Initial Metastatic Site Research Articles

Disease progression of metastatic breast cancer by first relapse site after definitive radiotherapy.

36 Background: Bone metastasis as initial distant relapse is commonly considered to have better prognosis than other sites in metastatic breast cancer. To elucidate true clinical course of metastatic disease, it is essential that we prospectively manage patients since primary setting. Methods: Overall, 3,417 patients with breast cancer treated with mastectomy (n = 379, 11.1%) or breast-conserving surgery (n = 3,029, 88.6%) followed by definitive radiotherapy at two institutions in Center of Tokyo between 1980 and 2014 were included in the study. Information on all patients was prospectively collected and rigorously-controlled. Initial metastatic relapse sites included bone, brain, and other (mainly visceral). Intrinsic subtypes of tumor were classified as luminal A, luminal-human epidermal growth factor receptor 2 (HER2), luminal B, triple negative, and HER2 identified by routine immunohistochemistry and histological grade. Cumulative incidence rates of overall survival (OS) for each affected site after metastatic relapse were estimated according to Kaplan-Meier method. Results: Median follow-up time for living patients was 113 months. A total of 370 patients experienced metastatic progression as first relapse event. Median duration of OS after initial metastatic relapse was 69 month in all subtypes. No difference was seen in OS among five subtypes after initial bone or brain relapse. Meanwhile, OS of luminal subtypes after initial other-site relapse was better than that of triple negative and HER2 subtypes (P = .003). Notably, OS rates of bone and non-bone/brain metastasis groups as initial relapse site were almost identical (P= .626). Conclusions: We find no difference in mortality after metastatic relapse between bone and other site except for brain metastasis as initial relapse in breast cancer patients following definitive radiotherapy in our cohort without primary metastatic setting. Careful consideration is needed for initial distant relapse regardless of which site is involved. However, prognosis of metastatic breast cancer after definitive radiotherapy is favorable based on real world data, attributable mainly to improved systemic therapy and modern multidisciplinary approach.

Prognostic analysis of patients with metastatic triple-negative breast cancer: a report of 120 cases

To analyze the clinical features and survival for patients with metastatic triple negative breast cancer (MTNBC), especially such a metastatic site as brain. The clinical data and survival status of 120 cases of operable MTNBC treated at our hospital from January 2002 to December 2004 were collected. SPSS 13.0 software was used for statistic treatment. Statistical significance was considered at P < 0.05. At the time of last follow-up, the median time after metastasis was 22 months. Nine deaths (65.8%) were recorded. In terms of all metastatic sites (initial + subsequent), lung (58.3%), liver (41.7%) and brain (40.8%) were most common sites. The patients with brain metastasis had a worse survival than those with non-brain metastases. Twenty-two (18.3%) patients were found to have brain metastasis at the time of first metastatic presentation. The initial metastatic site in patients with brain metastasis had a worse survival than those with non-brain metastases. The median survival time after metastasis was 8 and 31 months respectively (P = 0.000). Triple-negative breast cancer is associated with a poor survival after metastases. The patients with brain metastases have a worse survival than those with non-brain metastases. New treatment strategies are needed.

Initial Metastatic Site as a Prognostic Factor in Patients With Stage IV Pancreatic Ductal Adenocarcinoma.

Few studies have evaluated the presence of hepatic or peritoneal metastasis as a prognostic factor in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). This study aimed to elucidate the prognostic value of the initial metastatic, extrahepatic, or hepatic site in patients with metastatic PDAC.Between January 2007 and December 2013, the medical records of 343 patients with metastatic PDAC treated at Seoul National University Bundang Hospital were retrospectively reviewed. Patients were classified as having extrahepatic metastasis alone (EH), hepatic metastasis alone (LV), and both hepatic and extrahepatic metastasis (BOTH).The median age was 67 years; 207 patients were men. Patients were classified as having EH (111 patients), LV (106), and BOTH (126). Totally, 212 patients underwent chemotherapy with a FOLFIRINOX (23 patients) or gemcitabine-based regimen (189). On multivariate analysis, an ECOG score ≥2 (hazard ratio [HR]: 3.2, 95% confidence interval [CI]: 2.2–4.5), albumin < 35 g/L (HR: 1.6, 95% CI: 1.1–2.3), C-reactive protein > 10 mg/L (HR: 2.3, 95% CI: 1.6–3.2), neutrophil-lymphocyte ratio > 5 (HR: 1.4, 95% CI: 1.0–2.0), no chemotherapy (HR: 2.0, 95% CI: 1.0–4.1), and metastatic site (LV, HR: 2.1, 95% CI: 1.4–3.1; BOTH, HR: 2.2, 95% CI: 1.6–3.2) were significantly associated with shorter overall survival (OS). Considering the initial metastatic site, the median OS of patients with EH, LV, and BOTH were 7.5 (95% CI: 6.3–8.8), 4.8 (95% CI: 4.1–5.5), and 2.4 (95% CI: 1.9–2.9) months, respectively.The initial metastatic site is significantly and independently associated with OS in patients with metastatic PDAC, serving as an effective prognostic factor.

Abstract P3-07-23: Patient characteristics, clinical and economic outcomes of women with first-line therapy for HR+/HER2- metastatic breast cancer in a large US managed care health plan: Chemotherapy first vs. no chemotherapy first

Abstract BACKGROUND: NCCN guidelines clearly identify when chemotherapy may be an appropriate therapeutic approach for metastatic breast cancer (mBC). This study compared patient characteristics, mortality rates, and health care costs by initial chemotherapy (CT) use among women with HR+/HER2- mBC. METHODS: A retrospective cohort study design was used to analyze administrative claims data linked to clinical information for commercial health plan enrollees with evidence of mBC between 1/2008 and 4/2013. Clinical status at diagnosis was obtained from physician reports, including date of diagnosis, hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Women with known HR+/HER2- subtype and diagnosed initially with Stage IV or Stages I-III with evidence of progression later to metastatic disease were evaluated for at least 6 months after their Stage IV diagnosis or first metastatic claim, or until death if sooner. Clinical characteristics were compared descriptively between women who initiated therapy with/without chemotherapy (CT 1st vs. no CT 1st, respectively) using t-test for continuous and chi-square test for categorical variables. Mortality was compared using the incidence rate ratio (IRR) and 95% confidence interval (CI) from a negative binomial distribution. Total average per-member-per-month (PMPM) health care costs were compared using a generalized linear model. Both the mortality rates and costs were adjusted for age, geographic region, stage at diagnosis, initial metastatic site(s), and initial use of CT. RESULTS: Of 349 women with HR+/HER2- mBC, 204 (58%) had CT 1st and 145 (42%) had no CT 1st. Median follow-up was 17 months, and median length of the first-line of therapy (1st LOT) was 4 months (including censored LOTs). The mean age of women with CT 1st was slightly lower than those without CT 1st (52 vs. 55 years, p&amp;lt;0.01), although the proportion ≥ 50 years old did not differ between cohorts (35% vs. 28%, p=0.14). Cohorts did not differ by geographic region or initial metastatic site(s) to brain, liver, or lung. Compared to women without CT 1st, a lower proportion of women with CT 1st were diagnosed de novo Stage IV (34% vs. 48%, p=0.01). Among women with CT 1st, 24 (12%) also received hormonal therapy (HT) during their 1st LOT. All women with no CT 1st (100%) initiated treatment with HT, of which the most common were 52 (36%) with tamoxifen, 41 (28%) with anastrozole, and 39 (27%) with letrozole. After adjustment for baseline characteristics, no cohort differences were found in mortality (IRR: 0.93, 95% CI: 0.50-1.72), however adjusted total average PMPM costs were significantly higher in women with CT 1st than those without ($11,666 vs. $6,639, p&amp;lt;0.001). CONCLUSION: In this study of commercially insured women with HR+/HER2- mBC, use of CT 1st (&amp;gt;50%) was higher than expected. While there were minor cohort differences in patient characteristics, CT 1st does not appear to be associated with a survival benefit, but was associated with significantly higher costs when compared to no CT 1st. Additional research is needed to determine subset(s) of mBC women with CT 1st likely to benefit from initial HT. Citation Format: Tanya Burton, Stacey DaCosta Byfield, Ying Fan, Yiyu Fang, Feng Cao, Gregory L Smith, Giovanni Zanotti, Timothy J Bell, Julia J Perkins, Ruslan Horblyuk, April Teitlebaum. Patient characteristics, clinical and economic outcomes of women with first-line therapy for HR+/HER2- metastatic breast cancer in a large US managed care health plan: Chemotherapy first vs. no chemotherapy first [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-07-23.

Tu1948 Initial Metastatic Site As a Prognostic Factor in Patients With Stage IV Pancreatic Adenocarcinoma

Tu1948 Initial Metastatic Site As a Prognostic Factor in Patients With Stage IV Pancreatic Adenocarcinoma

Predictors of long-term survival with metastatic pancreatic cancer (mPC) in the gemcitabine era: The Fox Chase Cancer Center experience.

253 Background: Although median survival (OS) for patients (pts) with mPC was ~6 months (m) in the gem era, a subset of pts lived significantly longer as long term survivors (LTS). We compared the patterns of care and outcomes of pts living &lt; 12 m (Gp 1) and ≥ 12 m (Gp 2) to identify predictors for LTS. Methods: With IRB approval, we retrospectively analyzed medical charts of mPC pts treated at our center between 2000 and 2010. Gp 1 and Gp 2 were compared with respect to pt, tumor and treatment characteristics. Fisher’s exact and Mann-Whitney tests were used, respectively, to compare categorical and continuous variables, and the log-rank test to compare OS. All tests were two-sided and a Type I Error of 5% was used to determine statistical significance. Results: 579 mPC pts (median age 64 y, 56% males) were identified, 476 pts in Gp1 and 103 in Gp 2 (OS 4m vs 18 m, respectively). There was no significant difference in the age, site of pancreatic primary, comorbidities, tobacco use or stage at diagnosis between the two. 341 (72%) pts in Gp1 and 86 (83%) in Gp 2 had an initial PS &lt;2 (p 0.06). Alcohol use was more prevalent in LTS [170 (36%) in Gp1 vs 50 (49%) in Gp2 (OR 1.8, p 0.008)]. 170 (36%) pts in Gp 1 and 55 (52%) in Gp 2 had serum albumin (alb) &gt; 3.5 gm/dl (p&lt; 0.001) and this predicted survival (OS 4m if Alb &lt; 3.5 and 7m if Alb &gt; 3.5, p &lt;0.001). Use of chemotherapy in the metastatic setting (66% in Gp1 vs 93% in Gp 2) and number of agents used also predicted survival with 202 (42%) pts in Gp 1 and 79 (87%) in Gp 2 having received &gt; one agent in the metastatic setting (p &lt; 0.001). Liver metastases were more common as an initial site in Gp1 vs Gp2 [329 (70%) vs 48 (47%) respectively, p &lt; 0.001]. In contrast, lung metastases were more common in Gp 2 [42 (9%) Gp 1 vs 20 (19%) in Gp 2, p&lt; 0.001]. The median survival for pts with liver as initial metastatic site was worse than those with lung metastases (5m vs 7m, p &lt; 0.001). Conclusions: Use of chemotherapy and increasing number of agents are associated with better survival in mPC, in line with the current practice of using combination chemotherapy. The site of initial metastasis and serum albumin also predict for survival. Clinical trial designs should consider the latter as stratification factors.

Cerebellum as Initial Site of Distant Metastasis from Papillary Carcinoma of Thyroid: Review of Three Cases.

Background. The cerebellum as initial site of distant metastasis from differentiated thyroid carcinoma (DTC) including papillary (PTC) and follicular thyroid carcinoma (FTC) is rare manifestation. Case Presentations. Herein, we present three cases of cerebellar metastasis (CBM) of PTC. Mean age of patients was 67 years (range: 64–72), and mean duration between initial diagnosis and CBM was 49.6 months (range: 37–61). Frequent location was left cerebellar hemisphere and was associated with hydrocephalus. All patients underwent suboccipital craniectomy, and in two patients postoperative intensity modulated radiation therapy (IMRT) was given to deliver 5000 cGy in 25 fractions to residual lesions. Patient without postoperative IMRT had cerebellar recurrence along with lung and bone metastasis after 38 months. However, two patients were found alive and free of disease at the time of last follow-up. Conclusion. CBM from PTC is a rare clinical entity and is often associated with hydrocephalus. Histopathological diagnosis is important to initiate effective treatment, which relies on multidisciplinary approach to prolong the disease-free and overall survival rates.

Prospect and guideline update of sentinel lymph node biopsy for patients with early-stage breast carcinoma

Axillary lymph nodes are the most common and initial site of metastasis of breast carcinoma. Precise axillary staging of breast carcinoma before initial treatment is crucial as it allows efficient identification for local and systemic treatment options, and provides prognostic information. Sentinel lymph node biopsy (SLNB) is an accurate minimally invasive technology for axillary staging. Although top evidence of high-quality clinical trials showed that SLNB could safely and effectively replace axillary lymph node dissection (ALND) for axillary negative patients with decrease in complications and improvement in quality of life, there are specific indications and contraindications for SLNB. Clinicians should balance the compliance of guideline and native clinical practice, especially for the circumstance of multifocal/multicentric lesion, breast biopsy history, and neoadjuvant chemotherapy. With the accumulation of clinical practice and new results of clinical trials, axillary therapy has changed from unique surgery to patient-tailored multi-disciplinary intervention, although ALND should be recommended traditionally if SLNB is positive. Intensive and accurate preoperative axillary staging is gradually valued by clinicians. Development of imaging modality especially ultrasonography and ultrasound-guided biopsy can identify some extra lymph node positive patients directly to ALND with avoidance of unnecessary SLNB. Thus, the positive rate of SLNB will decline significantly. It seems possible that axillary management will step into a noninvasive era abandoning SLNB in some patients with small breast cancer. In this article we review the prospect and guideline update of SLNB for patients with early-stage breast cancer.

L’inhibition du RANK Ligand dans le traitement médical des métastases osseuses

Bone is the most common metastatic site. The skeleton is also the preferential initial metastatic site in breast and prostate carcinomas. Objective complications of bone metastases are named « skeletal-related events » (SREs) and generally include the need for radiotherapy on bone, surgery to bone, pathologic fracture and spinal cord compression. Recent phase III double-blind trials have demonstrated the superiority of denosumab to zoledronic acid for delaying the time to first SRE in patients with breast or prostate cancer and bone metastases. Non-inferiority was shown in the trial including other solid tumors and multiple myeloma. The overall burden of the disease was also significantly reduced in the breast and prostate cancer studies, and in the pre-specified integrated analysis that included all three comparative trials. Denosumab is conveniently administered by subcutaneous injections and is devoid of renal toxicity. However, denosumab induces more cases of hypocalcaemia than zoledronate. Calcium and vitamin D supplementation is recommended during therapy and it is advised to regularly monitor calcium levels during denosumab long-term treatment. There are numerically more cases of osteonecrosis of the jaw, but the differences are not statistically significant between zoledronate and denosumab, whether in the individual studies or in the integrated analysis. Treatment with these potent inhibitors of bone resorption should be progressively ‘individualized’ to better define the place of intermittent treatments, to decrease the occurrence of toxic effects and to improve the cost-effectiveness ratio of new compounds.

Prognosis of metastatic breast cancer subtypes: the hormone receptor/HER2-positive subtype is associated with the most favorable outcome

Contrary to the situation in early breast cancer, little is known about the prognostic relevance of the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) in metastatic breast cancer. The objectives of this study were to present survival estimates and to determine the prognostic impact of breast cancer subtypes based on HR and HER2 status in a recent cohort of metastatic breast cancer patients, which is representative of current clinical practice. Patients diagnosed with metastatic breast cancer between 2007 and 2009 were included. Information regarding patient and tumor characteristics and treatment was collected. Patients were categorized in four subtypes based on the HR and HER2 status of the primary tumor: HR positive (+)/HER2 negative (-), HR+/HER2+, HR-/HER2+ and triple negative (TN). Survival was estimated using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic impact of breast cancer subtype, adjusted for possible confounders. Median follow-up was 21.8 months for the 815 metastatic breast cancer patients included; 66% of patients had the HR+/HER2- subtype, 8% the HR-/HER2+ subtype, 15% the TN subtype and 11% the HR+/HER2+ subtype. The longest survival was observed for the HR+/HER2+ subtype (median 34.4months), compared to 24.8months for the HR+/HER2- subtype, 19.8months for the HR-/HER2+ subtype and 8.8months for the TN subtype (P<0.0001). In the multivariate analysis, subtype was an independent prognostic factor, as were initial site of metastases and metastatic-free interval. The HR+/HER2+ subtype was associated with the longest survival after diagnosis of distant metastases.

Stereotactic Body Radiation Therapy (SBRT) and Image Guided Accelerated Hypofractionated Radiation Therapy (IGAHRT) for the Treatment of Oligometastatic Cancers

Data in support of aggressive treatment of oligometastatic cancers is still relatively modest in scope. We report our experience treating single or multiple sites, as well as outcomes for patients receiving sequential treatment during the course of their disease. Patients treated between 2009 and 2011 with stereotactic body radiation therapy [SBRT] or image-guided accelerated hypofractionated radiation therapy [IGAHRT] for metastatic cancer were screened and included. Patients were treated using an SBRT technique, with a stereotactic body-fixation device and abdominal compression for immobilization during non-spine treatment. SBRT was defined as 1 to 5 fractions (fxs) with a minimum of 9 Gy/fxs. IGAHRT was defined as 6 to 10 fxs and minimum 5 Gy/fxs. 4D CT was used to define an ITV with a 5 mm PTV expansion. Toxicities were recorded per NCI CTCAE v4.0. Kaplan Meier estimates were performed for local control (LC) and overall survival (OS). A Wilcoxon log-rank test was used for comparison. Fifty-seven patients (pts) were treated for oligometastatic cancer (AJCC 7th ed), 2009-2011. Represented histologies included lung (15 pts), GI (16 pts), sarcoma (6 pts), breast (4 pts), head and neck (H&N) (10 pts), and renal (6 pts). Initial metastatic sites treated included lung (36 pts), liver (8 pts), spine (6 pts), adrenal gland (5 pts), lung/liver (1 pt), and lung/adrenal (1 pt). SBRT/IGAHRT dose by site are as follows: lung 26-54 Gy, 1-10 fxs; liver 45-54 Gy, 3-10 fxs; spine 24-50 Gy, 1-10 fxs; adrenal 50 Gy, 10 fxs. The most common IGAHRT dose was 50 Gy/10 fxs. Median follow-up was 19 months (range, 1-43 months) from treatment. 43 pts received chemotherapy prior to SBRT/IGAHRT. 29/57 pts were treated to multiple lesions during a single course. 12/57 pts were treated with several single courses over 36 m, with a maximum of 3 courses. Two yrs LC was 86% (95% CI 70-95%). Median and 2 year OS from diagnosis of metastatic disease were 55 m and 75% respectively. Median OS from first SBRT/IGAHRT was 35 m for all pts, 35 m for lung cancer pts, 29 m GI, 23 m for breast, 13 m for sarcoma, and was not reached in H&N/renal pts. Median OS for lung site vs all other sites was not reached vs 13.5 months (p = 0.01). Two-yr OS for lung site vs all others: 74% vs 43%. Median OS for single vs multi-target: not reached vs 27 months (p = 0.06); Median OS for single SBRT vs multiple courses: 29 m vs 39 m (p = 0.21). No grade 4 or 5 toxicity noted. In these highly selected patients with oligometastatic cancers, multiple courses of SBRT/IGAHRT were used with durable local control. Prolonged survival from original metastatic diagnosis suggests favorable selection bias. Patients with metastasis to lung had superior outcomes when compared to other sites. Patients with multiple lesions during single course tended to fair worse. Additional prospective study is warranted.

Graded prognostic assessment index for renal cell carcinoma with brain metastases.

e15537 Background: The GPA is a commonly used prognostic index based on RTOG protocols in patients with brain metastases (BM). The purpose of this study was to evaluate the utility of GPA index in a contemporary cohort of renal cell carcinoma with brain metastases (RCCBM) at a larger tertiary care center to predict overall survival. Methods: IRB approval was obtained and the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify RCCBM patients (pts) treated in the recent era (2000-12). A proportional hazards model was used to assess OS, which was measured from the date of diagnosis of brain metastases to death or last follow-up. Results: 136 RCCBM (100 males), median age 60 years (range 32-79), were evaluated. Pts had a median of 2 (range 1-15) BM; Karnofsky Performance Scale (KPS) was 90-100 in 57%, 70-80 in 38% and &lt;70 in 5%. Extracranial metastasis was present in 93% of pts. OS was 15.0 months (95% C.I. 10.9-17.5). GPA for RCC consists of KPS (90-100, 70-80, &lt;70) and the number of BM present (1, 2-3, &gt;3).GPA was not prognostic for survival (p=.40), and neither GPA coding of KPS nor BM (1, 2-3, &gt;3) was associated with outcome (p=.90 and .26, respectively). In contrast, diagnosis of RCC to BM &gt;5 years, p=.004, brain as an initial site of metastasis, p=.005, normal hemoglobin, p=.01, a single BM, p=.02, controlled primary, p=.02, and age≤65 were found to be independently prognostic for improved OS. Using these factors, an alternative index can be formed. Conclusions: RCCBM specific GPA was notprognostic for OS in this study (p=.40), however a new index was developed based on a revised set of independent prognostic factors that was significant (p&lt;.0001). [Table: see text]

Abstract P3-12-06: Clinicopathological Analysis of Breast Cancer Patients with Brain Metastases

Abstract Background: Recent advances in chemotherapy have enabled to control the progression of metastases from breast cancer except for the brain, highlighting the symptoms associated with brain metastases. In addition, improvement in our understanding of breast cancer biology changed the treatment strategy, possibly leading to improved outcomes in patients with breast cancer and brain metastases. Object: The aim of this study was to investigate the correlation between biology of primary tumors and prognosis of patients with breast cancer metastasis to the brain. Patients and method: Among 3,171 patients with primary breast cancer undergoing surgery at out hospital from 2003 to 2010, 35 patients (1.1%) who developed brain metastases, excluding stage IV at the initial diagnosis. We reviewed 35 patients for a correlation between survival and clinicopathological variables, including stage, hormonal sensitivity, HER2 expression status, the number of brain metastases, and treatment for brain metastases. Results: The mean age of 35 patients was 52.1 years (range 22–68) and the median follow-up period was 41.0 months. The subtypes of primary tumors included triple-negative (TN) in 14 patients (40%), luminal in 11 patients (31.4%), luminal HER2-positive (luminal HER2) in 2 patients (5.7%), and HER2-positive (HER2) in 2 patients (5.7%). The duration from surgery to recurrence (disease-free survival, DFS, months) was 14.7 in TN, 26.5 in luminal, 29.8 in luminal HER2, and 31.0 in HER2. The duration from the first recurrence to the detection of brain metastases (months) was 7.2 in TN, 14.4 in luminal, 15.8 in luminal HER2, and 4.0 in HER2. The mean survival time after the diagnosis of brain metastases was 8.6 months (range, 0–40) with a survival time of ³ 1 year in 8/35 patients (23%) and that of &amp;lt; 1 year in 21/35 patients (60%). Both DFS and the duration from the first recurrence to the diagnosis of brain metastases were shorter in TN compared with other subtypes. In HER2 subtype, DFS was long but, once recurrence was detected, the duration to the development of brain metastases was short. In multivariate analysis of clinicopathological variables (age, DFS, ER, HG, HER2, the number of brain metastases (solitary versus multiple), the site of initial metastasis (brain versus other organs), and the presence or absence of chemotherapy after brain metastases, revealed solitary brain metastasis (p = 0.002) and the initial metastatic site of brain (p = 0.003) to be independent factors predicting survival. Conclusion: The clinical outcomes of brain metastases were different among tumor subtypes. Factors predicting survival in patients with breast cancer and brain metastases may be the site of initial metastasis, the number of brain metastasis, and local treatment for brain metastases. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-12-06.

O3-029 - Time to Brain Metastasis (TTBM) from Initial Diagnosis of Distant Metastasis in Breast Cancer: Prediction of TTBM According to Breast Cancer Subtypes and Treatment Effect

ABSTRACT Background Brain metastasis (BM) from breast cancer (BC) is a growing problem. About 10–15% patients with metastatic breast cancer (MBC) developed BM, with a 1-year survival of 20%. Currently, one-third of MBC patients with either HER2 + ve tumors or triple negative BC (TNBC) tumors develop brain metastases. We hypothesized that MBC patients may predispose to BM differently during the disease courses according to BC subtype and treatment. We analyzed TTBM from initial diagnosis of distant metastasis how BC subtypes and treatment affect on TTBM. Methods We retrospectively investigated 189 consecutive patients who were diagnosed with BM from BC between 2000 and 2009 at Samsung Medical Center. We analyzed TTBM according to BC subtypes and treatment effect. Results The median age of 189 BM patients from BC was 48 (range 26–87) years. The numbers of patients with hormone receptor (HR) + ve and HER2-ve, HER2 + ve irrespective of HR status, and TNBC were 43 (22.8%), 88 (46.6%), and 58 (30.7%), respectively. Median TTBM of all 189 patients was 10.4 (95% CI, 7.7–13.1) months. We analyzed TTBC into four groups considering BC subtypes and treatment; HR + ve/HER2-ve (n = 43), HER2 + ve with trastuzumab (T) (n = 59), HER2 + ve without T (n = 29), and TNBC patients (n = 58). The median TTBMs for each group were 17.7, 13.8, 4.3, and 2.9 months, respectively (P = 0.002). BM as an initial site of distant metastasis was much more common in HER2 + ve without T and TNBC patients than in the other patient groups (40.2% versus 20.6%, P = 0.003). Conclusions TTBMs were much shorter in patients with HER2 + ve without T and TNBCs than in other BC patients. Different approaches for evaluation and therapeutic strategy for BM at the time of distant metastasis may be considered for these populations.

Different metastatic pattern according to the KRAS mutational status and site-specific discordance of KRAS status in patients with colorectal cancer

BackgroundWe evaluated the association between a KRAS mutational status and various clinicopathologic features including the metastatic pattern in patients with metastatic or recurrent colorectal cancer (MRCRC). The concordance rates of the KRAS status between primary tumor sites and paired metastatic organs were also analyzed.MethodsThe KRAS mutational status in codons 12, 13, and 61 from formalin-fixed sections of both primary tumors and related metastases was determined by sequencing analysis. One hundred forty-three Korean patients with MRCRC with available tissues (resection or biopsy) from both primary tumors and related metastatic sites were consecutively enrolled.ResultsThe KRAS mutation rate was 52.4% (75/143) when considering both the primary and metastatic sites. When the relationship between the KRAS status and initial metastatic sites at the time of diagnosis of MRCRC was analyzed, lung metastasis was more frequent as the initial metastatic site in patients with the KRAS mutation than in patients without the KRAS mutation (45.3% vs. 22.1%; P = 0.003). However, liver (37.3% vs. 70.6%; P < 0.001) or distant lymph node metastases (6.7% vs. 19.1%; P = 0.025) were less frequent as the initial metastatic organ in patients with the KRAS mutation than in patients without the KRAS mutation. The discordance rate of KRAS mutational status between primary and paired metastatic sites other than the lung was 12.3% (13/106). Compared with primary tumor sites, the KRAS discordance rate was significantly higher in matched lung metastases [32.4% (12/37)] than in other matched metastatic organs (P = 0.005).ConclusionsOrgans initially involved by distant metastasis were different according to the KRAS mutational status in MRCRC patients. The concordance rate (87.7%) of the KRAS mutation status at metastatic sites other than the lung was generally high compared with primary tumor sites; however, lung metastasis had a high rate of KRAS discordance (32.4%).

Immune response in melanoma: an in-depth analysis of the primary tumor and corresponding sentinel lymph node

AbstractThe sentinel lymph node is the initial site of metastasis. Downregulation of antitumor immunity has a role in nodal progression. Our objective was to investigate the relationship between immune modulation and sentinel lymph node positivity, correlating it with outcome in melanoma patients. Lymph node/primary tissues from melanoma patients prospectively accrued and followed at New York University Medical Center were evaluated for the presence of regulatory T cells (Foxp3+) and dendritic cells (conventional: CD11c+, mature: CD86+) using immunohistochemistry. Primary melanoma immune cell profiles from sentinel lymph node-positive/-negative patients were compared. Logistic regression models inclusive of standard-of-care/immunological primary tumor characteristics were constructed to predict the risk of sentinel lymph node positivity. Immunological responses in the positive sentinel lymph node were also compared with those in the negative non-sentinel node from the same nodal basin and matched negative sentinel lymph node. Decreased immune response was defined as increased regulatory T cells or decreased dendritic cells. Associations between the expression of these immune modulators, clinicopathological variables, and clinical outcome were evaluated using univariate/multivariate analyses. Primary tumor conventional dendritic cells and regression were protective against sentinel lymph node metastasis (odds ratio=0.714, 0.067; P=0.0099, 0.0816, respectively). Antitumor immunity was downregulated in the positive sentinel lymph node with an increase in regulatory T cells compared with the negative non-sentinel node from the same nodal basin (P=0.0005) and matched negative sentinel lymph node (P=0.0002). The positive sentinel lymph node also had decreased numbers of conventional dendritic cells compared with the negative sentinel lymph node (P<0.0001). Adding sentinel lymph node regulatory T cell expression improved the discriminative power of a recurrence risk assessment model using clinical stage. Primary tumor regression was associated with prolonged disease-free (P=0.025) and melanoma-specific (P=0.014) survival. Our results support an assessment of local immune profiles in both the primary tumor and sentinel lymph node to help guide therapeutic decisions.

Time to brain metastasis (TTBM) from initial diagnosis of distant metastasis in breast cancer: Prediction of TTBM according to breast cancer subtypes and treatment effect.

644 Background: Brain metastasis (BM) from breast cancer (BC) is a growing problem. About 10-15% patients with metastatic breast cancer (MBC) developed BM, with a 1 year survival of 20%. Currently, one-third of MBC patients with either HER2+ve tumors or triple negative BC (TNBC) tumors develop brain metastases. We hypothesized that MBC patients may predispose to BM differently during the disease courses according to BC subtype and treatment. We analyzed TTBM from initial diagnosis of distant metastasis how BC subtypes and treatment affect on TTBM. Methods: We retrospectively investigated 189 consecutive patients who were diagnosed with BM from BC between 2000 and 2009 at Samsung Medical Center. We analyzed TTBM according to BC subtypes and treatment effect. Results: The median age of 189 BM patients from BC was 48 (range 26-87) years. The numbers of patients with hormone receptor (HR)+ve and HER2-ve, HER2+ve irrespective of HR status, and TNBC were 43 (22.8%), 88 (46.6%), and 58 (30.7%), respectively. Median TTBM of all 189 patients was 10.4 (95% CI, 7.7-13.1) months. We analyzed TTBC into four groups considering BC subtypes and treatment; HR+ve/HER2-ve (n=43), HER2+ve with trastuzumab (T) (n=59), HER2+ve without T (n=29), and TNBC patients (n=58). The median TTBMs for each group were 17.7 months, 13.8 months, 4.3 months, and 2.9 months, respectively (p=0.002). BM as an initial site of distant metastasis was much more common in HER2+ve without T and TNBC patients than in the other patients’ groups (40.2% vs 20.6%, p= 0.003). Conclusions: TTBMs were much shorter in patients with HER2+ve without T and TNBCs than in other BC patients. Different approaches for evaluation and therapeutic strategy for BM at the time of distant metastasis may be considered for these populations.

Extrahepatic recurrence of hepatocellular carcinoma after curative hepatic resection.

Backgrounds/AimsThis study was designed to compare the recurrence patterns after curative hepatectomy, to compare the prognosis according to the initial site of metastasis, and to investigate the independent predictive factors associated with extrahepatic recurrence in hepatocellular carcinoma (HCC) patients after curative hepatectomy.MethodsFrom January 2000 to July 2009, 307 patients underwent curative hepatectomies for HCC at our institution; 152 patients showed recurrences. Patients were divided into 2 groups according to their initial recurrence site: the intrahepatic recurrence (IHR) group and extrahepatic recurrence (EHR) group. The IHR group was comprised of 111 patients and the EHR group was comprised of 41 patients. The study investigated the preoperative, intraoperative, and postoperative factors related to the recurrence pattern retrospectively and compared the prognoses of the patients.ResultsA five-year survival rate after an initial recurrence was lower in the EHR group (21.5%) than the IHR group (36.3%) (p<0.001). The preoperative alpha-fetoprotein (AFP) level was an independent risk factor for extrahepatic recurrence (p=0.014).ConclusionsPatients with a preoperative AFP level greater than 200 ng/ml have a higher incidence of extrahepatic metastases after a curative resection of HCC. Increased level of preoperative AFP is an indication for a short-term follow up hepatectomy.

Myxoid\Round Cell Liposarcoma (MRCLS) Revisited: An Analysis of 418 Primarily Managed Cases

Objectives of this study were to evaluate oncologic outcomes and to provide guidelines for the management of primary myxoid (MLS) and round cell liposarcoma (RCLS). A multicenter, retrospective study of 418 cases of MRCLS primarily managed by Canadian multidisciplinary sarcoma teams. Study included 418 cases (MLS: 311 patients and RCLS: 107; >5% round cell) with a median age of 45 years and a median follow-up of 5.2 years. Median tumor size was 10 cm, and 81% were deep and 90% were in lower limb. The majority of patients underwent surgical resection and radiotherapy, with a small percentage (6%) receiving chemotherapy. The overall 10-year local control rate was 93% with no differences between MLS and RCLS. Radiotherapy was significant in preventing local relapse and reducing tumor diameter (median=18%) and improving microscopic margin status, but did not impact survival. Radiotherapy and the margin status were independent predictors of local recurrence. The 5- and 10-year metastatic-free survivals were 84 and 77% respectively for MLS and 69 and 46% for RCLS. The initial site of metastasis was found in multiple locations (34%) and bone involvement was frequent (40%) with predilection for spine (79%). Round cell percent (>5%) and tumor diameter (>10 cm) correlated with increased risk for metastasis and death. MLS and RCLS showed different metastatic risk but equally good local control. Radiotherapy was effective in preventing local recurrence and should be delivered as neoadjuvant. New staging strategies are to be defined to account for the unusual metastatic pattern.

Sarcoma metastases to the skin

Sarcoma metastases to the skin are relatively rare, because most involve the lung, liver, or deep soft tissues. The authors of this report examined the distribution and clinical significance of cutaneous and superficial subcutaneous sarcoma metastases. Sixty-five patients with histologically confirmed dermal and superficial subcutaneous sarcoma metastases were identified in pathology files from more than 25,000 patients with sarcoma who were evaluated at The University of Texas M. D. Anderson Cancer Center from 1989 to 2009. Pathology slides and clinical and radiological information were evaluated. Cutaneous metastases were documented histologically in <0.25% of patients. The mean patient age was 49 years (range, 16-79 years), and there was an equivalent ratio of men to women. The most common source of metastasis was leiomyosarcoma (28 of 65 patients; 43%). The most common region of first skin metastasis was head and neck (33 patients; 51%), and the scalp predominated (25 patients; 38%). The mean time from primary tumor diagnosis to skin metastasis was 48 months (range, 0-166 months). Fifty-three patients (81%) had multiple metastases (skin and other). Among the patients who had complete clinical information available, 31 patients (62%) had other metastases diagnosed before skin involvement, 17 patients (34%) had skin metastases diagnosed first, and 2 patients (4%) had simultaneous presentation. The following clinical outcomes were documented: Twenty-nine patients (45%) died of disease, 24 patients (37%) remained alive with disease, and 12 patients were lost to follow-up. The mean time to death was 80 months (range, 9-224 months) after primary diagnosis, 45 months (range, 5-94 months) after the first metastasis to any site, and 27 months (range, 5-65 months) after the first skin metastasis. Sarcoma metastases to the skin are rare. In this large study, leiomyosarcoma was the most common source, and the scalp was the most frequent site. The majority of patient with skin metastases harbored metastases elsewhere. However, skin was the initial site of metastasis in approximately 1 in 3 patients. Thus, clinical correlation is needed before establishing a diagnosis of primary cutaneous sarcoma, particularly leiomyosarcoma of scalp. Finally, the current results indicated that skin metastasis usually is a late event in sarcoma clinical progression and heralds a poor prognosis.