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Changing molecular profile of brain metastases compared with matched breast primary cancers and impact on clinical outcomes
Changing molecular profile of brain metastases compared with matched breast primary cancers and impact on clinical outcomes Thomson AH, McGrane J, Mathew J, et al (Royal Cornwall Hosp, Truro, UK; et al) Br J Cancer 114:793-800, 2016
Background.dBreast cancer commonly metastasises to the brain, but little is known about changes in the molecular profile of the brain secondaries and impact on clinical outcomes. Methods.dPatients with samples from brain metastases and matched breast cancers were included. Immunohistochemical analysis for oestrogen receptor, progesterone receptor, p27kip1, cyclin D1, epidermal growth factor receptor, insulin like growth factor 1, insulin like growth factor 1 receptor, vascular endothelial growth factor A, transforming growth factorb and HER2 receptor was performed. Borderline HER2 results were analysed by fluorescent in situ hybridisation. Levels of expression were compared, with review of effect on clinical outcomes. Results.dA total of 41 patients were included. Of the patients, 20% had a change in oestrogen receptor or HER2 in their brain metastasis that could affect therapeutic decisions. There were statistically significant rises in brain metastases for p27kip1 (P ¼ 0.023) and cyclin D1 (P ¼ 0.030) and a fall in vascular endothelial growth factor A (P ¼ 0.012). Overall survival from the time of metastasis increased significantly with oestrogen receptorpositive (P ¼ 0.005) and progesterone receptor-positive (P ¼ 0.013) brain lesions and with a longer duration from diagnosis of the breast primary (P < 0.001). Conclusions.dIn this cohort there were phenotypic differences in meta-
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static brain tumours compared with matched primary breast tumours. These could be relevant for aetiology, and have an impact on prognostication, current and future therapies. The treatment approaches for brain metastases have largely been local therapies, including neurosurgical resection and radiotherapy in the form of stereotactic radiosurgery and whole-brain radiotherapy, whereas systemic therapies have played a limited role until recently. Because brain metastases are common in patients with breast cancer and targeted therapies are available for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, clinical trials are investigating various combinations of systemic agents, with and without radiotherapy, in patients with breast cancer brain metastases. Discordance between the molecular profiles of primary untreated breast cancer and those of subsequent biopsies of primary tumors and metastatic sites raises the clinical question of the optimal choice of systemic therapy. A recent meta-analysis of 48 publications on discordances in estrogen receptor (ER), progesterone receptor (PR), and HER2 status between primary breast tumors and metastases reported pooled discordance proportions of 20% (95% confidence interval [CI]: 16%-35%) for ER, 33% (95% CI: 29%-38%) for PR, and 8% (95% CI: 6%-10%) for HER2.1 Transitions between the primary tumor and metastasis from positive to negative, as well as from negative to positive, were reported for all 3 markers. This article by Thomson and colleagues reported discordance rates and directions that are consistent with the findings of the studies included in the recent metaanalysis. One hypothesis for this discordance is missed detection due to tumor heterogeneity, which Thomson and
Breast Diseases: A Year BookÒ Quarterly Vol 27 No 4 2017
colleagues attempted to address by testing 3 random samples from breast and brain tumors. Another possible explanation for the discordance is evolution in the molecular profile during the natural history of the disease and as a result of treatment. In a large Japanese cohort of 21 755 patients treated with neoadjuvant chemotherapy for non-metastatic breast cancer, the molecular profiles of the primary breast tumors were altered from the baseline to after chemotherapy. A total of 499 of 10 973 cases converted from ER positive to ER negative, and 519 (9.3%) of 5607 cases converted from ER negative to ER positive. HER2 status also changed, with 601 (21.4%) of 2811 HER2-positive tumors converting to HER2 negative and 340 (3.4%) of 9947 HER2-negative tumors converting to HER2 positive after chemotherapy.2 Thomson and colleagues emphasized that ER-positivity was associated with better survival only for the brain metastases but not for the breast tumors. Considering that this difference was based on 3 cases in which the initial breast tumor was ER negative while the brain metastases were ER positive, the true prognostic value of the ER status of brain metastases requires further validation. Differences in other established clinical prognostic factors may have affected the survival of these 3 patients, including differences in extracranial control, overall intracranial tumor burden, and performance status, all of which were not reported in this article. Furthermore, as observed in this retrospective study and prior randomized trials, local treatments for brain metastases, including the extent of surgery or radiotherapy, have not shown any effect on overall survival. As this article did not report neurological death or intracranial control, it raises the question of whether the ER positivity of the brain metastases
reflected the ER status of both intracranial and extracranial metastases and whether systemic response to ERtargeted therapy may have improved survival. Despite its limitations, this article supports the larger growing body of evidence that motivates further investigation of the molecular evolution of breast cancer through treatment and the natural course of the disease,
recognizing the potential effect of these findings on optimizing systemic therapy. C. Chung, MD, MSc, FRCPC, CIP
References 1. Aurilio G, Disalvatore D, Pruneri G, et al. A meta-analysis of oestrogen receptor, progesterone receptor and
human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases. Eur J Cancer. 2014;50:277-289. 2. Niikura N, Tomotaki A, Miyata H, et al. Changes in tumor expression of HER2 and hormone receptors status after neoadjuvant chemotherapy in 21,755 patients from the Japanese breast cancer registry. Ann Oncol. 2016;27:480-487.
ECONOMIC, LEGAL, AND SOCIAL ISSUES Annual Medical Expenditure and Productivity Loss among Colorectal, Female Breast, and Prostate Cancer Survivors in the United States Zheng Z, Yabroff KR, Guy GP Jr, et al (American Cancer Society, Atlanta, GA; Natl Cancer Inst, Bethesda, MD; Ctrs for Disease Control and Prevention, Atlanta, GA; et al) J Natl Cancer Inst 108:djv382, 2015
Background.dThere are limited nationally representative estimates of the annual economic burden among survivors of the three most prevalent cancers (colorectal, female breast, and prostate) in both nonelderly and elderly populations in the United States. Methods.dThe 2008 to 2012 Medical Expenditure Panel Survey data were used to identify colorectal (n ¼ 540), female breast (n ¼ 1568), and prostate (n ¼ 1170) cancer survivors and individuals without a cancer history (n ¼ 109 423). Excess economic burden attributable to cancer
included per-person excess annual medical expenditures and productivity losses (employment disability, missed work days, and days stayed in bed). All analyses were stratified by cancer site and age (nonelderly: 18e64 years vs elderly: $65 years). Multivariable analyses controlled for age, sex, race/ ethnicity, marital status, education, number of comorbidities, and geographic region. All statistical tests were two-sided. Results.dCompared with individuals without a cancer history, cancer survivors experienced annual excess medical expenditures (for the nonelderly population, colorectal: $8647, 95% confidence interval [CI] ¼ $4932 to $13 974, P < .001; breast: $5119, 95% CI ¼ $3439 to $7158, P < .001; prostate: $3586, 95% CI ¼ $1792 to $6076, P < .001; for the elderly population, colorectal: $4913, 95% CI ¼ $2768 to $7470, P < .001; breast: $2288, 95% CI ¼ $814 to $3995, P ¼.002; prostate: $3524, 95% CI ¼ $1539 to $5909, P < .001). Nonelderly colorectal and breast cancer survivors experienced statistically significant annual excess
employment disability (13.6%, P < .001, and 4.8%, P ¼ .001) and productivity loss at work (7.2 days, P < .001, and 3.3 days, P ¼.002) and at home (4.5 days, P < .001, and 3.3 days, P ¼ .003). In contrast, elderly survivors of all three cancer sites had comparable productivity losses as those without a cancer history. Conclusions.dColorectal, breast, and prostate cancer survivors experienced statistically significantly higher economic burden compared with individuals without a cancer history; however, excess economic burden varies by cancer site and age. Targeted efforts will be important in reducing the economic burden of colorectal, breast, and prostate cancer. As reported in this article, Zheng and colleagues used the Medical Expenditure Panel Survey (MEPS), a nationally representative survey, to estimate the annual medical expenditures and productivity loss among survivors of 3 cancers: colorectal, female breast, and prostate. This article contributes to the field of
Breast Diseases: A Year BookÒ Quarterly Vol 27 No 4 2017
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Background.dBreast cancer commonly metastasises to the brain, but little is known about changes in the molecular profile of the brain secondaries and impact on clinical outcomes. Methods.dPatients with samples from brain metastases and matched breast cancers were included. Immunohistochemical analysis for oestrogen receptor, progesterone receptor, p27kip1, cyclin D1, epidermal growth factor receptor, insulin like growth factor 1, insulin like growth factor 1 receptor, vascular endothelial growth factor A, transforming growth factorb and HER2 receptor was performed. Borderline HER2 results were analysed by fluorescent in situ hybridisation. Levels of expression were compared, with review of effect on clinical outcomes. Results.dA total of 41 patients were included. Of the patients, 20% had a change in oestrogen receptor or HER2 in their brain metastasis that could affect therapeutic decisions. There were statistically significant rises in brain metastases for p27kip1 (P ¼ 0.023) and cyclin D1 (P ¼ 0.030) and a fall in vascular endothelial growth factor A (P ¼ 0.012). Overall survival from the time of metastasis increased significantly with oestrogen receptorpositive (P ¼ 0.005) and progesterone receptor-positive (P ¼ 0.013) brain lesions and with a longer duration from diagnosis of the breast primary (P < 0.001). Conclusions.dIn this cohort there were phenotypic differences in meta-
320
static brain tumours compared with matched primary breast tumours. These could be relevant for aetiology, and have an impact on prognostication, current and future therapies. The treatment approaches for brain metastases have largely been local therapies, including neurosurgical resection and radiotherapy in the form of stereotactic radiosurgery and whole-brain radiotherapy, whereas systemic therapies have played a limited role until recently. Because brain metastases are common in patients with breast cancer and targeted therapies are available for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, clinical trials are investigating various combinations of systemic agents, with and without radiotherapy, in patients with breast cancer brain metastases. Discordance between the molecular profiles of primary untreated breast cancer and those of subsequent biopsies of primary tumors and metastatic sites raises the clinical question of the optimal choice of systemic therapy. A recent meta-analysis of 48 publications on discordances in estrogen receptor (ER), progesterone receptor (PR), and HER2 status between primary breast tumors and metastases reported pooled discordance proportions of 20% (95% confidence interval [CI]: 16%-35%) for ER, 33% (95% CI: 29%-38%) for PR, and 8% (95% CI: 6%-10%) for HER2.1 Transitions between the primary tumor and metastasis from positive to negative, as well as from negative to positive, were reported for all 3 markers. This article by Thomson and colleagues reported discordance rates and directions that are consistent with the findings of the studies included in the recent metaanalysis. One hypothesis for this discordance is missed detection due to tumor heterogeneity, which Thomson and
Breast Diseases: A Year BookÒ Quarterly Vol 27 No 4 2017
colleagues attempted to address by testing 3 random samples from breast and brain tumors. Another possible explanation for the discordance is evolution in the molecular profile during the natural history of the disease and as a result of treatment. In a large Japanese cohort of 21 755 patients treated with neoadjuvant chemotherapy for non-metastatic breast cancer, the molecular profiles of the primary breast tumors were altered from the baseline to after chemotherapy. A total of 499 of 10 973 cases converted from ER positive to ER negative, and 519 (9.3%) of 5607 cases converted from ER negative to ER positive. HER2 status also changed, with 601 (21.4%) of 2811 HER2-positive tumors converting to HER2 negative and 340 (3.4%) of 9947 HER2-negative tumors converting to HER2 positive after chemotherapy.2 Thomson and colleagues emphasized that ER-positivity was associated with better survival only for the brain metastases but not for the breast tumors. Considering that this difference was based on 3 cases in which the initial breast tumor was ER negative while the brain metastases were ER positive, the true prognostic value of the ER status of brain metastases requires further validation. Differences in other established clinical prognostic factors may have affected the survival of these 3 patients, including differences in extracranial control, overall intracranial tumor burden, and performance status, all of which were not reported in this article. Furthermore, as observed in this retrospective study and prior randomized trials, local treatments for brain metastases, including the extent of surgery or radiotherapy, have not shown any effect on overall survival. As this article did not report neurological death or intracranial control, it raises the question of whether the ER positivity of the brain metastases
reflected the ER status of both intracranial and extracranial metastases and whether systemic response to ERtargeted therapy may have improved survival. Despite its limitations, this article supports the larger growing body of evidence that motivates further investigation of the molecular evolution of breast cancer through treatment and the natural course of the disease,
recognizing the potential effect of these findings on optimizing systemic therapy. C. Chung, MD, MSc, FRCPC, CIP
References 1. Aurilio G, Disalvatore D, Pruneri G, et al. A meta-analysis of oestrogen receptor, progesterone receptor and
human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases. Eur J Cancer. 2014;50:277-289. 2. Niikura N, Tomotaki A, Miyata H, et al. Changes in tumor expression of HER2 and hormone receptors status after neoadjuvant chemotherapy in 21,755 patients from the Japanese breast cancer registry. Ann Oncol. 2016;27:480-487.
ECONOMIC, LEGAL, AND SOCIAL ISSUES Annual Medical Expenditure and Productivity Loss among Colorectal, Female Breast, and Prostate Cancer Survivors in the United States Zheng Z, Yabroff KR, Guy GP Jr, et al (American Cancer Society, Atlanta, GA; Natl Cancer Inst, Bethesda, MD; Ctrs for Disease Control and Prevention, Atlanta, GA; et al) J Natl Cancer Inst 108:djv382, 2015
Background.dThere are limited nationally representative estimates of the annual economic burden among survivors of the three most prevalent cancers (colorectal, female breast, and prostate) in both nonelderly and elderly populations in the United States. Methods.dThe 2008 to 2012 Medical Expenditure Panel Survey data were used to identify colorectal (n ¼ 540), female breast (n ¼ 1568), and prostate (n ¼ 1170) cancer survivors and individuals without a cancer history (n ¼ 109 423). Excess economic burden attributable to cancer
included per-person excess annual medical expenditures and productivity losses (employment disability, missed work days, and days stayed in bed). All analyses were stratified by cancer site and age (nonelderly: 18e64 years vs elderly: $65 years). Multivariable analyses controlled for age, sex, race/ ethnicity, marital status, education, number of comorbidities, and geographic region. All statistical tests were two-sided. Results.dCompared with individuals without a cancer history, cancer survivors experienced annual excess medical expenditures (for the nonelderly population, colorectal: $8647, 95% confidence interval [CI] ¼ $4932 to $13 974, P < .001; breast: $5119, 95% CI ¼ $3439 to $7158, P < .001; prostate: $3586, 95% CI ¼ $1792 to $6076, P < .001; for the elderly population, colorectal: $4913, 95% CI ¼ $2768 to $7470, P < .001; breast: $2288, 95% CI ¼ $814 to $3995, P ¼.002; prostate: $3524, 95% CI ¼ $1539 to $5909, P < .001). Nonelderly colorectal and breast cancer survivors experienced statistically significant annual excess
employment disability (13.6%, P < .001, and 4.8%, P ¼ .001) and productivity loss at work (7.2 days, P < .001, and 3.3 days, P ¼.002) and at home (4.5 days, P < .001, and 3.3 days, P ¼ .003). In contrast, elderly survivors of all three cancer sites had comparable productivity losses as those without a cancer history. Conclusions.dColorectal, breast, and prostate cancer survivors experienced statistically significantly higher economic burden compared with individuals without a cancer history; however, excess economic burden varies by cancer site and age. Targeted efforts will be important in reducing the economic burden of colorectal, breast, and prostate cancer. As reported in this article, Zheng and colleagues used the Medical Expenditure Panel Survey (MEPS), a nationally representative survey, to estimate the annual medical expenditures and productivity loss among survivors of 3 cancers: colorectal, female breast, and prostate. This article contributes to the field of
Breast Diseases: A Year BookÒ Quarterly Vol 27 No 4 2017
321