Metastatic triple-negative breast cancer patient with TP53 tumor mutation experienced 11 months progression-free survival on bortezomib monotherapy without adverse events after ending standard treatments with grade 3 adverse events

Abstract

A triple-negative breast cancer patient had no hereditary BRCA1, BRCA2, or TP53 risk variants. After exhaustion of standard treatments, she underwent experimental treatments and whole-exome sequencing of tumor, blood, and a metastasis. Well-tolerated experimental bortezomib monotherapy was administered for a progression-free period of 11 mo. After progression, treatments were changed and the exome data were evaluated, expanded with RNA and exome sequencing of a late-stage metastasis. In the final stage, eribulin alone and in combination with anthracyclines were administered. While suffering from grade 3 adverse events, skin metastases progressed. She lived 51 mo after initial diagnosis.Toxicity from anthracyclines and cisplatin may have been due to associated germline variants CBR3 C4Y and V224M and GSTP1 I105V, respectively. Somatic mutations predicted or reported as pathogenic were detected in 38 genes in tumor tissues. All tumor samples harbored the heterozygous TP53 Y220C variant, known to destabilize p53 and down-regulate p53-mediated apoptosis. The success of bortezomib may be explained by the previously reported up-regulation of caspase-mediated apoptosis, which is p53-independent. Phylogenetic analysis of blood, primary tumor, and two metastases inferred an ancestral tumor cell with 12 expressed tumor mutations from which all three tumors may have evolved.Although our first urgent analysis could only include 40 genes, postmortem analysis uncovered the aggressiveness and suggested experimental therapies including 16 actionable targets, partly validated by immunohistochemistry. Exome and transcriptome analyses yielded comprehensive therapy-relevant information and should be considered for patients at first diagnosis.

RNA based individualized drug selection in breast cancer patients without patient-matched normal tissue

“…Figure 2 shows a principal component analysis (PCA) plot of the samples based on read counts per million using all unfiltered 23686 genes. We included a previously published triple-negative breast cancer sample sequenced with TruSeq RNA Access [ 5 ]. The PCA plot shows very strong differences between total RNA and targeted RNA in the first principal component (Figure 2 ).…”

“…Table 3 shows the overexpressed genes that were matched to inhibitors and annotated to indicate which gene may be an unreliable biomarker. To exemplify a personalized differential expression analysis, Table 4 shows the overexpressed genes of our previously published patient [ 5 ] that we associated with inhibitors or drugs and which we now annotated with gene expression variability in healthy normals.…”

“…a 21-gene real-time PCR assay (Oncotype DX, Genomic Health). More recently, whole exome and whole transcriptome sequencing of tumor versus normal tissue is increasingly being considered to help guide drug selection, especially for aggressive forms of breast cancer, metastatic breast cancer, and recurrences [ 4 , 5 ]. Whole exome sequencing can inform of actionable mutations, tumor mutation burden and pharmacogenomic variants.…”

“…Whole transcriptome sequencing with paired-end reads can additionally inform of actionable fusion genes, expressed mutations (especially neoantigenic mutations), and loss or gain of gene expression compared to healthy normal tissue. However, currently, patient-matched normal breast tissue is not routinely asservated and therefore not routinely available when needed, especially when the patient experiences a relapse after bilateral mastectomy [ 5 ]. Even when a patient-matched sample of normal breast tissue is available, additional healthy samples are required to distinguish normal gene expression variability in healthy breast tissue from pathological gene expression in tumor tissue.…”

Combination Immunotherapy Strategies in Breast Cancer

“…Proteasome inhibition thus poses an attractive target by which to enhance the accumulation of misfolded protein, which triggers an unfolded protein response and leads to cell cycle arrest and apoptosis, an approach that is promising in breast cancer models [113][114][115]. A phase II trial of 12 patients did not show any benefit against mTNBC as monotherapy [116].…”