Molecular features of TNBC are relevant for treatment response

Created by oncoXchange

November 2019



Waybe Kuznar for oncoXchange

Several molecular features of triple-negative breast cancer (TNBC) are relevant for treatment response.

Several molecular features of triple-negative breast cancer (TNBC) are relevant for treatment response. At the 2019 ESMO Congress, Carsten Denkert, MD, provided a look at the biology of TNBC as it is currently understood.

Classical pathology, gene expression platforms, and genomic alterations support the existence of four common molecular motives to TNBC: high proliferation, increased immune infiltrate, BRCAness/homologous recombination deficiency (HRD)/genomic scars, and androgen receptor expression.

Tumors with 1 to 9% hormone receptor (HR) expression represent a borderline area between luminal and triple-negative tumors, and these low-HR tumors behave similarly to HR-negative tumors. From the GBG neoadjuvant trials, low HR-positive tumors constitute 8% of all TNBCs. They have a high response rate to neoadjuvant chemotherapy, similar to the HR-negative tumors, and they have a high probability of relapse, said Denkert, professor of pathology, Philipps University Marburg, Germany. Similar results are observed from German population-based cancer registry data (Munich cancer registry). The best-cut point for HR expression is still being considered.

Germline BRCA testing in metastatic breast cancer is a new biomarker approach to predict response to therapy. Most BRCA-mutated cancers will be TNBC but some will be luminal/HER2- negative. Two clinical trials—OlympiAD and EMBRACA—confirm the efficacy of PARP inhibition in BRCA-mutated breast cancer.

Many different immune signatures are linked to an increased response to chemotherapy and to improved prognosis.

Some tumors have a cold immune phenotype, some have a hot immune phenotype, and some have an intermediate phenotype, which correspond to chemotherapy response rates. “We can also see it simply by looking at the TILs [tumor-infiltrating lymphocytes]; hot tumors typically have a higher amount of tumor lymphocyte,” said Denkert.

In 2019, a new development is that TILs are integrated into some breast cancer guidelines. The St. Gallen International Consensus guidelines recommend that TILs should be routinely characterized upon pathologic evaluation in TNBC because of their prognostic value. A new WHO classification of breast cancer (in press) will also include TILs as a standard biomarker in TNBC.

TILs should be routinely characterized upon pathologic evaluation in TNBC because of their prognostic value.

How to test for PD-L1, a new biomarker in metastatic TNBC, is an open challenge. Two main questions are: which antibody and which scoring system should be used. In Europe, any diagnostic antibody can be used for any drug. In the US, the Food and Drug Administration requires that a specific diagnostic antibody be used for each drug. The SP142 is specific for atezolizumab.

Two scoring systems for PD-L1 staining are now in use. One is the IC A (immune cell area) score, which is defined as the percentage of tumor area covered by PD-L1-positive immune cells (designed for atezolizumab), and the other is the combined positive score (CPS), which is the number of positive tumor or immune cells as a percentage of all tumor cells (designed for pembrolizumab).

An IC A area ≥1% is considered positive for PD-L1, as is a CPS score of ≥21. The CPS score will always be much higher than the IC A score. “

The IC A scoring is similar with most antibodies. SP263 had higher levels of immune cell staining in one investigation. The take home message is to use the IC A score for atezolizumab, said Denkert. It is not possible to convert one score into the other “so if the pathology report contains the wrong score, the evaluation must be repeated,” said Denkert. “Do not use SP142 for tumor cell staining (it’s not relevant for breast cancer) and you cannot calculate a valid CPS score with SP142.”

Different roles for immune biomarkers (including PD-L1) in early and metastatic TNBC are emerging, he said. Immune markers in early breast cancer are predictive for neoadjuvant chemotherapy response but are not specific for immunotherapy.

In Keynote-522, in early breast cancer, an improvement in the pCR rate regardless of PD-L1 status was observed with pembrolizumab in combination with chemotherapy compared with chemotherapy alone. In the metastatic setting, from Impassion130, PD-L1 was predictive for immunotherapy response.

Denkert highlighted two important research results from the GeparNuevo trial, which compared durvaluamb and nab-paclitaxel versus chemotherapy alone in patients with TNBC. One was that although there was no significant effect of the combination on pCR compared with chemotherapy, in an exploratory analysis, the pCR rate was increased when one dose of durvalumab was given before the start of chemotherapy, corresponding to a shift of TILs inside the tumor after the single dose of durvalumab. “Another interesting finding from GeparNuevo was that the proliferation signature was relevant only in the placebo arm,” he said. “There was no role of the proliferation signature in the durvalumab arm, so the hypothesis would be that in a highly proliferative tumor, chemotherapy alone may be sufficient, but in a low proliferative tumor, immunotherapy in addition to chemotherapy contributes to an increased response.”