Discrepancies between biomarkers of primary breast cancer and subsequent brain metastases: an international multicenter study

Kaidar‐Person, Orit; Meattini, Icro; Jain, Parveen; Bult, Peter; Simone, Nicole L.; Kindts, Isabelle; Steffens, Rachel F.; Weltens, Caroline; Navarria, Pierina; Belkacémi, Yazid; López-Guerra, José Luis; Livi, Lorenzo; Baumert, Brigitta G.; Vieites, Begoña; Limon, Dror; Kurman, Noga; Ko, Kevin; Yu, James B.; Chiang, Veronica; Poortmans, Philip; Zagar, Timothy M.

doi:10.1007/s10549-017-4526-8

Cited by 29 publications

(27 citation statements)

References 18 publications

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“…Taylor et al [26] found an increase in myocardial perfusion defects in the region supplied by the left anterior descending artery 6 months after it was irradiated. The data of Kaidar-Person et al [27] suggested that irradiation of the left ventricle can result in early post-RT perfusion defects and there appeared to be a strong dose/volume dependence to the risk. In our study, three techniques showed similar mean dose of left anterior descending artery (p > 0:05).…”

Section: Discussionmentioning

confidence: 99%

Dosimetric Comparison of Three Radiotherapy Techniques in Irradiation of Left-Sided Breast Cancer Patients after Radical Mastectomy

Hân

et al. 2020

BioMed Research International

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Introduction. This study is aimed at evaluating the dosimetric differences among target segmented planning (TSP), conventional 9-field intensity modulated radiation therapy (9FIMRT) planning, and volumetric modulated arc therapy (VMAT) planning for postmastectomy radiotherapy of left-sided breast cancer patients. Material and Methods. Fifteen left-sided breast cancer patients who underwent radical mastectomy were enrolled. In TSP, the planning target volume (PTV) was divided into four regions (supra/infraclavicular, chest wall, external mammary region, and internal mammary region), and each individual PTV region was treated with respective fixed fields. Results. The VMAT plans showed superior to PTV dose conformity index (CI), homogeneity index (HI), protection of the ipsilateral lung, monitor units (MUs), and maximum dose (Dmax) to the contralateral breast compared with TSP and 9FIMRT plans. The TSP provided better protection for Dmean of the heart and left ventricle (p<0.05). A dose for left anterior descending artery from the three techniques had no significant difference. Compared with the 9FIMRT plans, the V5Gy (%) and V10Gy (%) for the ipsilateral lung were significantly reduced with TSP and VMAT (p<0.05). The V5Gy (%) and V10Gy (%) for the ipsilateral lung turned out to be similar between VMAT and TSP techniques. Conclusions. Our study indicates that VMAT should be a better choice of radiotherapy for left-sided breast cancer patients after radical mastectomy. If VMAT is unavailable, 9FIMRT can achieve better CI and HI values and be more MU-efficient compared with TSP; however, TSP can effectively reduce the low dose volume of the ipsilateral lungs and heart.

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Section: Discussionmentioning

confidence: 99%

Dosimetric Comparison of Three Radiotherapy Techniques in Irradiation of Left-Sided Breast Cancer Patients after Radical Mastectomy

Hân

et al. 2020

BioMed Research International

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“…Several studies have shown that 10%–26% of HER2‐negative primary breast cancers become HER2+ in a subsequent brain metastasis, whereas conversely, 13%–15% of HER2+ primary malignancies may become HER2 negative at sites of subsequent metastatic disease . A multi‐institutional analysis of 167 patients with breast cancer with paired primary and brain metastasis tissue available found that 19% of patients had discordance in estrogen receptor/progesterone receptor status or HER2 receptor status between the two sources of tissue .…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown that 10%-26% of HER2-negative primary breast cancers become HER2+ in a subsequent brain metastasis, whereas conversely, 13%-15% of HER2+ primary malignancies may become HER2 negative at sites of subsequent metastatic disease [33,34]. A multi-institutional analysis of 167 patients with breast cancer with paired primary and brain metastasis HER2 Amplification in GI Cancer Brain Metastases tissue available found that 19% of patients had discordance in estrogen receptor/progesterone receptor status or HER2 receptor status between the two sources of tissue [35]. Although this evolution in HER2 status may seem unexpected given that oncogenic drivers are frequently thought of as necessary for tumor maintenance, several recent analyses have highlighted the dynamic nature of tumor biology between primary and metastatic lesions.…”

Section: Discussionmentioning

confidence: 99%

Enrichment of HER2 Amplification in Brain Metastases from Primary Gastrointestinal Malignancies

et al. 2018

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Background In nongastric gastrointestinal (GI) cancers, HER2‐positive (HER2+) disease is not common. In breast cancer, HER2 status is associated with increased risk of brain metastases and response to HER2‐targeted therapy. The purpose of this project was to compare HER2 status in GI cancer brain metastases versus matched prior sites of disease in order to determine if HER2+ disease is more common intracranially. Materials and Methods We identified 28 patients with GI cancer who had craniotomy for brain metastases between 1999 and 2017 with intracranial metastatic tissue available at Massachusetts General Hospital. Twenty‐four patients also had tissue from a prior site of disease. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for HER2 were performed on all samples. A tumor was defined as HER2+ if it had 3+ staining by IHC or amplification by FISH. Results A prior site of disease (including intracranial metastases) was HER2+ for 13% of evaluable patients: 3 of 11 patients with colorectal cancer and no patients with esophageal or pancreatic cancer. The most recent brain metastases were HER2+ for 32% of patients: 2 of 3 esophageal squamous cell carcinomas, 3 of 10 esophageal adenocarcinomas (ACs), 3 of 14 colorectal ACs, and 1 of 1 pancreatic AC. Only 37.5% of patients with HER2+ brain metastasis had concordant HER2+ prior tissue (κ = 0.38, p = .017). Conclusion In this cohort of patients with GI cancer with brain metastases, HER2+ status was more common intracranially compared with prior sites of disease. These findings suggest that testing HER2 in patients with GI cancer with brain metastases may lead to additional therapeutic options, regardless of HER2 status in previously examined tissue. Implications for Practice HER2 amplification is a well‐known driver of oncogenesis in breast cancer, with associated increased risk of brain metastases and response to HER2‐directed therapy. In nongastric gastrointestinal (GI) cancers, HER2 amplification is not common and consequently is infrequently tested. The current study shows that brain metastases in patients with GI primary malignancies have a relatively high likelihood of being HER2 positive despite HER2 amplification or overexpression being less commonly found in matched tissue from prior sites of disease. This suggests that regardless of prior molecular testing, patients with GI cancer with brain metastases who have tissue available are likely to benefit from HER2 assessment to identify potential novel therapeutic options.

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“…In clinical practice, BCBM therapeutically-relevant subtypes are usually inferred from the IHC profiling of the primary tumor or extra-cranial metastatic tissues. However, significant discrepancies have been recently demonstrated in the expression levels of ER and HER2 and the mutational landscape of primary and matched BCBM 36-38 . Therefore, if clinically feasible, it is currently recommended to perform a histopathological evaluation of the metastatic lesions to confirm the therapeutic subtype by at least reassessing the expression of HR and HER2 35 .…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Profiling for the Molecular Classification of Metastatic Brain Tumors

Orozco

Knijnenburg

Manughian-Peter

et al. 2018

Preprint

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1Optimal treatment of brain metastases is often hindered by limitations in diagnostic 2 capabilities. To meet these challenges, we generated genome-scale DNA methylomes of the 3 three most frequent types of brain metastases: melanoma, breast, and lung cancers (n=96). 4Using supervised machine learning and integration of multiple DNA methylomes from 5 normal, primary, and metastatic tumor specimens (n=1,860), we unraveled epigenetic 6 signatures specific to each type of metastatic brain tumor and constructed a three-step DNA 7 methylation-based classifier (BrainMETH) that categorizes brain metastases according to the 8 Brain metastases (BM) are the most common intracranial neoplasm in adults and are 1 the next frontier for the management of metastatic cancer patients. Large population-based 2 studies have shown that 8-10% of cancer patients develop brain metastases, with this 3 proportion increasing up to 26% when autopsy studies were included 1-5 . Lung cancer, breast 4 cancer, and cutaneous melanoma account for the vast majority (75-90%) of secondary 5 neoplasms in the brain 1-4 . Treatment options for BM include surgery, whole-brain 6 radiotherapy, stereotactic radiosurgery, and systemic-drug therapy, such as immunotherapy 6 . 7While systemic chemotherapy has limited efficacy, targeted therapies have recently shown 8 promise for the management of patients with specific subtypes of cancer 6 . These tailored 9therapies have significantly affected treatment decision making for patients with breast 10 cancer BM (BCBM). For example, patients with human epidermal growth factor receptor 2 11 (HER2)-positive BCBM can be treated with anti-HER2 agents 7 and patients with estrogen 12 receptor (ER)-positive BCBM can be treated with endocrine agents, cyclin dependent 13 kinases 4 and 6 (CDK4/6) inhibitors, and the mechanistic target of rapamycin kinase (mTOR) 14 inhibitors 8 . As such, accurate diagnosis is essential to effectively treat patients with 15 metastatic brain tumors. 16 17 Diagnosis of BM is currently based on neuro-imaging and confirmed by anatomic 18 pathology examination. When appropriate, the diagnostic algorithm begins by distinguishing 19 BM from primary brain tumors using histologic features guided by the clinical and radiologic 20 information 9 . Then, to identify the tissue of origin, morphological evaluation is supplemented 21 by several immunohistochemistry (IHC) markers including thyroid transcription factor (TTF-22 1), chromogranin and synaptophysin for lung cancer BM (LCBM); GATA3 binding protein 23 (GATA3), mammaglobin, gross cystic disease fluid protein 15 (GCDFP-15) and ER for 24 BCBM; and human melanoma black 45 (HMB45), melanoma antigen recognized by T-cells 1 25 4 (Melan A/MART-1), SRY-Box 10 (SOX-10), and the S100 calcium binding proteins (S-100) 1 for melanoma BM (MBM) 9,10 . However, a major limitation in achieving an accurate 2 pathological diagnosis is the often poor differentiation and/or limited availability of metastatic 3 brain tumor tissues to evaluate the complete panel of IHC mark...

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Discrepancies between biomarkers of primary breast cancer and subsequent brain metastases: an international multicenter study

Cited by 29 publications

References 18 publications

Dosimetric Comparison of Three Radiotherapy Techniques in Irradiation of Left-Sided Breast Cancer Patients after Radical Mastectomy

Dosimetric Comparison of Three Radiotherapy Techniques in Irradiation of Left-Sided Breast Cancer Patients after Radical Mastectomy

Enrichment of HER2 Amplification in Brain Metastases from Primary Gastrointestinal Malignancies

Epigenetic Profiling for the Molecular Classification of Metastatic Brain Tumors

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