Upfront Metastases Research Articles

Experience With Palbociclib in Metastatic Breast Cancer Patients Managed Under a Government Health Scheme at a Cancer Care Center in Southern India.

Introduction According to Globocan 2022, breast cancer ranks number one among the cancers worldwide. South Asian women have a higher incidence comparedto Westerners. Estrogen receptor (ER) and progesterone receptor (PR) positive tumors, termed hormonal receptor-positive tumors, account for most breast cancer presentations. In India, advanced-stage presentations are more common. In metastatic hormone receptor-positive breast cancer, hormonal therapy combined with cyclin-dependent kinase (CDK) 4/6 inhibitors is the standard treatment. Aim This study aimed to analyze the experience with generic palbociclib provided under the Government Health Scheme for metastatic hormone receptor-positive breast cancer at our institution. Methods This retrospective study was conducted on breast cancer patients admitted to a tertiary carecenter in South India. The data of ER and PR receptor-positive metastatic breast cancer patients who received palbociclib were identified and reviewed using medical records from 2023 to 2024. Results A total of 238 patients were analyzed, of which41 received palbociclib for hormone receptor-positive metastatic breast cancer. The median age was 49 (33-75), with 53.5% (22) of women above 50. Denovo stage IV presentation was observed in 21patients (51.2%), while progression to stage IV disease was noted in 11 patients (26.8%), and stages II and IIIwere noted in nine patients (22%). Invasive ductal carcinoma was the most common histology. All patients were ER-positive, and 38 (92.7%) were PR-positive. About 17 patients (41.5%) had visceral metastasis, and 12 (29.3%) had bone-only metastasis. Local recurrence was seen in six patients (14.6%), and bone with visceral metastasis was seen in another six patients (14.6%). Progression within one year of hormonal therapy initiation was observed in 50% (10) of patients. Among 21 patients with upfront metastasis, nine were treated with prior chemotherapy. All patients were given 125 mg of oral palbociclib. Fatigue was the most common side effect in 34.1% (14), followed by myalgia in 21.9% (9), low hemoglobin levels of less than 8 g/dl in 14.6% (6), and nausea and vomiting in only 9.8% (4) of patients. Conclusion Hormone therapy combined with CDK4/6 inhibitors is the backbone of treatment for metastatic hormone-positive breast cancer. However, in developing countries like India, where most patients come from rural areas, using innovator palbociclib may not be feasible for many. With the availability of generic palbociclib under the Government Health Scheme, patients of metastatic hormone receptor-positive breast cancer will receive the protocol-based treatment.

Metastatic patterns and hormone receptor status among breast cancer patients in Tanzania

Introduction: Metastatic breast cancer is a common presentation in Tanzania. Estrogen-receptor (ER)-positive tumors are known to metastasize to the bones and require hormonal treatment as first-line therapy. Challenges with accessing immunohistochemistry services can delay information on breast cancer subtypes, further delaying treatment with effective hormonal therapy. Objectives: This study aimed to assess the pattern of distribution of metastatic lesions in patients with metastatic breast cancer and evaluate its association with their hormone and HER-2 status, which could help provide recommendations on the use of front-line hormone therapy in areas where access to immunohistochemistry is a challenge. Methods: A retrospective study covering histologically confirmed breast cancer patients in 2020 with metastatic lesions and complete medical records at Ocean Road Cancer Institute. Clinical information on the number, state and sites of metastasis, presence of symptoms and treatment received, and pathological variables, including histology, ER, PR and HER-2 status, were documented. Results: Forty-nine (96.1%) of 51 patients analysed were female, with a mean age of 49.5 years. 47% presented with up-front metastatic disease. Lung was the most common metastatic site (76.5%) followed by bone/spine (53%). About half the patients had multiple sites involved. ER-positive tumors accounted for 47%, PR positive for 31% and HER-2 positive 39.2%. ER-positive tumors were more likely to present as a recurrence than up-front metastasis. ER-positive tumors were significantly more likely to be associated with bone and spine metastasis (59%) compared to ER-negative tumors (29%) Conclusion: The clinical and pathological features of MBC in Tanzanian women are similar in many ways to those in other African regions. However, the ER positivity rate is lower. This study found a significant association between ER-positive tumours and skeletal metastasis, which has implications for the up-front treatment of these patients, especially where access to immunohistochemistry can be a challenge.

Extraosseous ewing sarcoma: Experience from a tertiary cancer institute in South India

Background: Extraosseous Ewing sarcoma (EOES) is the rare soft-tissue counterpart of Ewing sarcoma (ES) of bone. However, studies on clinical behavior and outcome of EOES are scarce. In this retrospective study, we described the pattern of clinicodemographic characteristics, treatment, and outcomes of EOES and explored predictors of outcomes. Materials and Methods: A total of 46 diagnosed EOES patients were treated at our institute from September 2017 to January 2020. The detailed data were retrieved from hospital records and were analyzed. Progression-free survival (PFS) was estimated by the method of Kaplan and Meier curve. Comparison of different parameters for PFS was calculated by using log-rank test. Results: The mean age at diagnosis was 29.6 years with a male-to-female ratio of 1.4:1. The most common primary site of location for EOES was lower limb (n = 14), followed by retroperitoneum (n = 13) and trunk (n = 10). Seven (15.2%) patients presented with upfront metastasis and the rest 39 cases were nonmetastatic. Treatment outcome was evaluated in 43 patients (38 nonmetastatic and 5 metastatic) in terms of median PFS (mPFS). Extremity EOES in comparison to nonextremity (axial) EOES (P = 0.030) and localized versus upfront metastatic EOES (P = 0.001) had better mPFS. The localized EOES patients who received surgical treatment approach had higher mPFS than those who received nonsurgical treatment (18 months versus 14 months; P = 0.009). EOES patients with subcutaneous (SC) lesions had a trend of higher mPFS than other patients (19 months versus 15 months; P = 0.055). We did not find any difference in mPFS for gender and size of the tumor at presentation. Conclusions: Lower limb and retroperitoneum are the common primary sites of presentation for EOES. EOES patients with extremity location, SC lesion in comparison to deeper presentation, upfront nonmetastatic, and those receiving surgical treatment approach performed better.

Abstract 3902: Novel therapeutic targeting of epigenetic aberrations in pediatric sarcomas through combination of ONC201 and HDAC inhibitors

Abstract Patients diagnosed with pediatric sarcomas have poor outcomes with current standard therapy in the setting of relapse, progressive disease, or upfront metastasis. Imipridones, a class of novel small molecules, specifically ONC201, have shown pre-clinical and clinical efficacy in adult malignancies and in brain tumors with aberrant methylation of histone H3 on lysine 27 (associated with H3K27M mutation). ONC201 is an antagonist of dopamine receptor D2 (DRD2), which is a G protein-coupled receptor that is overexpressed in several malignancies. ONC201 inactivates cell proliferation kinases Akt/ERK and induces cell death through the pro-apoptotic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptor DR5. Prior in vitro studies of pediatric sarcomas have produced promising data with ERK pathway inhibition, leading to apoptosis and inhibition of metastasis formation. Some pediatric sarcomas, such as malignant peripheral nerve sheath tumors and fusion-positive sarcomas, have been noted to have aberrant activation or modifications of H3K27. H3K27 can be methylated or acetylated and both modifications are abrogated in H3K27M mutated alleles. Changes in histone acetylation and the epigenetic effects of imipridones remain under investigation. We hypothesized that sarcomas with aberrant H3K27 modifications may respond to the novel small molecule similarly to H3K27-mutated brain tumors, and that the combination of ONC201 with histone deacetylase inhibitors (HDACi) could lead to a synergistic effect on cell death mechanisms, potentially through effects of histone acetylation. We performed drug treatment with ONC201 on established pediatric sarcoma cell lines and applied combinatory drug treatment with HDACi, including vorinostat (SAHA). Cell viability was measured after drug treatment in vitro. We investigated markers of cell death in established pediatric sarcoma cell lines via protein analysis and flow cytometry analysis. Using protein quantification studies and downstream target analysis on combination drug-treated cells, we investigated the mechanisms of how these two targeted therapies interact synergistically to cause cell death. We show that ONC201 inactivates cellular proliferation in pediatric sarcomas through the Akt/ERK pathway and induces cell death through the TRAIL pathway. We demonstrated that treatment of cells with ONC201 modified the mitochondrial Clp protease complex, by activating the ClpP protease and by decreasing the chaperone subunit ClpX. Our studies demonstrate that ONC201 induces cell death in pediatric sarcomas, and that ONC201 has potent synergistic effects causing tumor cell death when combined with HDACi. Further studies are underway in elucidating the combinatory epigenetic effects of HDACi and ONC201 in H3K27-aberrant sarcomas, leading to synergistic cell death mechanisms. Our studies present a novel therapeutic combination for pediatric sarcomas that have relapsed or are refractory to standard chemotherapy. Citation Format: Wen-I Chang, Lanlan Zhou, Attila A. Seyhan, Yiqun Zhang, Wafik S. El-Deiry. Novel therapeutic targeting of epigenetic aberrations in pediatric sarcomas through combination of ONC201 and HDAC inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3902.

Robot-assisted laparoscopic radical nephrectomy and inferior vena cava thrombectomy: A multicentre Indian experience

ABSTRACT Objective To assess feasibility of robot-assisted laparoscopic radical nephrectomy (RALRN) and inferior vena cava thrombectomy (IVCT) in treating renal tumours with level I–III IVC thrombi and to assess their outcomes. Patients and methods We conducted a retrospective analysis of RALRN-IVCTs, involving four centres across India, from September 2015 to June 2019. We analysed patients who underwent RALRN-IVCT for level I–III thrombi according to the Mayo classification. The total operative duration with console time, length of hospital stay, preoperative and postoperative creatinine, IVC clamp time and intraoperative blood loss were recorded. Results Of the 13 patients that underwent RALRN-IVCT, five had a level I thrombus, seven had level II, and one had a level III thrombus. In all, 11 of the patients had right-sided tumours and the remaining two had left-sided tumours. The mean (SD) age of the patients was 56.5 (12.3) years, the mean (SD) operative time was 329.5 (97.22) min, the mean (SD) console time was 222.5 (70) min, the mean (SD) blood loss was 395 (170) mL, and the mean (SD) IVC clamp time was 19.14 (9.5) min. The mean (SD) length of hospital stay was 7.8 (3.27) days. Of the 13 patients, 12 had clear cell renal cell carcinoma (RCC) and one had papillary RCC. The mean (range) follow-up was 19 (4–50) months. One patient had upfront metastasis and two patients developed metastasis, while 10 patients remained disease-free during the follow-up. Conclusion With appropriate patient selection, surgical planning and robotic experience, completely intracorporeal robotic level I–III IVCT is feasible and can be performed efficiently. Larger experiences, with longer follow-ups and comparisons with open surgery are needed to confirm these initial outcomes. Abbreviations ECOG: Eastern Cooperative Oncology Group; IVC: inferior vena cava; IVCT: inferior vena cava thrombectomy; (RAL)RN: (robot-assisted laparoscopic) radical nephrectomy

Unusual Gastric Metastasis in Triple-Negative (Estrogen Receptor/Progesterone Receptor/HER2neu Negative) GATA-Binding Protein 3-Positive Breast Cancer.

Triple-negative breast cancer (TNBC) accounts for 20%–25% of breast cancer cases. Around 10%–15% of patients with breast cancer present with upfront metastasis. Lymph node, bone, and liver are common sites of metastasis in hormone-positive breast cancer while brain, lungs, and liver in TNBC. Although visceral metastasis is common in TNBC, metastasis to stomach is unusual. Morphological similarity of primary gastric carcinoma and lobular invasive breast carcinoma often leads to misdiagnosis. Meticulous review of histopathology and immunohistochemistry is essential for diagnosis. We present a case of carcinoma breast with unusual gastric nodular metastasis detected on 18F-fluorodeoxyglucose positron emission tomography–computed tomography.

Clinicopathologic Characteristics and Treatment Outcomes of Patients With Up-Front Metastatic Breast Cancer: Single-Center Experience in India.

PURPOSEApproximately 5% to 10% of patients with breast cancer present with up-front metastasis and carry a poor prognosis (5-year survival rates of approximately 20%). To date, little is known about the long-term outcome of patients with metastatic breast cancer from developing nations.MATERIALS AND METHODSWe performed an ambispective review of approximately 1,800 patients who were registered in breast cancer clinics between January 2012 and August 2018. Approximately 410 (22.8%) patients presented with up-front metastasis. Out of 410, 375 were considered for additional analysis. Clinical, pathologic, and radiologic details were obtained from the medical records.RESULTSMedian age of presentation was 49 years (range, 22 to 80 years), and median duration of symptoms was 6 months (interquartile range, 3-12 months). Baseline receptor status suggested that 234 patients (62.4%) were hormone receptor (HR) positive, 145 (38.6%) were human epidermal growth factor receptor positive, and 69 (18.6%) had triple-negative breast cancer. Various sites of metastasis were: visceral 219 (58.4%), bone only 100 (26.7%), nonregional lymph node metastasis 21 (5.6%), brain 10 (2.7%), and others 25 (5.8%). Approximately 309 patients (82.4%) received up-front chemotherapy, 192 HR-positive patients (82.1%) received endocrine therapy, and 78 human epidermal growth factor receptor–positive patients (53.8%) received targeted agents. Median progression-free survival was 14.2 months (95% CI, 12.7 to 16.8 months), and median overall survival (OS) was 31.7 months (95% CI, 25.8 to 38.2 months) for the cohort. Median time of follow-up was 22.2 months. On multivariable Cox regression analysis, HR-positive disease, good performance status (0 or 1), and oligometastasis were associated with better OS, whereas triple-negative breast cancer and liver and brain metastasis were associated with inferior OS.CONCLUSIONThis is the first comprehensive study, to our knowledge, of metastatic breast cancer from India. HR-positive status, oligometastasis, and good performance status were associated with better outcomes.

Profile of metastatic breast carcinoma: Single center experience from a developing country.

e13102Background: Around 5-10 % patients presents with upfront metastasis & 20 -30% patients develop metastasis during follow up. Till date, little is known about pattern and profile of patients wi...

Identification of prognostic groups in patients with hormone-sensitive metastatic prostate cancer at the present time: An analysis of the GETUG 15 phase III trial.

26 Background: Patients with upfront metastases at the time of prostate cancer (PC) diagnosis are less frequent than in the past in Western countries, but still represent 5-10% of all patients and almost one half of PC patients will eventually die of the disease. Prognostic factors (lymph node metastases/appendicular vs axial bone disease, performance status > 1, Gleason score > 8 and PSA > 65 ng/ml) have been proposed (Glass et al., 2003), leading to the definition of three subgroups with good, intermediate and poor prognosis. However, the current natural history of metastatic prostate cancer has not been well described. Methods: Patients with hormone sensitive metastatic PC were randomized to receive continuous androgen deprivation therapy (ADT) plus docetaxel (75 mg/m²/21d up to 9 cycles) and prednisone or ADT alone. Glass risk groups were used as stratification factors. Results: From October 2004 to December 2008, 385 pts were included. They were distributed into good (50%), intermediate (29%), and poor (21%) prognosis groups. The median follow up was 50 months [95% CI: 49 - 54]. The primary endpoint analysis showed no difference in overall survival (OS) (HR: 1.01 [95%CI: 0.75-1.36]) between the 2 arms but a significant PFS improvement was observed in the docetaxel group (HR: 0.75 [0.59-0.94] p=0.0147) (Gravis, ESMO 2012). The median OS in the ADT alone arm was 54 months [42-NR]. It was 69 [95% CI: 60.9-NR], 47 [95% CI: 37.7-NR, HR = 1.6] and 37 [95% CI: 28.5-58.9, HR = 2.12] months respectively in the good, intermediate, and poor prognosis groups (p=0.001) in the whole cohort. No interaction between prognosis groups and treatment was found. A detailed analysis using the Cox model will be presented. Conclusions: At the present time, median life expectancy of patients with metastatic PC seems to exceed 4 years. Subgroups with favorable or unfavorable outcome can be identified. Clinical trial information: NCT00055731.