Carol Tweed

PURPOSE: Patients with stage II/III human epidermal growth factor receptor 2 (HER2)–positive or triple-negative breast cancer (TNBC) frequently receive neoadjuvant therapy (NAT). Although pathologic complete response (pCR) correlates with improved outcomes, many non-pCR patients have long-term survival. Circulating tumor-DNA (ctDNA) minimal residual disease (MRD) assessment may provide additional or superior risk stratification. METHODS: Pathologic Response Evaluation and Detection in Circulating Tumor-DNA is a prospective, multicenter study evaluating ctDNA as a biomarker of treatment response using a tumor-informed, ultrasensitive (P = .001), independent of pCR. Additionally, detectable ctDNA after surgery identified patients at extremely high recurrence risk (HR, 128 [95% CI, 15 to 1,083]; P < .001), while ctDNA-negative patients after surgery had 94% 5-year IDFS. CONCLUSION: In HER2-positive breast cancer and TNBC, ctDNA after NAT does not discriminate pCR from non-pCR. However, ctDNA provides markedly superior prognostic stratification, identifying patients with exceptional outcomes and those at extreme risk. These findings support ctDNA-guided therapeutic de-escalation and escalation strategies.

Supplemental Fig. 3. ERB-B-2 Status of Patients.

Supplemental Fig. 4. Histogram illustrating ERBB2 relative copy number in plasma and CSF cfDNA samples from 12 patients during their T samples from 12 patients during their Tsamples from 12 patients during their T samples from 12 patients during their T-DM1/TMZ combination therapy.

Supplemental Fig 2. Total mutation Burden by MB.

Supplemental Fig. 1. Neurocognitive assessments comparing patients presenting progression versus no progression.

Purpose:Preclinical data showed that prophylactic, low-dose temozolomide (TMZ) significantly prevented breast cancer brain metastasis. We present results of a phase I trial combining T-DM1 with TMZ for the prevention of additional brain metastases after previous occurrence and local treatment in patients with HER2+ breast cancer.Patients and Methods:Eligible patients had HER2+ breast cancer with brain metastases and were within 12 weeks of whole brain radiation therapy (WBRT), stereotactic radiosurgery, and/or surgery. Standard doses of T-DM1 were administered intravenously every 21 days (3.6 mg/kg) and TMZ was given orally daily in a 3+3 phase I dose escalation design at 30, 40, or 50 mg/m2, continuously. DLT period was one 21-day cycle. Primary endpoint was safety and recommended phase II dose. Symptom questionnaires, brain MRI, and systemic CT scans were performed every 6 weeks. Cell-free DNA sequencing was performed on patients’ plasma and CSF.Results:Twelve women enrolled, nine (75%) with prior SRS therapy and three (25%) with prior WBRT. Grade 3 or 4 AEs included thrombocytopenia (1/12), neutropenia (1/12), lymphopenia (6/12), and decreased CD4 (6/12), requiring pentamidine for Pneumocystis jirovecii pneumonia prophylaxis. No DLT was observed. Four patients on the highest TMZ dose underwent dose reductions. At trial entry, 6 of 12 patients had tumor mutations in CSF, indicating ongoing metastatic colonization despite a clear MRI. Median follow-up on study was 9.6 m (2.8–33.9); only 2 patients developed new parenchymal brain metastases. Tumor mutations varied with patient outcome.Conclusions:Metronomic TMZ in combination with standard dose T-DM1 shows low-grade toxicity and potential activity in secondary prevention of HER2+ brain metastases.

Individuals with pathogenic variants in the BRCA1 or BRCA2 genes have an increased risk of developing breast, ovarian, pancreatic, and prostate cancers. BRCA variants can be of germline origin (ie, inherited) or arise spontaneously during tumor development (ie, somatic). Germline BRCA mutation status is determined by analyzing DNA from nontumor cells in blood or saliva. Tumor BRCA tests detect both germline and somatic BRCA mutations in tumor DNA, and somatic BRCA mutation status is determined when the tumor BRCA test is positive and the germline BRCA test is negative. BRCA1/BRCA2 inactivation results in homologous recombination deficiency, which sensitizes tumor cells with BRCA mutation to poly(ADP-ribose) polymerase (PARP) inhibitors. Thus, timely determination of BRCA status in patients with cancer can help guide optimal disease management. PARP inhibitors are approved across a range of treatment settings for several tumor types, as monotherapy or in combination, as well as in biomarker selected and unselected populations. For patients with human epidermal growth factor receptor 2-negative breast cancer and germline BRCA mutation (United States, European Union, and other markets) or germline or somatic BRCA mutation (Japan), PARP inhibitors are approved in early adjuvant (olaparib) and metastatic (olaparib, talazoparib) settings. Emerging evidence now suggests possible biological similarities in breast tumors with germline BRCA mutation and somatic BRCA mutation, with preclinical and translational data demonstrating that both can result in high levels of biallelic inactivation, homologous recombination deficiency phenotypes, and PARP inhibitor sensitivity. There is also evidence from clinical trials demonstrating the benefit of PARP inhibitor therapy in patients with somatic BRCA–mutated breast cancer, suggesting that the inclusion criteria of more trials should be expanded to include patients with somatic BRCA mutation.

Supplemental Fig. 3. ERB-B-2 Status of Patients.

Supplemental Fig 2. Total mutation Burden by MB.