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Table 1.  Baseline Characteristics, Intracranial Management, and Outcomes for Patients With Newly Diagnosed Brain Metastases Secondary to Breast Cancer vs Non–Small Cell Lung Cancer
Baseline Characteristics, Intracranial Management, and Outcomes for Patients With Newly Diagnosed Brain Metastases Secondary to Breast Cancer vs Non–Small Cell Lung Cancer
Table 2.  Intracranial Outcomes for Patients With Brain Metastases Secondary to Breast Cancer vs Non–Small Cell Lung Cancer Following Brain-Directed Radiation
Intracranial Outcomes for Patients With Brain Metastases Secondary to Breast Cancer vs Non–Small Cell Lung Cancer Following Brain-Directed Radiation
1.
Cagney  DN, Martin  AM, Catalano  PJ,  et al.  Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study.  Neuro Oncol. 2017;19(11):1511-1521.PubMedGoogle ScholarCrossref
2.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. https://www.nccn.org/professionals/physician_gls/. Accessed November 1, 2017.
3.
Martin  AM, Cagney  DN, Catalano  PJ,  et al.  Brain metastases in newly diagnosed breast cancer: a population-based study.  JAMA Oncol. 2017;3(8):1069-1077.PubMedGoogle ScholarCrossref
4.
Lin  NU, Claus  E, Sohl  J, Razzak  AR, Arnaout  A, Winer  EP.  Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases.  Cancer. 2008;113(10):2638-2645.PubMedGoogle ScholarCrossref
5.
Pestalozzi  BC, Holmes  E, de Azambuja  E,  et al.  CNS relapses in patients with HER2-positive early breast cancer who have and have not received adjuvant trastuzumab: a retrospective substudy of the HERA trial (BIG 1-01).  Lancet Oncol. 2013;14(3):244-248.PubMedGoogle ScholarCrossref
6.
American Joint Committee on Cancer.  AJCC Cancer Staging Manual. Cham, Switzerland: Springer International Publishing AG; 2017.
Research Letter
July 2018

Implications of Screening for Brain Metastases in Patients With Breast Cancer and Non–Small Cell Lung Cancer

Author Affiliations
  • 1Department of Radiation Oncology, Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, Massachusetts
  • 2Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
  • 3Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 4Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
  • 5Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
JAMA Oncol. 2018;4(7):1001-1003. doi:10.1001/jamaoncol.2018.0813

Brain metastases affect many patients with cancer.1 Given the limited intracranial penetration of most systemic therapies, the size and number of brain metastases at diagnosis determines management, with more invasive or toxic therapies such as neurosurgical resection and whole brain radiation therapy (WBRT) used for bulky and multifocal disease, respectively. Consequently, consensus guidelines from the National Comprehensive Cancer Network recommend screening magnetic resonance imaging (MRI) of the brain for patients with stage II to IV non–small cell lung cancer (NSCLC), small cell lung cancer of any stage, and stage IIIC to IV melanoma—all cancers that frequently metastasize to the brain.2

Brain metastases are common in select patients with breast cancer as well: 8% to 11% of patients with de novo metastatic human epidermal growth factor receptor 2 (ERBB2/HER2)–positive or triple negative breast cancer harbor brain metastases,3 and 46% to 53% of such patients develop brain metastases during their clinical course.4,5 Yet, the National Comprehensive Cancer Network does not recommend brain-directed screening for any patients with breast cancer,2 a recommendation that is based only on expert consensus given the lack of definitive or prospective studies on this issue. To identify the potential value of brain-directed MRI screening to select patients with breast cancer, we compared the presentation, management, and outcome of patients with breast cancer and brain metastases (which are largely unscreened with brain MRI) with those of patients with NSCLC and brain metastases (which are largely screened with brain MRI at diagnosis of systemic malignant neoplasm).

Methods

We identified patients treated for newly diagnosed brain metastases between January 1, 2000, and December 31, 2015, at Dana-Farber/Brigham and Women's Cancer Center. We then compared intracranial disease burden at presentation, intracranial management, and intracranial outcomes between patients with breast cancer and patients with NSCLC. Using SAS, version 9.4 (SAS Institute Inc), we compared continuous outcome measures using the 2-tailed unpaired t test or Wilcoxon rank sum test with categorical outcome measures using Fisher exact test; we performed a multivariable Cox regression analysis for time-to-event outcomes, except for neurologic death, which was assessed using the Fine and Gray competing risks regression. A 2-sided P < .05 defined statistical significance. Proportional hazards were verified. This study was approved by the Dana-Farber/Harvard Cancer Center institutional review board, which waived the need for written or oral patient informed consent.

Results

Table 1 compares the baseline characteristics between 349 patients with breast cancer and 659 patients with NSCLC. Patients with breast cancer, compared with patients with NSCLC, presented with larger (median [interquartile range (IQR)] diameter, 17 [10-29] mm vs 14 [8-23] mm; P < .001) and more numerous (median [IQR], 3 [1-8] vs 2 [1-4]; P < .001) brain metastases. Patients with breast cancer were also more likely than patients with NSCLC to be symptomatic at presentation (265 [75.9%] vs 399 [60.5%]; P < .001), present with seizures (59 [16.9%] vs 75 [11.4%]; P = .01), harbor brainstem involvement (28 [8.0%] vs 28 [4.2%]; P = .02), have leptomeningeal disease at diagnosis (40 [11.5%] vs 14 [2.1%]; P < .001), and receive WBRT as initial management (209 [59.9%] vs 283 [42.9%]; P < .001;Table 1). After initial brain-directed therapy, no significant differences in recurrence or treatment-based intracranial outcomes were found between the 2 groups. However, neurological death was more common in patients with breast cancer than patients with NSCLC, both as a percentage of total deaths (103 [37.3%] vs 98 [19.9%]; P < .001; Table 1) and as a time-to-event based outcome (hazard ratio, 1.54; 95% CI, 1.10-2.17; P = .01; Table 2).

Discussion

Patients with breast cancer presented with more advanced intracranial disease than did patients with NSCLC and more frequently required WBRT as initial management. However, after initial brain-directed therapy, no differences in recurrence or salvage therapy–based outcomes between the 2 cohorts were noted. This finding suggests that intracranial disease in patients with breast cancer was not more aggressive or resistant to treatment but rather was diagnosed at a later stage.

Brain-directed MRI screening for patients who harbor malignant neoplasms with potential for intracranial involvement is important given the impact of neurological compromise on quality of life. In addition, early identification of intracranial disease facilitates less invasive or less toxic approaches, such as stereotactic radiosurgery or careful use of promising systemic agents rather than WBRT or neurosurgical resection.

The limitations of our study include its retrospective nature, inherent selection bias, and potential clinical confounders. In addition, 84 patients with breast cancer (24.0%) were screened for brain metastases (eg, patient/provider preference, clinical trial)—representing a higher percentage than in previous studies, which screened less frequently5—whereas some patients with NSCLC were not, including patients diagnosed with NSCLC due to symptomatic brain metastases. Our results are, therefore, biased toward the null. Despite these limitations, this study strongly supports further investigation into MRI screening of the brain among select patients with metastatic breast cancer.

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Article Information

Accepted for Publication: February 19, 2018.

Corresponding Author: Daniel N. Cagney, MD, Department of Radiation Oncology, Dana-Farber/Brigham and Women’s Cancer Center, 75 Francis St, Boston, MA 02115 (dcagney@bwh.harvard.edu).

Published Online: May 17, 2018. doi:10.1001/jamaoncol.2018.0813

Author Contributions: Drs Cagney and Aizer had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Lin and Aizer contributed equally to this study.

Study concept and design: Cagney, Martin, Lin, Aizer.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Cagney, Lin, Aizer.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Cagney, Martin, Catalano, Lin, Aizer.

Obtained funding: Alexander, Lin.

Administrative, technical, or material support: Alexander.

Study supervision: Alexander, Lin, Aizer.

Other: Brown.

Conflict of Interest Disclosures: None reported.

Meeting Presentation: This study was presented in abstract form at the Annual Meeting of the American Society for Radiation Oncology; September 24-27, 2017; San Diego, California.

Additional Contributions: We acknowledge the contribution to this work of the following people: Rachel H. Brigell, MPH; Puyao C. Li, MD; Gabrielle A. Mezochow, BS; Luke Besse, BS; Shyam K. Tanguturi, MD; and Daphne A. Haas-Kogan, MD, all of whom are from the Department of Radiation Oncology, Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School; Eudocia Q. Lee, MD, MPH, and Patrick Y. Wen, MD, Center for Neuro-Oncology, Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School; Stephanie E. Weiss, MD, Department of Radiation Oncology, Fox Chase Cancer Center; Nils D. Arvold, MD, Department of Radiation Oncology, St. Luke's Radiation Oncology Associates; and Amanda J. Redig MD, PhD, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School. These contributors received no compensation for their work.

References
1.
Cagney  DN, Martin  AM, Catalano  PJ,  et al.  Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study.  Neuro Oncol. 2017;19(11):1511-1521.PubMedGoogle ScholarCrossref
2.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. https://www.nccn.org/professionals/physician_gls/. Accessed November 1, 2017.
3.
Martin  AM, Cagney  DN, Catalano  PJ,  et al.  Brain metastases in newly diagnosed breast cancer: a population-based study.  JAMA Oncol. 2017;3(8):1069-1077.PubMedGoogle ScholarCrossref
4.
Lin  NU, Claus  E, Sohl  J, Razzak  AR, Arnaout  A, Winer  EP.  Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases.  Cancer. 2008;113(10):2638-2645.PubMedGoogle ScholarCrossref
5.
Pestalozzi  BC, Holmes  E, de Azambuja  E,  et al.  CNS relapses in patients with HER2-positive early breast cancer who have and have not received adjuvant trastuzumab: a retrospective substudy of the HERA trial (BIG 1-01).  Lancet Oncol. 2013;14(3):244-248.PubMedGoogle ScholarCrossref
6.
American Joint Committee on Cancer.  AJCC Cancer Staging Manual. Cham, Switzerland: Springer International Publishing AG; 2017.
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