NGS, Prediction Tools Show Similarities Between Metastatic Breast Cancer, Other Advanced Cancers

Next-generation sequencing (NGS) and the use of prediction tools in 2 patients with a rare form of metastatic breast cancer revealed mutations in malignant phyllodes tumors that are often detected in other advanced cancers, providing insight into potential therapeutic targets for these patients.

Next-generation sequencing (NGS) followed by prediction tools on samples from 2 patients with progressed malignant phyllodes tumors associated with breast cancer revealed that the tumors share some of the major genomic alterations that occur in other advanced cancers, according to a recent analysis.

The study, published in the Orphanet Journal of Rare Diseases, provided insight into the molecular pathogenesis of metastatic and recurrent malignant phyllodes tumors and discovered a strong similarity with the 10 most altered genes in other advanced cancers, and suggested possible therapeutic options for these patients.

Phyllodes tumors of the breast are rare fibroepithelial neoplasms that represent up to 0.5% of all breast tumors. Malignant phyllodes tumors account for 10% to 15% of all phyllodes tumors cases and have a 54% 5-year survival rate. Patients with this kind of tumor often have a poor prognosis and don’t respond well to standard systemic therapy. The pathogenesis and underlying genomic landscape of phyllodes tumors are unclear.

Over the past 8 years, the use of advanced DNA sequencing technologies has allowed for standardized investigation of several hundred genes associated with cancer in phyllodes tumors for genetic mutations. However, alterations of genes thought to be associated with the development and progression of phyllodes tumors is rarely reported.

“Aside from purely research-driven motivations, a refinement of the genomic profile and subsequent identification of drug targets could create an opportunity for personalized therapy,” wrote the investigators.

The investigators examined 2 female patients who presented at the Breast Unit at the Klinken Essen-Mitte in Essen, Germany.

Researchers performed NGS on paired primary and progressed tumor samples from these patients with malignant phyllodes tumors followed by functional analysis of genetic alterations using 2 prediction tools.

Patient 1 was a 55-year-old postmenopausal woman from Kazakhstan who had undergone mastectomy in her right breast and axillary lymph node dissection. She also had a primary tumor and distant metastases and was originally diagnosed with triple-negative breast sarcoma without lymphovascular invasion. Patient 1 had no family history of phyllodes tumors.

Patient 2 was a 29-year-old premenopausal woman with no significant medical history beyond an aunt who had died of metastatic breast cancer at age 45. She has a lumpectomy of the right breast with wide margins and reconstructive surgery with defect coverage using medial and caudal rotation flaps.

Investigators used details from the NGS report (containing the coding DNA reference sequence, the transcript number, and chromosomal position) in order to use the in silico prediction tools (FATHMM-XF and MutationTaster2).

Results detected 38 genomic alterations, of which 11 were predicted to be most likely benign. In patient 1, 14 alterations were found in her primary tumor and 17 in her pulmonary metastasized tumors, of which 12 were identical. In patient 2’s tumors, 17 sequence variants were detected in the primary tumor and 15 were found in the recurrent tumor, with 13 variants overlapping.

Among the affected genes, 7 of the top 10 most frequently altered genes in other advanced cancer entities, including TP53, TERT, APC, ARID1A, EGFR, KMT2D, and RB1, were found. Additionally, 4 actionable targets for therapy were identified, including EGFR, KIT, PDGFRA, and BRIP1.

Notably, 7 genes responsible for receptor tyrosine kinase coding were affected, of which 3 were in patient 1 and 4 were in patient 2. Also, multiple genes were found to be altered in phyllodes tumors that had not been observed before, including EPHA3, EPHA7, and EPHB1.

One study limitation, the investigators said, is that the use of in silico prediction tools has been criticized for potentially leading to false positives during NGS.


Reinsch M, Kuemmel S, Breit E, et al. Two progressed malignant phyllodes tumors of the breast harbor alterations in genes frequently involved in other advanced cancers. Orphanet J Rare Dis. Published online August 16, 2021. doi: 10.1186/s13023-021-01986-z