In the Journals

Biomarker linked to improved outcomes for triple-negative breast cancer

Priyanka Sharma

Patients with triple-negative breast cancer who had homologous recombination deficiency-causing alterations experienced improved DFS when treated with adjuvant doxorubicin and cyclophosphamide, according to findings published in Annals of Oncology.

“The dearth of reliable response/resistance biomarkers for standard chemotherapy has slowed the development of newer agents for triple-negative breast cancer,” Priyanka Sharma, MD, professor of medicine at University of Kansas Cancer Center, and colleagues wrote.

Homologous recombination is a DNA repair mechanism responsible for repair of double-strand breaks,” they added. “Inherited and acquired defects in homologous recombination might serve as response biomarkers or as therapeutic targets in breast cancer.”

The researchers isolated genomic DNA and RNA from 425 tumor samples collected during a previous trial assessing adjuvant chemotherapy with doxorubicin and cyclophosphamide. Although the trial stopped enrolling patients in 1997, the tumor samples had been preserved in blocks of paraffin wax at the SWOG bank.

Sharma and colleagues determined homologous recombination deficiency status for 379 samples (89%). They defined positive homologous recombination deficiency status as a deleterious BRCA1/2 tumor mutation, or having a homologous recombination deficiency score of 42 or higher.

Roughly two-thirds (67%) of samples were positive for homologous recombination deficiency, including 27% with tumor BRCA mutation, and 40% based on homologous recombination deficiency score.

Homologous recombination deficiency appeared associated with significantly improved DFS (HR = 0.72; 95% CI, 0.51-1) and a nonsignificant trend toward longer OS (HR = 0.71; 95% CI, 0.48-1.03).

Among patients with BRCA-negative tumors (n = 274), a homologous recombination deficiency score of 42 or higher also appeared associated with longer DFS (HR = 0.64; 95% CI, 0.43-0.94) and OS (HR = 0.65; 95% CI, 0.42-1).

The researchers successfully evaluated BRCA1 promoter methylation among 82% of patients (n = 425) and detected it in 32%. BRCA1 promoter methylation had a similar HR for DFS as homologous recombination deficiency, but this was not statistically significant (HR = 0.79; 95% CI, 0.54-1.17).

“We showed that assays tested in our study worked well in very old tissue samples,” Sharma said in a press release. “We also learned that 25% of [patients with triple-negative breast cancer] harbored BRCA1 or BRCA2 mutations, and tumors in these patients were homologous recombination deficiency positive.

“Finally, and most importantly, we learned that 67% of [patients with triple-negative breast cancer] — a solid majority — respond well to a standard, backbone chemotherapy combination,” researchers wrote. “So, [although] adjuvant doxorubicin and cyclophosphamide chemotherapy is an old treatment, for many, it’s still a good one. Homologous recombination deficiency status is a biomarker that, when identified, can potentially help a physician best tailor a chemotherapy treatment for that particular triple-negative breast cancer patient.” – by Andy Polhamus

Disclosures: Sharma reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

Priyanka Sharma

Patients with triple-negative breast cancer who had homologous recombination deficiency-causing alterations experienced improved DFS when treated with adjuvant doxorubicin and cyclophosphamide, according to findings published in Annals of Oncology.

“The dearth of reliable response/resistance biomarkers for standard chemotherapy has slowed the development of newer agents for triple-negative breast cancer,” Priyanka Sharma, MD, professor of medicine at University of Kansas Cancer Center, and colleagues wrote.

Homologous recombination is a DNA repair mechanism responsible for repair of double-strand breaks,” they added. “Inherited and acquired defects in homologous recombination might serve as response biomarkers or as therapeutic targets in breast cancer.”

The researchers isolated genomic DNA and RNA from 425 tumor samples collected during a previous trial assessing adjuvant chemotherapy with doxorubicin and cyclophosphamide. Although the trial stopped enrolling patients in 1997, the tumor samples had been preserved in blocks of paraffin wax at the SWOG bank.

Sharma and colleagues determined homologous recombination deficiency status for 379 samples (89%). They defined positive homologous recombination deficiency status as a deleterious BRCA1/2 tumor mutation, or having a homologous recombination deficiency score of 42 or higher.

Roughly two-thirds (67%) of samples were positive for homologous recombination deficiency, including 27% with tumor BRCA mutation, and 40% based on homologous recombination deficiency score.

Homologous recombination deficiency appeared associated with significantly improved DFS (HR = 0.72; 95% CI, 0.51-1) and a nonsignificant trend toward longer OS (HR = 0.71; 95% CI, 0.48-1.03).

Among patients with BRCA-negative tumors (n = 274), a homologous recombination deficiency score of 42 or higher also appeared associated with longer DFS (HR = 0.64; 95% CI, 0.43-0.94) and OS (HR = 0.65; 95% CI, 0.42-1).

The researchers successfully evaluated BRCA1 promoter methylation among 82% of patients (n = 425) and detected it in 32%. BRCA1 promoter methylation had a similar HR for DFS as homologous recombination deficiency, but this was not statistically significant (HR = 0.79; 95% CI, 0.54-1.17).

“We showed that assays tested in our study worked well in very old tissue samples,” Sharma said in a press release. “We also learned that 25% of [patients with triple-negative breast cancer] harbored BRCA1 or BRCA2 mutations, and tumors in these patients were homologous recombination deficiency positive.

“Finally, and most importantly, we learned that 67% of [patients with triple-negative breast cancer] — a solid majority — respond well to a standard, backbone chemotherapy combination,” researchers wrote. “So, [although] adjuvant doxorubicin and cyclophosphamide chemotherapy is an old treatment, for many, it’s still a good one. Homologous recombination deficiency status is a biomarker that, when identified, can potentially help a physician best tailor a chemotherapy treatment for that particular triple-negative breast cancer patient.” – by Andy Polhamus

Disclosures: Sharma reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.