Chemo dose levels were adjusted based on haematological toxicity during the preceding cycle.

Following chemo, participants received standard adjuvant radiotherapy, endocrine therapy for those who were HR-positive for at least 5 years, and trastuzumab for HER2-positive disease for a year.

The primary analysis (median follow-up 5.3 years) demonstrated an improvement in event-free survival with tailored dose-dense vs standard-interval chemo, but there was no significant difference in BCRFS (88.7 percent vs 85 percent). [JAMA 2016;16:1888-1896]

“[The long-term data suggest that] dose-dense schedules should be the standard of care for primary resected high-risk early breast cancer,” said Foukakis.

“Toxicity-based dose tailoring is a promising strategy for optimizing delivery of chemo and warrants further investigation,” he concluded.

Caveats

Senkus-Konefka pointed out a couple of caveats that should be taken into context. First, she noted that the algorithm used for dose tailoring was quite complicated as it requires two additional blood counts performed during the cycle. “This, from a practical point of view, may make it logistically difficult at least in some centres.”

Also, all patients in the investigational arm were given ciprofloxacin, which could have impacted the microbiome and introduced bias, she added.