Extracranial Disease Research Articles

Skull Metastasis From Uterine Leiomyosarcoma, a Rare Presentation for a Rare Tumor: A Case Report and Review of the Literature

Uterine leiomyosarcoma (uLMS) is a rare and aggressive malignancy with poor clinical outcomes. Even when localized, uLMS is associated with high rates of local and distant recurrences that are usually fatal. Common sites of recurrence are lung, liver, pelvic lymph nodes, and vertebral and long bones, though atypical patterns of recurrence have been described. Among them, intracranial recurrence appears as a rare finding, almost exceptional in skull and dura. We describe the case of a solitary skull metastasis from uLMS in a 39-year-old woman, which represents the third reported case of skull recurrence in literature. After multidisciplinary discussion, the patient underwent surgery and received adjuvant radiotherapy. After 4 months, she is currently alive, without evidence of extracranial disease. This case highlights the importance of suspecting and recognizing atypical and extremely rare metastasis to this region. We encourage the need for large case series in order to provide further information about cranial recurrences of uLMS taking into account the paucity of data currently available in literature and the frequently unpredictable behavior of this rare and highly lethal disease.

Melanoma brain metastases: is it time to eliminate radiotherapy?

Immunotherapy has demonstrated efficacy in treatment of intracranial metastasis from melanoma, calling into question the role of intracranial radiotherapy (RT). Herein, we assessed the utilization patterns of intracranial RT in patients with melanoma brain metastasis and compared outcomes in patients treated with immunotherapy alone versus immunotherapy in addition to intracranial RT. We queried the National Cancer Database (NCDB) for patients with melanoma brain metastases treated with immunotherapy and intracranial RT or immunotherapy alone. Multivariable logistic regression identified variables associated with increased likelihood of receiving immunotherapy alone. Multivariable Cox regression was used to identify co-variates predictive of overall survival (OS). Propensity matching was used to account for indication bias. We identified 528 and 142 patients that were treated with combination therapy and immunotherapy alone, respectively. Patients with lower comorbidity score were more likely to receive immunotherapy alone. Extracranial disease and treatment at a non-academic center were associated with worse OS. Median OS for all patients was 11.0months. Treatment with stereotactic radiosurgery (SRS) in addition to immunotherapy was superior to immunotherapy alone, median OS of 19.0 versus 11.5months (p = 0.006). Whole brain radiation therapy (WBRT) in combination with immunotherapy performed worse than immunotherapy alone, median OS of 7.7 versus 11.5months (p = 0.0255). For melanoma patients requiring WBRT, immunotherapy alone may be reasonable in asymptomatic patients. For those eligible for SRS, combination therapy may provide better outcomes. Results of ongoing prospective studies will help provide guidance regarding the use of radioimmunotherapy in this population.

Advances in Management of Brain and Leptomeningeal Metastases.

The management of brain and leptomeningeal metastases has changed significantly over the past decade. Historically, radiation therapy had been the mainstay of treatment. Several strategies to limit toxicities with radiation have been developed in the recent years. Increasingly systemic therapy options are being considered an important therapeutic option for CNS metastases. Numerous novel small molecule inhibitors and immunotherapy agents have intracranial activity to varying degrees, in addition to good extracranial disease control. Overall, the prognosis of select patients with CNS metastases has improved over the past several years with advent of new therapeutic strategies. Systemic therapy options with CNS benefit should be considered in select patients with small and asymptomatic CNS metastases. Further areas of research focus on molecular alterations predisposing to CNS metastases, identification of small molecule inhibitors with CNS activity, and the combination of radiation therapy and immunotherapy.

Evaluation of First-line Radiosurgery vs Whole-Brain Radiotherapy for Small Cell Lung Cancer Brain Metastases

Although stereotactic radiosurgery (SRS) is preferred for limited brain metastases from most histologies, whole-brain radiotherapy (WBRT) has remained the standard of care for patients with small cell lung cancer. Data on SRS are limited. To characterize and compare first-line SRS outcomes (without prior WBRT or prophylactic cranial irradiation) with those of first-line WBRT. FIRE-SCLC (First-line Radiosurgery for Small-Cell Lung Cancer) was a multicenter cohort study that analyzed SRS outcomes from 28 centers and a single-arm trial and compared these data with outcomes from a first-line WBRT cohort. Data were collected from October 26, 2017, to August 15, 2019, and analyzed from August 16, 2019, to November 6, 2019. SRS and WBRT for small cell lung cancer brain metastases. Overall survival, time to central nervous system progression (TTCP), and central nervous system (CNS) progression-free survival (PFS) after SRS were evaluated and compared with WBRT outcomes, with adjustment for performance status, number of brain metastases, synchronicity, age, sex, and treatment year in multivariable and propensity score-matched analyses. In total, 710 patients (median [interquartile range] age, 68.5 [62-74] years; 531 men [74.8%]) who received SRS between 1994 and 2018 were analyzed. The median overall survival was 8.5 months, the median TTCP was 8.1 months, and the median CNS PFS was 5.0 months. When stratified by the number of brain metastases treated, the median overall survival was 11.0 months (95% CI, 8.9-13.4) for 1 lesion, 8.7 months (95% CI, 7.7-10.4) for 2 to 4 lesions, 8.0 months (95% CI, 6.4-9.6) for 5 to 10 lesions, and 5.5 months (95% CI, 4.3-7.6) for 11 or more lesions. Competing risk estimates were 7.0% (95% CI, 4.9%-9.2%) for local failures at 12 months and 41.6% (95% CI, 37.6%-45.7%) for distant CNS failures at 12 months. Leptomeningeal progression (46 of 425 patients [10.8%] with available data) and neurological mortality (80 of 647 patients [12.4%] with available data) were uncommon. On propensity score-matched analyses comparing SRS with WBRT, WBRT was associated with improved TTCP (hazard ratio, 0.38; 95% CI, 0.26-0.55; P < .001), without an improvement in overall survival (median, 6.5 months [95% CI, 5.5-8.0] for SRS vs 5.2 months [95% CI, 4.4-6.7] for WBRT; P = .003) or CNS PFS (median, 4.0 months for SRS vs 3.8 months for WBRT; P = .79). Multivariable analyses comparing SRS and WBRT, including subset analyses controlling for extracranial metastases and extracranial disease control status, demonstrated similar results. Results of this study suggest that the primary trade-offs associated with SRS without WBRT, including a shorter TTCP without a decrease in overall survival, are similar to those observed in settings in which SRS is already established.

Systemic therapy for patients with breast cancer and one to three brain metastases (BM).

1090 Background: Despite advances in systemic therapies and improved overall survival of metastatic breast cancer (MBC) patients, the development of brain metastases (BMs) remains a challenging complication that affects quality of life and increases morbidity and mortality. Current clinical practice guidelines recommend local treatment of BMs without changing systemic therapy (CST) in patients with stable systemic disease. Methods: We retrospectively investigated the impact of CST (when applicable as per treating physician’s discretion) after diagnosis of the initial 1-3 BMs on the patient’s progression-free survival time (PFS), defined as time to death, to a second BMs or to extracranial metastases. All MBC patients with 1 to 3 BMs only (without extracranial disease) treated at our institution between 2002 and 2017 were identified. For each patient, full information on follow-up and administered therapies were mandatory for inclusion. Hazard ratios (HR) were calculated using the Cox proportional hazard model. We also computed the restricted mean survival time (RMST) up to 5 years of follow-up. Results: Among the 2645 patient with BM treated at our institution, 80 were included for analysis. In regards to primary BMs management in patients, 46 of 80 (57%) were treated by radiation therapy, 6 of 80 (7.5%) underwent surgical resection, and 28 of 80 (35%) were managed by a combination of surgery and radiation therapy. All patients had staging imaging documenting lack of extracranial metastases at the time of local therapy of BMs. Following the primary management of BM, we observed that providers changed systemic therapy in 32 of 80 (40%), defined as the CST group. CST included both initiation of therapy in 16 of 80 (20%) and switching of adjuvant therapy in 16 of 80 (20%). Median PFS among CST was 7.7 months vs. 7.2 months among no CST (HR = 0.855, 95% confidence interval (CI) 0.53-1.38, p = 0.52). 5-year RMST for the CST group was 16.6 months vs. 12.8 months in no CST group. The difference of 3.8 months (95% CI 4.3-11.8) was not statistically significant. Conclusions: Patients with 1-3 BMs without extracranial disease had a median PFS close to 7.5 months after local therapy. Consistent with current standard of care of maintaining the same systemic therapy approach upon developing isolated BMs, our findings did not demonstrate a significant difference in PFS between patients who experienced a change in systemic therapy compared to those who did not.

Institutional outcomes of whole brain radiotherapy for metastatic melanoma brain metastases.

e14504 Background: The management of melanoma with multiple brain metastases (MBM) is complex given improvements in targeted agents, immunotherapy, and radiotherapy. Whole brain radiation therapy (WBRT) is a radiotherapy technique with limited outcomes data. We report our institutional outcomes for MBM patients receiving WBRT and assess whether certain clinical factors impact prognosis. Methods: A retrospective review of a single institution database was performed. Patients diagnosed with MBM from 2000-2018 treated with WBRT, with or without systemic treatments, were included. Post-WBRT brain MRI scans were assessed at timed intervals for radiographic response. Clinical and treatment variables associated with overall survival (OS), progression free survival (PFS), intracranial failure-free survival (IFFS), and local failure-free survival (LFFS) were assessed. Data was collected on radiation-induced side effects, including radionecrosis, hemorrhage, and memory deficits. Results: Of 1347 patients treated with WBRT from 2000-2018, 63 patients had melanoma. 69% of patients had ≥5 brain metastases at the time of WBRT, 68% had extracranial disease, and 71% received steroids during their overall treatment course. Most had received previous therapies and had WBRT as a last resort. Median WBRT dose was 30 Gray over 10 fractions. Median follow-up was 4.0 months. Six-month OS, PFS, IFFS, and LFFS were 52.7%, 20.4%, 52.3%, and 43%. Median OS, PFS, IFFS, and LFFS were 7.0 months, 2.2 months, 6.1 months, and 4.9 months. Performance status correlated with OS on univariate and multivariate analysis. BRAFi was the only systemic therapy to significantly impact OS on univariate analysis (HR 0.24, 95% CI 0.07-0.79, p = 0.019), although this was not seen on multivariate analysis. There was a 19% rate of memory deficits. Among the 46 patients with post-WBRT brain scans, 17% had radionecrosis and 28% had intralesional hemorrhage. Not all radiographically noted radiotoxicities were clinically significant, although hemorrhage decreased IFFS on both univariate and multivariate analysis. Conclusions: Outcomes for MBM patients receiving WBRT indicate that WBRT remains a worthy option to control intracranial disease. Treatment-related effects such as hemorrhage, necrosis, or cognitive changes are considerations. Median PFS and IFFS suggest that systemic disease control continues to be the greater issue. The role of WBRT should be re-evaluated in the modern era, which features advanced imaging detection ability, newer systemic agents, and improved steroid avoidance strategies.

Author response: Lower carotid revascularization rates after stroke in racial/ethnic minority-serving US hospitals.

We respectfully disagree with Dr. Willey's conclusions about our study.1 The International Classification of Diseases, Ninth Revision, Clinical Modification ( ICD-9-CM ) codes used in our study (433.11 and 433.31) do not apply to asymptomatic internal carotid artery (ICA) stenosis and only capture extracranial disease resulting in infarction.2,3 Therefore, racial differences in the prevalence of intracranial disease or in the use of carotid endarterectomy (CEA) or carotid artery stenting (CAS) in asymptomatic ICA stenosis are an unlikely source of bias. The included ICD-9-CM codes indeed also capture patients with <50% stenosis or complete ICA occlusions, for whom revascularization would not be appropriate. We acknowledge this in the discussion as a well-known limitation of the data source; this has also been commented on elsewhere.4 However, it is important to distinguish differences between white and minority patients from differences between white and minority hospitals. Our results describe the latter and are adjusted for, and therefore independent of, individual patient race and other socioeconomic covariates. In other words, differences in eligibility by individual patient race/ethnicity may in part explain within-hospital differences between white and minority patients but would not explain between-hospital differences among patients of the same race. Figure 3 shows that the between-hospital difference in carotid revascularization is driven by lower odds of CEA/CAS in whites and Hispanics in minority, compared with white, hospitals. Individual-level racial differences in eligibility would not explain why white patients in minority-serving hospitals have lower adjusted odds of CEA/CAS than white patients in white hospitals or why Hispanic patients in minority-serving hospitals have lower adjusted odds of CEA/CAS than Hispanic patients in white hospitals. Last, we did not exclude transferred patients as suggested by Dr. Willey. Rather, we excluded records of patients transferred out to another acute care hospital while including those who were transferred in. Since the unit of observation in the data source is hospitalization, this is common practice to prevent double counting of transferred patients who may have 2 hospitalizations pertaining to the same event; this reduces rather than introduces bias.

Carotid duplex criteria: What have we learned in 40 years?

Before the development of the first prototype duplex ultrasound scanner at the University of Washington in the late 1970s, the only noninvasive tests available for extracranial carotid artery disease were indirect methods, such as the periorbital Doppler examination and oculoplethysmography. The duplex scanner combined real-time two-dimensional B-mode imaging and pulsed-Doppler flow detection in a single instrument and provided Doppler spectral waveforms from discrete sites within the vessel lumen. Spectral waveforms allowed characterization of the flow patterns and velocity changes associated with normal and diseased arteries. In a series of validation studies, Dr. D. Eugene Strandness, Jr. and colleagues compared various spectral waveform parameters obtained from internal carotid arteries to independently read carotid arteriograms and established quantitative threshold criteria for classification of carotid artery disease. These criteria were based on peak systolic velocity and end-diastolic velocity, as well as features such as spectral broadening and flow separation. Internal carotid arteries were classified as normal, 1% to 15% diameter reduction, 16% to 49% diameter reduction, 50% to 79% diameter reduction, 80% to 99% diameter reduction, and occluded. Since the 1980s, the University of Washington carotid duplex criteria have been widely used and modified in vascular laboratories throughout the world. Additional clinically relevant criteria have also been developed, such as a threshold for the 70% to 99% North American Symptomatic Carotid Endarterectomy Trial (NASCET) stenosis. Validation of carotid criteria has always depended on comparing spectral waveform parameters to the “gold standard” of contrast arteriography. However, experience has shown that the relationship between velocity and arteriographic stenosis is subject to significant variability. Based on these observations, standardization of carotid duplex criteria should lead to more consistent reporting among vascular laboratories, but it is unlikely to result in improved correlation with arteriography.

Current Treatment of Melanoma Brain Metastasis.

With greater understanding of underlying biology and development of effective BRAF-targeted therapy and immunotherapy, along with remarkable advances in local treatment such as stereotactic radiosurgery, melanoma brain metastasis (MBM) is witnessing continually improving outcome, with 1-year overall survival rate approaching 85%. Given disease complexity and myriad treatment options, all patients with MBM should ideally be evaluated in a multidisciplinary setting to allow an individualized treatment approach based on prognostic groups, molecular classification, number and size of brain metastasis, and performance status. With improving outcome, pendulum has now swayed to focus more on effective treatment modalities with minimal neurological toxicity while maintaining quality of life. Surgery is usually considered in symptomatic and large MBMs, while stereotactic radiosurgery considered in 1-4 lesions, and now also being explored for up to 15 brain metastases for improved local control. The role of whole brain radiotherapy is diminishing given its neurocognitive toxicities and is reserved for patients with diffuse brain involvement. Cytotoxic chemotherapy has largely been ineffective without evidence for survival benefit. Immune checkpoint inhibitors have become the cornerstone of management for melanoma brain metastasis with durable intracranial tumor control and excellent toxicity profile. For patients with asymptomatic MBMs, ipilimumab and nivolumab have shown intracranial response near 60% and provides comparable clinical benefit in MBMs as for extracranial metastases. For patients with driver BRAF mutation, BRAFi-/MEKi-targeted agents are proven to be effective in MBM with high rate intracranial responses (44-59%). However, the durability of intracranial responses induced by BRAFi/MEKi seems to be shorter than that of extracranial disease. Emerging data support novel combination of systemic therapy and stereotactic radiosurgery, which appears to be safe and effective; however, potential benefits and risks should be evaluated prospectively. Promising ongoing trials will further expand therapeutic evidence in MBM, and patients should be encouraged to participate in clinical trials.

Evaluation of intracranial and extracranial atherosclerotic lesions in patients with symptomatic coronary artery disease

ABSTRACT Objectives Patients with coronary artery disease (CAD) concomitant with extracranial and intracranial atherosclerotic disease (EICAD) may have an increased risk of stroke and myocardial ischemic events. This study aimed to evaluate the concomitant atherosclerotic lesions in extra- and intracranial arterial beds in patients with CAD. Methods A total of 1274 patients who underwent coronary angiography due to ischemic heart disease were included. All patients underwent ultrasound screening of the extra- and intracranial arteries before coronary angiography, and the degrees of extracranial carotid artery disease (ECAD) and intracranial cerebral artery disease (ICAD) were recorded. Results A total of 1062 cases of CAD were confirmed. The prevalence of ECAD, ICAD, and EICAD (ECAD combined with ICAD) in patients with CAD was 15.6%, 11.2% and 11.9%, respectively. For patients with 3-vessel disease, the prevalence was 20.5%, 13.8% and 18.1%, and for patients with severe coronary artery stenosis, the prevalence was 15.8%, 12.1% and 13.2%, respectively. The presence and extent of ECAD and ICAD were positively correlated with the number of lesion vessels and degree of CAD. The posterior circulation arteries were more prone to lesions in patients with ECAD, while the anterior circulation arteries were more vulnerable to lesions in patients with ICAD. Conclusions The prevalence of ECAD, ICAD and EICAD is high in patients with CAD, and the presence of these conditions is positively correlated with the extent and degree of CAD. Evaluations of ECAD and ICAD should be highly recommended for CAD patients to reduce the future risk of cardiovascular diseases.

External Validation of a Prognostic Score for Patients with Brain Metastases: Extended Diagnosis-Specific Graded Prognostic Assessment

Purpose: The aim of our study was the external validation of an extended variant of the four-tiered diagnosis-specific graded prognostic assessment (DS-GPA) that includes more information about extracranial disease burden and blood test results, and predicts survival of patients with brain metastases. The extracranial DS-GPA (EC-GPA) includes serum albumin, lactate dehydrogenase, and number of extracranial organs involved. Originally, the score was developed in Germany. Patients and Methods: A retrospective analysis of 236 patients with brain metastases treated with primary whole-brain radiotherapy in North-Norway was performed (independent external validation cohort). Results: The four-tiered EC-GPA score showed good discrimination between all prognostic groups (log-rank test p < 0.05 for all pairwise comparisons). One-year survival was 0, 11, 30, and 100%, respectively. Median survival was 0.7 months (95% CI, 0.5–0.9) in the worst prognostic group, with a hazard ratio for death of 44.31 (95% CI, 5.78–339.50) compared to the best group. In the German database, the corresponding HR was 31.64 (median survival 0.4 months). The remaining hazard ratios in this validation study were 7.13 and 12.10, compared with 4.84 and 9.26 in the score development study. Conclusions: This study provides an independent validation of the EC-GPA, which was the best prognostic model for defining patients who did not benefit from radiation therapy of brain metastases in terms of overall survival in the original German study. The proposed modification of the established DS-GPA should undergo further validation in multi-institutional databases.

Challenges in the treatment of breast cancer brain metastases: evidence, unresolved questions, and a practical algorithm.

Breast cancer is the leading cause of brain metastases in women. Large randomized clinical trials that have evaluated local therapies in patients with brain metastases include patients with brain metastases from a variety of cancer types. The incidence of brain metastases in the breast cancer population continues to grow, which is, aside from the rising breast cancer incidence, mainly attributable to improvements in systemic therapies leading to more durable control of extracranial metastatic disease and prolonged survival. The management of breast cancer brain metastases remains challenging, even more so with the continued advancement of local and highly effective systemic therapies. For most patients, a metastases-directed initial approach (i.e., radiation, surgery) represents the most appropriate initial therapy. Treatment should be based on multidisciplinary team discussions and a shared decision with the patients taking into account the risks and benefits of each therapeutic modality with the goal of prolonging survival while maintaining quality of life. In this narrative review, a multidisciplinary group of experts will address challenging questions in the context of current scientific literature and propose a therapeutic algorithm for breast cancer patients with brain metastases.

Risk Of Post-Operative Stroke In Asymptomatic Patients With Known Extra-Cranial Carotid Artery Disease Undergoing Non-Cardiac Surgery

Risk Of Post-Operative Stroke In Asymptomatic Patients With Known Extra-Cranial Carotid Artery Disease Undergoing Non-Cardiac Surgery

Brain metastases treated with radiosurgery or hypofractionated stereotactic radiotherapy: outcomes and predictors of survival.

To assess treatment outcome and prognostic factors associated with prolonged survival in patients with brain metastases (BM) treated with stereotactic radiosurgery (SRS) or hypofractionated stereotactic radiotherapy (HFSRT). This study retrospectively reviewed 200 patients with 324 BM treated with one fraction (15-21Gy) or 5-10 fractions (25-40Gy) between January 2010 and August 2016. 26.5% of patients received whole brain radiotherapy (WBRT) and 25% initial surgery. Demographics, prognostic scales, systemic and local controls, patterns of relapse and rescue, toxicity, and cause of death were analyzed. A stratified analysis by primary tumor was done. Median overall survival (OS) was 8months from SRS/HFSRT. Breast cancer patients had a median OS of 17months, followed by renal (11months), lung (8months), colorectal (5months), and melanoma (4months). The univariate analysis showed improved OS in females (p 0.004), RPA I-II (p < 0.001) initial surgery (p < 0.001), absence of extracranial disease (p 0.023), and good disease control (p 0.002). There were no differences in OS or local control between SRS and HFSRT or in patients receiving WBRT. Among 44% of brain recurrences, 11% were in field. 174 patients died, 10% from confirmed intracranial progression. SRS and HSFRT are equally effective and safe for the treatment of BM, with no exceptions among different primary tumors. Disease control, surgery, age, and prognostic scales correlated with OS. However, the lack of survival benefit regarding WBRT might become logical evidence for its omission in a subset of patients.

Treating Brain Metastases from Breast Cancer: Outcomes after Stereotactic Radiosurgery

AimsStereotactic radiosurgery (SRS) is an alternative to surgery or whole brain radiotherapy for the control of single or multiple brain metastases in patients with breast cancer. To date, there is no clear consensus on factors that might predict overall survival following SRS. The aim of this study was to assess the overall survival of breast cancer patients with brain metastases treated with SRS at a single centre and to examine the factors that might influence survival. Materials and methodsA retrospective analysis of consecutive patients with breast cancer and brain metastases, considered suitable for SRS by the regional neuro-oncology multidisciplinary team. All patients were treated at a single National Health Service centre. ResultsIn total, 91 patients received SRS between 2013 and 2017, of whom 15 (16.5%) were alive at the time of analysis. The median overall survival post-SRS was 15.7 months (interquartile range 7.7–23.8 months) with no significant effect of age on survival (67 patients ≤ 65 years, 16.3 months; 26 patients > 65 years, 11.4 months, P = 0.129). The primary tumour receptor status was an important determinant of outcome: 31 oestrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2–) patients had a median overall survival of 13.8 months, 14 ER+/HER2+ patients had a median overall survival of 21.4 months, 30 ER–/HER2+ patients had a median overall survival of 20.4 months and 16 patients with triple negative breast cancer (TNBC) had a median overall survival of 8.5 months. A larger total volume of tumour treated (>10 cm3), but not the number of individual metastases treated, was associated with worse survival (P = 0.0002) in this series. Patients with stable extracranial disease at the time of SRS had improved overall survival compared with those with progressive extracranial disease (30 patients stable extracranial disease overall survival = 20.1 months versus 33 patients progressive extracranial disease overall survival = 11.4 months; P = 0.0011). Seventeen patients had no extracranial disease at the time of SRS, with a median overall survival of 13.1 months. ConclusionsThis single-centre series of consecutive patients with brain metastases from breast cancer, treated with SRS, had a similar overall survival compared with previous studies of SRS. TNBC and ER+/HER2– histology, metastatic volumes >10 cm3 and progressive extracranial disease at the time of SRS were associated with worse survival.

MYOCARDIAL INFARCTION FROM EXTERNAL COMPRESSION OF THE OSTIAL LEFT MAIN CORONARY ARTERY IN A PATIENT WITH MOYAMOYA DISEASE

Extracranial vascular disease in patients with Moyamoya disease is increasingly recognized, with a wide spectrum of observed coronary artery pathology. A 54-year-old female with a history of bilateral internal carotid artery occlusion and ischemic strokes due to Moyamoya disease, left external

Abstract P4-05-22: A systematic review of the receptor status and genomic landscape of breast cancer brain metastases

Abstract Introduction Breast cancer brain metastasis (BCBM) is a growing clinical problem common and one which is associated with significant morbidity and mortality. However the efficacy of systemic treatment is extremely limited and, at present, no systemic therapies are specifically approved for the treatment of BCBM. Given this there is a need to develop treatments. In the era of genomic medicine one avenue is to understand the specific genomic aberrations that are contained within brain metastasis with the aim of developing therapies specifically targeted at these aberrations. Several studies have undertaken DNA sequencing of BCBMs to understand the genomic landscape. The aim of this study was to perform a comprehensive systematic review of these sequencing studies to generate a compendium of genomic aberrations and their actionability, as well as receptor and PAM50 status switching where this was reported. Methods A systematic search of the literature was performed on the Web of Science databases encompassing MEDLINE and with the results screened. Additional potential studies were found by hand searching of the literature. The search terms were “breast AND brain AND metast* AND sequenc*”. Studies were required to be in English, be published before 31st May 2019 and have greater than 3 patients with sequenced BCBMs with data on point mutations of at least one gene contained within the article or supplementary information. Results 11 of 203 (5.4%) literature search results met the requisite inclusion criteria. These studies contained 147 patients (range per study 4-45); of which 111 (76%) had matched pairs of primary BC and BCBM. Paired Oestrogen receptor (ER) and HER2 status was available for 52 and 51 cases respectively. Receptor switching between primary tumour and BCBM occurred as follows: ER+ to ER- 3/16 (19%) compared ER- to ER+ 1/36 (3%); HER2+ to HER2- 3/17 (18%) and HER2- to HER2+ 4/34 (12%). Paired PAM50 data was available for only 20 cases and subtype switching occurred in 11 of 20 (55%) of cases; the biggest switch was from basal-like to normal like occurring in 44% (4 of 9). 160 previously identified genes were found to be mutated in at least 1 BCBM; with 16 genes mutated in &amp;gt;3 BCBM cases (ATR, BRAF, BRCA2, CDH1, EPPKL1, ERBB2, FLT3, ITPR1, KIT, LAMA5, MET, MLH1, PIK3CA, PTEN, RB1, TP53, ZFHX3). The commonest mutated genes were TP53 (n=64 cases), PIK3CA (n=30), MLH1 (n=7), RB1 (n=7) and ERBB2 (n=6). MLH1 was reported as mutated in 7 BCBM cases (actual point mutation only reported in one case). Data on actionability and amplifications will be presented as will differences in the genomic data between the primary and the BCBM where available. Conclusion This systematic review provides an overview of the currently published genomic literature regarding BCBM. It demonstrates that receptor switching is in keeping with previous studies. While PAM50 switching occurs in a significant number of cases and the implications of this for treatment need to be explored. Overall the genes that are mutated in BCBM are similar to those reported in extracranial disease with a number of these being targetable. While the finding of a mutations in MLH1 is a novel finding which warrants further investigation. These data highlight the potential importance of IHC and genomic assessment of BCBM. The value of treatment strategies targeting the actionable mutations need to be explored in the context of clinical trials. PAM50 status switching (Primaries in Rows, Metastases in Columns)LumA (M)LumB (M)HER2 (M)Basal-like (M)Normal-like (M)LumA (P)12200LumB (P)00000HER2 (P)10201Basal-like (P)00054Normal-like (P)00011 Citation Format: Alexander James Morgan, Athina Giannoudis, Carlo Palmieri. A systematic review of the receptor status and genomic landscape of breast cancer brain metastases [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-05-22.

Abstract P3-08-60: Patterns of development and prognostic factors in central nervous system metastasis according to breast cancer subtypes

Abstract Introduction: Central nervous system (CNS) metastasis are detected in approximately 10-30% of breast cancer (BC) patients, being associated with poor prognosis despite local and systemic therapeutics available. In the current study, we aimed to evaluate the association between BC subtypes and CNS metastasis development and prognosis. Methods: Retrospective analysis of 258 BC patients’ records with pathological and/or radiological documented CNS metastasis, treated at a Cancer Center between 2003-2019, median follow-up of 61 months (range: 0-351). For analysis purpose, three BC subtypes were considered according to hormone receptor status and HER-2 expression: luminal, HER-2 positive and triple negative. Survival was evaluated by Kaplan-Meier method and groups were compared with log-rank test. Independent prognostic factors were identified using Cox regression model. A p value &amp;lt; 0.05 was considered statistically significant. Results: Ninety four (42%) patients had HER-2 positive, 87 (39%) luminal and 41 (19%) triple negative disease. The median time between the diagnosis of BC and the detection of CNS metastasis was significantly shorter in triple negative group (18 months) compared to the others (HER-2 positive: 31 months; luminal: 54 months; p=0.001), and CNS was more often the first site of recurrence (with or without concomitant extracranial disease progression) in this group (triple negative: 25 (61%) vs. HER-2 positive: 31 (33%) vs. luminal: 27 (31%); p=0.002). Most of the patients had parenchymal metastasis (n=245), being exclusively parenchymal in 227 (88%), and 31 (12%) had leptomeningeal (LM) disease, that was isolated in 13 (5%). More than half (n=136) had multiple (&amp;gt;3 lesions) CNS metastasis, without differences between BC subtypes. Among the patients with LM disease, 17 (68%) had luminal tumors, 5 (20%) HER2-positive and 3 (12%) triple negative (p=0.007). Forty five patients (17%) were treated with surgery for CNS metastasis, with similar proportions between BC groups. In the patients submitted to CNS surgery, the concordance between primary tumor and metastasis subtype was higher in HER-2 positive (73%) compared to 57% in triple negative and 50% in luminal groups (p=0.004). After CNS involvement, 62% (n=24) of patients with triple negative disease did not receive any systemic therapy, compared to 44% (n=37) in luminal and 33% (n=29) in HER-2 positive groups (p=0.010). Median survival after CNS metastasis documentation was longer in HER-2 positive group (27 months vs. luminal: 18 months vs. triple-negative: 14 months, p=0.004) and also in patients submitted to surgical resection of CNS metastasis (38 months vs. 6 months in other treatment modalities). In multivariate Cox regression analysis, having HER-2 positive tumor was an independent prognostic factor for increasing survival after CNS metastasis (HR 0.62, 95% CI: 0.47-0.84, p=0.002), regardless the therapeutic strategy. Conclusions: Pattern of CNS metastasis development and prognosis varies according to BC subtype. The association between LM disease and luminal tumors should be explored in future studies. Treatment modalities also play a decisive role in the prognosis of this patients, therefore, new and effective therapeutic strategies are needed. Citation Format: IoIanda Vieira, Miguel Abreu, Tiago Alpoim, Isabel Pereira, Susana Sousa, Isabel Azevedo, Machado Carvalho, Deolinda Pereira. Patterns of development and prognostic factors in central nervous system metastasis according to breast cancer subtypes [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-60.

Abstract P4-12-03: Patterns of progression in metastatic breast cancer: Does oligoprogression exist?

Abstract Background: While most patients with metastatic breast cancer (MBC) experience widespread disease progression on systemic therapy (ST), some have more limited progression, termed oligoprogression (OP). Patients with OP may benefit from local ablative therapies, such as stereotactic body radiation therapy (SBRT)/stereotactic radiosurgery (SRS), in order to avoid changing to the next line of ST. Here, we aim to evaluate patterns of progression in patients with MBC by breast cancer subtype (hormone-receptor positive/HER2- [HR+/HER2-], HER2+, and tripe-negative [TN]) to determine if and how often OP occurs. We hypothesize that OP does occur, and that it is more likely to occur in the HR+/HER2- and HER2+ BC subtypes compared to the TN subtype. Materials/Methods: We identified patients seen at our breast center from 1/2013-12/2017 with an associated ICD9/ICD10 code for metastases. We excluded patients that: did not have MBC; did not receive at least part of their treatment course for MBC at our institution; did not have imaging available for review. For the remaining cases, we reviewed each point at which a change in management was made to determine if OP of diffuse progression (DP) occurred. We defined OP as progression of disease in 1-4 lesions, with the exception of brain metastases, in which up to 10 lesions were allowed (provided patients received SRS and not whole brain radiation therapy). Findings such as malignant effusions, ascites, leptomeningeal disease, and lymphangitic/peritoneal carcinomatosis were scored as DP, regardless of the stability of other lesions. In addition, we collected demographic, tumor and treatment information. We set to determine the overall rate of OP and to compare the rate of OP amongst the HR+/HER2-, HER2+, and TN subtypes using a chi-square test. We also set to compare the overall survival in patients with OP vs. DP using the Kaplan-Meier method. A p-value&amp;lt;0.05 was considered significant. Results: The query yielded a set of 1931 patients, of which 1017 met all inclusion criteria. This included 647 HR+/HER2- (63.6%), 187 HER2+ (18.4%), and 183 TN (18.0%) patients. About 29% (N=292) presented with de novo metastatic disease. Amongst patients with a distant metastatic recurrence, the median time to development of metastases was 49 months (interquartile range [IQR], 26-104 months) from original diagnosis. The median age at diagnosis of metastatic disease was 57 years (IQR=47-64 years). Most presented with &amp;gt;4 metastases (84%). The median lines of ST for all patients was 3 (IQR=1-4). The crude rate of OP was 30% (N=306) and was highest amongst the HER2+ subtype (46.5%, 87/187) followed by HR+/HER2- (27.5%, 178/647) and TN (22.4%, 41/183), p&amp;lt;0.0001. Intracranial metastases were seen as the only site of disease in 68 patients (40 HER2+, 20 HR+/HER2-, 8 TN) and with OP extracranial disease in 5 additional patients (3 HR+/HER2-, 2 HER2+). OP disease in the breast/axilla occurred as an isolated event in 28 patients (9.4%) and as a component of extracranial OP in 4 patients. Excluding the 32 patients with disease in the breast/axilla, nearly 90% of patients could potentially receive SBRT/SRS to the OP disease sites. Median follow-up for all patients was 32 months (IQR, 18-55 months) and at last follow-up, 866 of the 1017 patients had experienced at least one progression event. The 3-yr OS rate was 72.1% vs. 37.3% for patients in OP vs. DP groups, respectively (p&amp;lt;0.0001). Conclusion: In summary, we found that OP does occur in MBC patients. The rate of OP is approximately 2-fold higher in HER2+ patients compared to TN and HR+/HER2- patients, reflected by a higher rate of intracranial OP disease. Nonetheless, all groups experienced an OP rate&amp;gt;20% and the majority have disease potentially amenable to SBRT/SRS. These data serve to inform and support the development of prospective clinical trials evaluating the role of SBRT/SRS for oligoprogressive MBC. Citation Format: Jose G Bazan, Amber Holbrook, Sachin Jhawar, Julia R White. Patterns of progression in metastatic breast cancer: Does oligoprogression exist? [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-12-03.

Abstract OT2-01-02: TBCRC049: A phase II non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab and capecitabine for treatment of leptomeningeal metastases in HER2 positive breast cancer TBCRC049: A phase II non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab and capecitabine for treatment of leptomeningeal metastases in

Abstract Background: Treatment options for patients with leptomeningeal disease (LMD) from HER2-positive breast cancer (HER2+ BC) are limited, and the prognosis is poor. Tucatinib is an oral, potent, HER2 specific tyrosine kinase inhibitor with good tolerability and notable early combinatory anti-tumor activity, including partial responses in heavily treated patients and those with parenchymal brain metastases (BM). Trial Design: This is a phase 2 single arm study to evaluate the efficacy of the combination of tucatinib plus trastuzumab (T) and capecitabine(C) in patients with HER2+ BC and newly diagnosed LMD. CNS disease will be evaluated at screening and every six weeks by MRI, CSF cytology, and neurological assessments according to RANO-LMD (adapted) and RANO-BM criteria. CT scans/PET-CT will evaluate extracranial disease according to RECIST criteria at screening and every 12 weeks. All patients will be followed for survival from the date of the last dose until death, lost to follow-up, or consent withdrawal. Symptom burden and quality of life assessments are conducted throughout the study. Blood and CSF sample collections occur at each cycle for the planned correlative analyses. Eligibility Criteria: Eligible patients are adults (&amp;gt;18 years old) with HER2+ BC, ECOG status&amp;lt;3/KPS&amp;gt;50, and newly diagnosed untreated LMD (defined as positive CSF cytology and/or radiographic evidence of LMD, plus clinical signs/symptoms. Patients with a history of treated BM or concurrent/new BM are allowed. Patients previously treated with tucatinib or capecitabine (within the last 12 months) are excluded. Specific Aims: The primary endpoint is OS. Secondary endpoints include safety, CNS PFS at 12 weeks, RR and CBR in CNS and extra-CNS disease, and symptom burden/quality of life. Statistical methods: This study has a Gehan-like design with an interim futility analysis and overall intent to estimate OS. For the interim analysis, we define success to be CNS PFS for 12 weeks. An event will be considered to be either CNS progression or death from any cause before 12 weeks.We will stop enrollment if there are fewer than two successes in the first 15 patients. If the trial continues to completion, the regimen will be considered worthy of future study if the median overall survival is &amp;gt; 4.4 months. Study Accrual: The target accrual is 30 patients. The study is currently active at UAB and MDACC. Other TBCRC sites throughout the country are to be activated this year. Citation Format: Rashmi K Murthy, Barbara J O'Brien, Ken R Hess, Nick Navin, Jason Johnson, Maria Gule-Monroe, Jose P Leone, Jennifer Specht, Michelle Melisko, Aki Morikawa, Anna M Storniolo, Adam Brufsky, Paula R Pohlmann, Deric M Park, Ben H Park, Ian Krop, Nancy U Lin, Antonio Wolff, Andres Forerro-Torres, Erica Stringer-Reasor. TBCRC049: A phase II non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab and capecitabine for treatment of leptomeningeal metastases in HER2 positive breast cancer TBCRC049: A phase II non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab and capecitabine for treatment of leptomeningeal metastases in HER2 positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-01-02.