Type Of Metastatic Disease Research Articles

Glycosylation Alterations in Cancer Cells, Prognostic Value of Glycan Biomarkers and Their Potential as Novel Therapeutic Targets in Breast Cancer.

Although we are lately witnessing major improvements in breast cancer treatment and patient outcomes, there is still a significant proportion of patients not receiving efficient therapy. More precisely, patients with triple-negative breast cancer or any type of metastatic disease. Currently available prognostic and therapeutic biomarkers are not always applicable and oftentimes lack precision. The science of glycans is a relatively new scientific approach to better characterize malignant transformation and tumor progression. In this review, we summarize the most important information about glycosylation characteristics in breast cancer cells and how different glycoproteins and enzymes involved in glycosylation could serve as more precise biomarkers, as well as new therapeutic targets.

Evolution of the CDK4/6 inhibitor abemaciclib: from palliative to adjuvant therapy. Clinical experience with abemaciclib in patients with hormone-receptor-positive, HER2-negative breast cancer

Introduction. Cyclin-dependent kinase 4/6 inhibitors are indicated in endocrine therapy for the treatment of hormone receptorpositive, HER2-negative, advanced, or metastatic breast cancer. In the recent past, abemaciclib made its debut as a combinatorial partner for adjuvant therapy in hormone-dependent breast cancer. This article demonstrates the analysis of our own experience of introducing abemaciclib into clinical practice.Aim. The aim of the study was to evaluate the preliminary results of treatment of patients with hormone receptor-positive HER2-negative metastatic breast cancer using abemaciclib outside the framework of clinical trials, in the real clinical practice of an oncological dispensary.Materials and methods. A retrospective analysis of the results of treatment was carried out in 27 patients who were prescribed abe-maciclib in various regimens and lines from April 2021 to January 2022 in the conditions of routine practice in the Krasnodar region.Results and discussion. Analysis of the total population of 27 patients at a median follow-up of 8 months showed that the median PFS was not reached. The one-year PFS was 68.8%. Treatment outcomes were independent of prescribing abemaciclib to treat baseline metastatic disease or breast cancer progression after previous radical treatment (p = 0.60). The PFS did not depend on the expression of progesterone receptors in the tumor tissue (p = 0.326) and the proliferative activity index Ki-67 (p = 0.618). Patients who received no more than 2 lines of previous drug treatment for a history of metastatic breast cancer had the greatest benefit from abemaciclib therapy (p = 0.001).Conclusions. Despite a relatively difficult group of patients (96% of patients with visceral metastases), abemaciclib has demonstrated efficacy and safety. The effectiveness did not depend on the analyzed factors: Ki-67, the level of expression of progesterone receptors, the type of metastatic disease (de novo metastatic or progressive breast cancer). In view of the best results, it is advisable to prescribe abemaciclib in the early lines of therapy.

Defining more precisely the effects of docetaxel plus ADT for men with mHSPC: Meta-analysis of individual participant data from randomized trials.

5070 Background: Adding docetaxel to androgen deprivation therapy(ADT) improves survival in metastatic, hormone-sensitive prostate cancer (mHSPC), but uncertainty remains about who benefits most. To investigate this thoroughly and reliably, the STOPCAP M1 collaborationconducted a meta-analysis of individual participant data (IPD) from relevant trials. Methods: Methods were included in a registered protocol ( CRD42019140591 ). Updated IPD from the GETUG-15, CHAARTED and STAMPEDE trials were harmonised and checked. The main outcomes were overall survival (OS), progression-free survival (PFS) and failure-free survival (FFS). Overall pooled effects were estimated using intention-to-treat, 2-stage, fixed-effect meta-analysis, adjusted for age, PSA, Gleason sum score, performance status, and timing of metastatic disease (missing covariate values imputed), with 1-stage and random-effects sensitivity analyses. We assessed subgroup effects using 2-stage, fixed-effect meta-analysis of within-trial interactions, adjusted for the same covariates. We based these on PFS to maximise power, and OS whenever interactions were found. To explore multiple subgroup interactions, and to derive subgroup-specific absolute treatment effects, we used 1-stage, flexible parametric modelling and standardisation. Results: We obtained IPD for all 2261 men randomised, with median FU of 6 years (all patients). There were clear relative benefits of docetaxel on OS (HR = 0.79, 95% CI 0.70 to 0.88, p<0.0001), PFS (HR = 0.70, 95% CI 0.63 to 0.77, p<0.0001) and FFS (HR = 0.64, 95% CI 0.58 to 0.71, p<0.0001). With evidence of non-proportional hazards, we also estimated 5-year absolute differences: OS 10% (95% CI 6 to 15%), PFS 9% (95% CI 5 to 13%) and FFS 9% (95% CI 6 to 12%). The relative effect of docetaxel on PFS differed by volume of metastases (interaction p=0.027; high volume HR = 0.60, 95% CI 0.52 to 0.68; low volume HR = 0.78, 95% CI 0.64 to 0.94), and timing of metastatic disease (interaction p=0.077; synchronous HR = 0.67, 95% CI 0.60 to 0.75; metachronous HR = 0.89, 95% CI 0.67 to 1.18). OS results were similar. When metastatic disease volume and timing were combined, docetaxel appeared to improve PFS and OS for all men, except those with low volume, metachronous disease (Table). Conclusions: This IPD meta-analysis provides the most detailed assessment of the effects of docetaxel for mHSPC, and suggests that men with low volume, metachronous disease should be managed differently to those with other types of metastatic disease. [Table: see text]

Abstract P1-17-06: Impact of body mass index on the efficacy of aromatase inhibitors in patients with metastatic breast cancer

Abstract Background: Aromatase inhibitors (AIs) are part of standard endocrine therapy for hormone receptor (HR)-positive breast cancer (BC) and are used in both adjuvant and metastatic settings. Since AIs work by inhibiting the conversion of androgens to estrogen in peripheral adipose tissue, the higher levels of estrogen in obese patients may lead to incomplete inhibition by AIs and influence their efficacy. A retrospective analysis of the ABCSG-12 trial found that overweight premenopausal patients with early-stage BC treated with anastrozole had a 60% increased risk of disease recurrence and more than doubling in risk of death compared with normal weight patients on anastrozole. Similarly, an exploratory analysis from the ATAC trial found that in post-menopausal women with early-stage BC, overall recurrence rates were lower in patients randomized to anastrozole versus tamoxifen but in women with body mass index (BMI) > 30, there was no significant difference in disease recurrence between anastrozole and tamoxifen. While these findings raise concern for the efficacy of adjuvant AI therapy in obese patients with early-stage BC, this has not yet been demonstrated in the metastatic setting. The aim of this study was to determine the impact of BMI on efficacy of AIs in patients with metastatic HR-positive BC. Methods: We performed a retrospective chart review of all female patients with metastatic HR-positive BC on an AI in first- or second-line settings and seen at our academic institution between 2001-2020. The primary endpoint was progression-free survival (PFS), defined as the time from start of AI to disease progression or death from any cause. PFS was compared across BMI groups using Kaplan-Meier curves and log-rank tests. Cox proportional hazards regression model was used for univariate and multivariate analyses. Results: We identified 219 patients who had received an AI in the first- or second-line settings for metastatic HR-positive BC and with documented information on BMI. The median age was 59 with 45% of patients White, 29% African American, 16% Hispanic/Latino, 5.5% Asian and remainder other/unknown. 32% (71) had HER-2 positive disease. 82% (179) were on an AI in the first-line setting. Overall, 53% were on letrozole, 42% on anastrozole and 5.5% on exemestane. Of the 219 patients, 56% (123) had a low BMI (defined as < 27 kg/m2) and 44% (96) had a high BMI (≥ 27 kg/m2; based on the Breast Cancer Weight Loss [BWEL] trial). The median PFS was 21.9 months (95% CI, 14.5 to 28.4) in the low BMI group versus 20.2 months (95% CI, 14.3 to 27.5) in the high BMI group with no statistically significant difference (p =0.73). There were 8 (6.5%) deaths in the low BMI group and 7 (7.3%) deaths in the high BMI group. Multivariate cox regression model did not demonstrate any significant impact of BMI on PFS when adjusting for age, race/ethnicity, HER2 status, type of AI, line of therapy, drug partner and type of metastatic disease (HR =0.91, 95% CI =0.64 to 1.30, p =0.6 for high BMI group). Subgroup analysis of patients on an AI in the first line setting also did not show a significant difference in PFS with median PFS 19.3 and 18 months in the low and high BMI groups, respectively. Conclusions: In patients on an AI for metastatic HR-positive breast cancer, there was no statistically significant difference in PFS in patients with low versus high BMI. While BMI influences efficacy of AIs in the adjuvant setting, our results demonstrate that in the metastatic setting, BMI does not significantly impact the efficacy of AIs among our patient population. This discrepancy could be due to other differences in disease characteristics that make complete aromatase inhibition more important in the adjuvant setting when disease burden is the lowest. Additional larger studies are needed to confirm this finding. Citation Format: Rima Patel, Zhiqiang Li, Brittney S. Zimmerman, Marc Y. Fink, Jason D. Wells, Xiang Zhou, Kristin L. Ayers, Arielle Redfern, Scott Newman, Rong Chen, William K. Oh, Amy Tiersten. Impact of body mass index on the efficacy of aromatase inhibitors in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-06.

Metastatic disease to the liver: Locoregional therapy strategies and outcomes

Secondary cancers of the liver are more than twenty times more common than primary tumors and are incurable in most cases. While surgical resection and systemic chemotherapy are often the first-line therapy for metastatic liver disease, a majority of patients present with bilobar disease not amenable to curative local resection. Furthermore, by the time metastasis to the liver has developed, many tumors demonstrate a degree of resistance to systemic chemotherapy. Fortunately, catheter-directed and percutaneous locoregional approaches have evolved as major treatment modalities for unresectable metastatic disease. These novel techniques can be used for diverse applications ranging from curative intent for small localized tumors, downstaging of large tumors for resection, or locoregional control and palliation of advanced disease. Their use has been associated with increased tumor response, increased disease-free and overall survival, and decreased morbidity and mortality in a broad range of metastatic disease. This review explores recent advances in liver-directed therapies for metastatic liver disease from primary colorectal, neuroendocrine, breast, and lung cancer, as well as uveal melanoma, cholangiocarcinoma, and sarcoma. Therapies discussed include bland transarterial embolization, chemoembolization, radioembolization, and ablative therapies, with a focus on current treatment approaches, outcomes of locoregional therapy, and future directions in each type of metastatic disease.

Molecular heterogeneity in breast carcinoma cells with increased invasive capacities.

BackgroundMetastatic progression of breast cancer is still a challenge in clinical oncology. Therefore, an elucidation how carcinoma cells belonging to different breast cancer subtypes realize their metastatic capacities is needed. The aim of this study was to elucidate a similarity of activated molecular pathways underlying an enhancement of invasiveness of carcinoma cells belonging to different breast carcinoma subtypes.Materials and methodsIn order to reach this aim, parental and invasive (INV) MDA-MB-231 (triple-negative), T47D (hormone receptor-positive), and Au565 (Her2-positive) breast carcinoma cells were used and their molecular phenotypes were compared using a proteomic approach.ResultsIndependently from breast cancer subtypes, INV cells have demonstrated fibroblast-like morphology accompanied by enhancement of invasive and migratory capacities, increased expression of cancer stem cell markers, and delayed tumor growth in in vivo animal models. However, the global proteomic analysis has highlighted that INV cells were different in protein expressions from the parental cells, and Her2-positive Au565-INV cells showed the most pronounced molecular differences compared to the triple-negative MDA-MB-231-INV and hormone receptor-positive T47D-INV cells. Although Au565-INV breast carcinoma cells possessed the highest number of deregulated proteins, they had the lowest overlapping in proteins commonly expressed in MDA-MB-231-INV and T47D-INV cells.ConclusionsWe can conclude that hormone receptor-positive cells with increased invasiveness acquire the molecular characteristics of triple-negative breast cancer cells, whereas Her2-positive INV cells specifically changed their own molecular phenotype with very limited partaking in the involved pathways found in the MDA-MB-231-INV and T47D-INV cells. Since hormone receptor-positive invasive cells share their molecular properties with triple-negative breast cancer cells, we assume that these types of metastatic disease can be treated rather equally with an option to add anti-hormonal agents. In contrast, Her2-positive metastasis should be carefully evaluated for more effective therapeutic approaches which are distinct from the triple-negative and hormone-positive metastatic breast cancers.

Intratumoral IL-12 gene electrotransfer-mediated regression of established B16F10 melanoma protects against rechallenge

Abstract Melanoma is an aggressive tumor with limited treatment options and poor prognosis. Interleukin-12 (IL-12) is a potent cytokine mediating antitumor activity. However, it has only achieved modest antitumor effects in clinical trials, often accompanied by unacceptable adverse events. We evaluated whether intratumoral delivery of a plasmid encoding IL-12 using gene electrotransfer (GET) to control the dose could induce rejection of an established poorly immunogenic tumor and avoid dose dependent toxicities. We treated B16F10 murine melanoma 3 times in 1 week by intratumoral injection of pUMVC3mIL-12 plasmid (pmIL-12, 50 μg) followed by GET. The GET protocols were; EP1 (six 300 V/cm, 100 μs pulses with an array of 6 penetrating electrodes), EP2 (ten 600 V/cm, 5ms pulses with non-penetrating caliper electrodes). Localized delivery of pmIL-12 with GET in the tumor microenvironment, significantly delayed disease development and prolonged disease free survival and induced long term immune memory protecting against rechallenge. The response was associated with a significant reduction in Treg and MDSC infiltration in B16F10 melanoma and increase of Granzyme B. Mice treated with pmIL-12 EP1 that achieved protection against rechallenge were observed to have CD62LlowCD44high memory T cells. Interestingly, pmIL-12 demonstrated stronger anti-tumor effects than pmIL-12 delivered by EP2. By manipulation of GET parameters the onset, level and duration of IL-12 protein expression can be controlled, resulting in meaningful therapeutic effects without associated IL-12 toxicities. Furthermore, the approach induced systemic antitumor immune activity and memory and therefore might have an impact against other types of metastatic disease.

Tumor Deposits in Colorectal Cancer: Improving the Value of Modern Staging-A Systematic Review and Meta-Analysis.

Purpose Colorectal cancer (CRC) treatment is largely determined by tumor stage. Despite improvements made in the treatment of various types of metastatic disease, staging has not been refined. The role of tumor deposits (TDs) in staging remains debated. We have assessed the relation of TDs with metastatic pattern to evaluate whether TDs might add significant new information to staging. Methods We performed a systematic literature search that was focused on the role of TDs in CRC. Studies with neoadjuvant-treated patients were excluded. Data on stage, histologic factors, and outcome were extracted. Data from four large cohorts were analyzed for the relevance of the presence of TDs, lymph node metastases (LNMs), and extramural vascular invasion (EMVI) on the pattern of metastases and outcomes. Results Of 10,106 included patients with CRC, 22% presented with TDs. TDs are invariably associated with poor outcome. Presence of TDs was associated with presence of LNMs and EMVI. In a pairwise comparison, effects of TD were stronger than those of both LNMs and EMVI. In the logistic regression model, TDs in combination with LNMs is the strongest predictor for liver (odds ratio [OR], 5.5), lung (OR, 4.3) and peritoneal metastases (OR, 7.0). Presence of EMVI adds information for liver and lung metastases, but not for peritoneal metastases. Conclusion We have shown that TDs are not equal to LNMs or EMVI with respect to biology and outcome. We lose valuable prognostic information by allocating TDs into nodal category N1c and only considering TDs in the absence of LNMs. Therefore, we propose that the number of TDs should be added to the number of LNMs to derive a final N stage.

Impact of Contralateral Tumor Nodules on Survival in Non-Small Cell Lung Cancer: A SEER Database Analysis

Purpose/Objective(s): We explored the prognostic implications of contralateral tumor nodules in patients with non-small cell lung cancer (NSCLC) using the SEER database. We hypothesized that many such cases represent a second primary tumor and exhibit a favorable prognosis compared to other types of metastatic disease. Materials/Methods: We analyzed overall survival (OS) in SEER data from 2004-2009 for patients age 25-85 with malignant primary tumors of the lung or bronchus and non-small cell histology. Patients were categorized as M0, M0 with ipsilateral nodule in separate lobe, M1a with contralateral nodule, M1a without contralateral nodule, or M1b with distant metastasis. We used Kaplan-Meier estimates and the log-rank test to compare OS between groups. Using a proportional hazards model, risk of death for patients with tumor nodules in a contralateral lobe was compared to what would be expected from a synchronous second primary tumor. Results: Of 208,691 patients who met inclusion criteria, 10,548 had contralateral tumor nodules without other metastatic disease. Median and 2 yr OS for these patients was 7 mo and 18%, respectively. This was greater than that observed in patients with other forms of M1a disease (4 mo and 8%; p < 0.001) but less than that with an ipsilateral nodule in a separate lobe (11 mo and 27%; p < 0.001). This pattern persisted when patients were stratified by N-stage and primary tumor size. Not unexpectedly, patients with ipsilateral nodules received more definitive treatment relative to those with contralateral nodules (21% surgery, 30% radiation vs 6% surgery, 23% radiation). Interestingly, patients with T1-2a N0-1 disease and a contralateral nodule achieved greater OS than those with no additional pulmonary nodule but with N3 disease. Patients with T1-2N0 disease and a contralateral nodule had a hazard for death that was not significantly different from that expected from a synchronous stage IA primary tumor. Patients with more advanced T and N stages had OS intermediate between that estimated for concurrent primaries and M1b disease. Conclusions: Contralateral tumor nodules in NSCLC carry a prognosis more favorable than other M1a or M1b disease but less favorable than no additional nodule or an ipsilateral nodule in a separate lobe. Collectively, our analyses suggest that M1a contralateral nodules represent two distinct biological subgroups: hematogenous metastatic disease and synchronous, early stage second primaries. This study points to (1) an opportunity for improvement in the current staging system, (2) a rationale for definitive treatment of T1-2N0 patients with contralateral nodules, and (3) a need for molecular pathologic sub-classification of contralateral pulmonary nodules in patients with more advanced disease in order to identify those who may benefit from aggressive loco-regional treatments. Author Disclosure: Z.S. Morris: None. D.M. Cannon: None. S.M. Bentzen: None. K.R. Kozak: None.

Multiple Myeloma Associated GI Polyposis

Abstract 5009Multiple myeloma is a neoplastic proliferation of monoclonal plasma cells that can result in osteolytic bone lesions, hypercalcemia, renal impairment, bone marrow failure, and the production of monoclonal gammopathy. The gastrointestinal tract is rarely involved in myeloma. GI polyposis is a rare manifestation of extra-medullary disease in multiple myeloma. Such cases usually present as gastrointestinal hemorrhage or intestinal obstruction.A 53-year-old African American male recently diagnosed with multiple myeloma presented with three-day history of rectal bleed and fatigue. EGD showed multiple raised, polypoid, rounded lesions with a superficial central ulceration in the stomach. Colonoscopy showed similar lesions in the ascending and transverse areas of the colon that ranged in size from 5 to 16 mm in diameter. Biopsies showed that these polyps were made of plasma cells. A bone marrow biopsy showed diffuse involvement (greater than 90%) of bone marrow with multiple myeloma with anaplastic features. The patient was started on bortezomib at diagnosis, however, he passed away a few weeks later.This type of metastatic disease has been described in isolated case reports in the literature, while solitary GI plasmacytoma has been reported more frequently. In rare cases, multiple myeloma can involve the GI tract which may lead to bleed or obstruction. This involvement is likely a marker of aggressivity. This example of extra-medullary disease in myeloma is an uncommon variant with features of poor prognosis and dedifferentiation. Disclosures:No relevant conflicts of interest to declare.

Preniche as missing link of the metastatic niche concept explaining organ-preferential metastasis of malignant tumors and the type of metastatic disease

Here we attempt to supplement the metastatic niche concept with a stage of "preniche" that determines the site of development of a premetastatic niche and of a subsequent metastasis. The "preniche" includes all cellular and molecular events in the site of a prospective metastasis preceding the entrance of myeloid progenitor cells. The "preniche" integrates an activation of vascular endothelium of the microcirculatory vessels of target organs in the site of a future metastasis under conditions of chronic persistent productive inflammation that can be induced by cytokines from the primary tumor and independently of it. The endothelium activation is responsible for adhesion and clustering of the recruited myeloid progenitor cells and also for the retention of cells of malignant tumors. The preniche easily arises in organs enriched with organ-specific macrophages (lungs, liver, brain, etc.) where the endothelium is predisposed for intensive recruiting of myeloid progenitor cells of macrophages, especially under conditions of inflammation. Introduction of the "preniche" concept allows us to avoid difficulties associated with the development of the metastatic niche concept, especially concerning the problem of organ-preferential localization of metastases, and to make some predictions for experimental verification and potential approaches for preventing metastasizing in some oncologic patients.

Realistic expectations for cryoablation of liver tumors.

While cryoablation has been shown to be an effective method of destruction of primary and metastatic liver tumors, there is a disturbingly high incidence of recurrence at the cryoablated site and there are conflicting reports concerning long-term survival. For this reason, resection remains the preferred surgical treatment of liver tumors. However, there is a population of patients who, because of age, pre-existing liver disease, or likely systemic dissemination, present a higher risk for major resection, and for whom cryoablation may be favored. This study examined the safety and effectiveness of cryoablation in patients thought to be at higher risk for conventional hepatic resection, or in whom resection would not eradicate all known disease. Twenty-eight consecutive patients underwent cryoablation, with or without resection, of 39 hepatic tumors for primary (n = 9) or metastatic (n = 19) disease. Their postoperative course and long-term follow-up were examined for complications, survivability, and recurrence of disease. With the use of cryoablation, a major hepatic resection was avoided in 20 patients, 11 of whom were 70 years or older, 4 who likely had disseminated cancer even though the liver was the only site of detectable disease, 2 who were cirrhotic, and 2 with bilobar disease. An additional 7 patients had recurrence of disease in a previously resected liver, for whom additional resection would be hazardous. There was one operative death from an exaggerated systemic inflammatory response syndrome. Seven patients developed complications, including 2 patients with cryoablation-induced coagulopathy. Excluding 2 patients (including the postoperative death) the average hospital length of stay was 6.7 +/- 2.8 days. Seven patients required some intensive care unit (ICU) care. Three patients with primary liver cancer are alive 29 to 47 months after cryoablation. Two patients with metastatic disease are alive without recurrence at 12 and 16 months, and 9 are alive with disease from 13 to 58 months after cryoablation. Fifteen patients developed liver recurrence, 5/27 (19%) at the cryoablated site. Cryoablation appears to be a safe treatment modality for primary and metastatic liver cancer. It is particularly appealing in those patients who may be at higher risk for major hepatectomy because of age, pre-existing liver disease, type of metastatic disease, previous resection, or bilobar tumors. Most disturbing is the high incidence of recurrence at the cryoablated site, which may reflect problems with ultrasound localization or proximity of tumors to major vasculature. Disease-free survival is low. From this standpoint the procedure should be considered palliative, even though all hepatic tumors can be eradicated. However, these limitations should not deter the use of cryoablation in selected patients. There is the potential for long-term survival, just as there is with resection.

Endobronchial Metastases due to Colorectal Carcinoma

Metastatic disease from colorectal carcinoma to the tracheobronchial tree has previously been reported in only 15 cases. Various modalities of treatment have been attempted but have met with limited success. We describe an additional nine cases, as documented by fiberoptic bronchoscopy, treated by Nd-Yag laser therapy debulking. Improvement in bronchial patency was evidenced visually in each case, and relief of symptoms occurred in eight cases. Survival periods of up to 21 months occurred. This type of metastatic disease may be more common than previously reported and combination therapy to include Nd-Yag laser debulking offers a safe and effective alternative in the palliative management of pulmonary symptoms and increased survival in select patients.