Tumor characteristics and treatment outcomes of older patients with breast cancer in Jordan.

BACKGROUND: Less than 10% of newly diagnosed breast cancer cases in Jordan are diagnosed in women 70 years or older. Treatment plans of such patients is less clear and could result in poor outcomes. In this paper, we describe clinical presentation, tumor characteristics and treatment outcomes in this population of breast cancer patients. METHODS: Consecutive patients aged 65 years or older with pathologically-confirmed diagnosis of breast cancer were included. Medical records and hospital databases were searched for patients' characteristics and treatment outcomes. RESULTS: A total of 553 patients, mean age ± SD (71 ± 5.1) years, were included. On presentation, 114 (20.6%) patients had metastatic disease and was mostly visceral (81; 71.1%). Patients with non-metastatic disease had poor pathological features including node-positive in 244 (55.6%), high grade (grade III) in 170 (38.7%) and lymphovascular invasion in 173 (39.4%). Patients were treated less aggressively; 144 (32.8%) patients with early-stage disease and 98 (86.0%) with metastatic disease never had chemotherapy. After a median follow up of 45 months, 5-year overall survival for the whole group was 67.6%. Survival was better for patients with non-metastatic disease (78.8% vs. 25.4%, P < 0.001) and for those with node-negative compared to node-positive disease (85.4% vs. 74.1%, P = 0.002). On Cox regression, only positive lymph nodes were associated with poor outcome in patients with non-metastatic disease (Hazard Ratio [HR], 1.75; 95% CI: 1.006-3.034, P = 0.048). CONCLUSIONS: Older Jordanian patients with breast cancer present with more aggressive features and advanced-stage disease that reflect poorly on treatment outcomes. Older patients were treated less aggressively with less than a third received any chemotherapy.

Thromboembolic events in cancer patients on active treatment with cisplatin-based chemotherapy: another look!

BACKGROUND: The risk of thromboembolic events is higher among cancer patients, especially in patients undergoing chemotherapy. Cisplatin-based regimens claim to be associated with a very high thromboembolic rate. In this study, we report on our own experience with thrombosis among patients on active cisplatin-based chemotherapy. METHODS: Medical records and hospital databases were searched for all the patients treated with any cisplatin-based regimen for any kind of cancer. Thrombosis was considered cisplatin-related if diagnosed any time after the first dose and up to 4 weeks after the last. The Khorana risk assessment model was performed in all cases. RESULTS: A total of 1677 patients (65.5% males, median age: 50 years) treated with cisplatin-based regimens were identified. Head and neck (22.9%), lung (22.2%), lymphoma and gastric (11.4% each) were the most common primary tumors. Thromboembolic events were reported in 110 (6.6%); the highest was in patients with gastric cancer (20.9%) and the lowest in patients with head and neck cancers (2.3%) and lymphoma (1.6%). Thrombosis included deep vein thrombosis (DVT) in 69 (62.7%), pulmonary embolism (PE) in 18 (16.9%) and arterial thrombosis in 17 (15.6%). A majority (51.1%) of the patients had stage IV disease and only 16% had stage I or II.In a multivariate analysis, significantly higher rates of thrombosis were associated with gastric as the primary tumor, advanced-stage disease, female sex but not age, and the Khorana risk score or type of cisplatin regimen. While the presence of CVC was significantly associated with the risk of thrombosis (p < 0.0001) in the univariate analysis, and such significance was lost in the multivariate analysis (odds ratio, 1.098; 95%CI, 0.603-1.999, p = 0.7599). CONCLUSIONS: Thromboembolic events in cancer patients on active cisplatin-based chemotherapy were commonly encountered. Gastric cancer, regardless of other clinical variables, was associated with the highest risk.

From clinical trials to clinical practice: outcome of NSABP-B27 neoadjuvant chemotherapy regimen for high-risk early-stage breast cancer.

PURPOSE: Majority of Jordanian breast cancer patients present at a relatively young age and with locally advanced disease highlight the importance of neoadjuvant chemotherapy. This study evaluated the efficacy and safety of NSABP-B27 regimen in high-risk patients in daily clinical practice. METHODS: Patients' medical records and hospital database were searched for all consecutive patients treated at our institution for breast cancer using neoadjuvant NSABP-B27 chemotherapy regimen. Chemotherapy was given at standard doses and schedule as originally reported in the NSABP-B27. RESULTS: 346 female patients (median age 51 years) were treated using this regimen. Majority had high-risk features including larger tumor size (>4 cm in 68.5%), positive axillary lymph nodes (78.3%), and Grade III disease (47.4%). While most patients tolerated and completed planned chemotherapy, 41 (11.8%) patients failed to complete all four cycles of docetaxel. Following neoadjuvant chemotherapy, complete pathological response (pCR) was achieved in 84 (25.0%) evaluable patients; pCR was higher in hormone receptor-negative disease (40.0 vs. 22.1%, p = 0.002), in patient with tumor size ≤4 cm (28.3 vs. 23.5%, p = 0.024) and in patients with node-negative disease (41.2 vs. 20.7%, p = 0.002). Age (<50 vs. ≥50) had no effect, with pCR of 24.2 and 26.4%, respectively (p = 0.607). Breast-conserving surgery was performed in 85 (24.6%). CONCLUSIONS: NSABP-B27 is an effective neoadjuvant regimen. Despite including higher risk patients, pCR is similar to the original NSABP-B27 and many other anthracycline-taxane-based regimens. Tumor size, LN status, hormone receptors status, but not age, were significant factors in achieving pCR.

Management of breast cancer patients with BRCA gene mutations in Jordan: perspectives and challenges.

BACKGROUND: This paper explores and discusses local challenges oncologists face for diagnosing and managing breast cancer patients with BRCA gene mutations in Jordan. METHODS: A task force involving key opinion leaders, experts in the management of breast cancer, and stakeholders in healthcare systems where genetic testing is available in Jordan discussed current evidence and local real-life practice. The task force then formulated recommendations to achieve better patient outcomes and satisfaction based on evidence-based medicine and their clinical experience in BRCA-mutated breast cancer management. RESULTS AND CONCLUSION: Eligibility of patients for genetic testing, physician acceptance and willingness to integrate genetic testing into routine practice is encouraging but remains restricted by testing availability and financial coverage. Until more data is available, genetic testing should be targeted for breast cancer patients based on tumor subtypes, as well as family and personal history of cancer, as per international guidelines. Whenever possible, genetic testing should aim to detect all actionable genes through a multigene panel including BRCA1/2. Major challenges faced in clinical practice in Jordan include fear of genetic discrimination and social stigmatization, as well as hesitancy toward risk-reducing surgery. Pre-testing counseling is therefore critical to promote acceptance of genetic testing. Since geneticists are in short supply in Jordan, genetic counseling can be offered through a specially trained genetic counselor or through a hybrid system that includes oncologist-based counselling. In addition to cancer prevention, germline genetic testing may assist in the selection of specific anti-cancer therapy, such as PARP inhibitors, in patients with BRCA1/2 mutation. Nationwide initiatives are also needed to ensure access to PARP inhibition therapy and provide financial coverage for genetic screening, mastectomies and reconstructive surgery across Jordan.

Guideline-Based, Multi-Gene Panel Germline Genetic Testing for at-Risk Patients with Breast Cancer.

Background: Genetic testing for at-risk patients with breast cancer should be routinely offered. Knowledge generated may influence both treatment decisions and cancer prevention strategies among the patients themselves and their relatives. In this study, we report on the prevalence and patterns of germline mutations, using commercially available next-generation sequencing (NGS)-based multi-gene panels (MGP). Patients and Methods: Consecutive at-risk breast cancer patients, as determined by international guidelines, were offered germline genetic testing using a 20-gene NGS-based panel at a reference lab. Samples of peripheral blood were obtained for DNA extraction and genetic variants were classified as benign/likely benign (negative), pathogenic/likely pathogenic (positive) or variants of uncertain significance (VUS). Results: A total of 1310 patients, median age (range) 43 (19-82) years, were enrolled. Age ≤45 years (n = 800, 61.1%) was the most common indication for testing. Positive family history of breast, ovarian, pancreatic or prostate cancers, and triple-negative disease were among the common indications. Among the whole group, 184 (14.0%) patients had pathogenic/likely pathogenic variants; only 90 (48.9%) were in BRCA1 or BRCA2, while 94 (51.9%) others had pathogenic variants in other genes; mostly in APC, TP53, CHEK2 and PALB2. Mutation rates were significantly higher among patients with positive family history (p = 0.009); especially if they were 50 years or younger at the time of breast cancer diagnosis (p < 0.001). Patients with triple-negative disease had relatively higher rate (17.5%), and mostly in BRCA1/2 genes (71.4%). Variants of uncertain significance (VUS) were reported in 559 (42.7%) patients; majority (90.7%) were in genes other than BRCA1 or BRCA2. Conclusion: Pathogenic mutations in genes other than BRCA1/2 are relatively common and could have been missed if genetic testing was restricted to BRCA1/2. The significantly high rate of VUS associated with multi-gene panel testing can be disturbing.

From clinical trials to clinical practice: the use of everolimus and exemestane in the treatment of hormone receptor-positive metastatic breast cancer: real-world data.

Everolimus combined with exemestane can modulate endocrine resistance. The combination showed significant improvement in progression-free survival (PFS) in phase III clinical trials for hormone receptor positive metastatic breast cancer patients. It also showed serious adverse events. We evaluate the efficacy and prevalence of serious adverse events in a real-world setting. We retrospectively examined 91 breast cancer patients; all were previously treated with chemotherapy and fulvestrant (84% and 59%, respectively). After a 13-month median follow-up, 29% had a partial response, and 32% had stable disease. The PFS was 7.8 months. Due to adverse events, 19% of patients stopped the treatment, while 31% required a dose reduction. Despite enrolling heavier-pretreated patients, our real-world outcome for the efficacy and safety of the exemestane and everolimus match those of the clinical trials. Such results should assure clinicians and lead to wider adoption of this oral, chemotherapy-sparing regimen.

Thromboembolic Events in Patients with HER2-Negative, Hormone Receptor-Positive, Metastatic Breast Cancer Treated with Ribociclib Combined with Letrozole or Fulvestrant: A Real-World Data.

Purpose: Cyclin dependent kinase (CDK) 4/6 inhibitors (palbociclib, ribociclib and abemaciclib) modulate endocrine resistance and are integral treatment for patients with advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Since their approval, CDK4/6 inhibitors are widely used in clinical practice. Thromboembolic events (TEE) were not a major issue in patients treated on clinical trials utilizing these agents. However, conflicting data started to emerge describing higher than expected rates of both arterial and venous thrombosis in patients treated with CDK4/6 inhibitors. In this study, we report our experience on TEE in patients treated with one of these agents (ribociclib) in real-world settings. Patients and Methods: All consecutive patients with metastatic breast cancer (mBC) treated with ribociclib combined with letrozole or fulvestrant were retrospectively reviewed. All episodes of radiologically confirmed arterial or venous thrombosis were recorded. TEE was considered ribociclib-related if diagnosed while patients are on the drug, or within 4 weeks after the last dose. Results: A total of 305 patients, median age (range), 49 (22-87) years were enrolled. All patients had metastatic disease, and most (n=241, 79.0%) were with visceral metastasis. Ribociclib was used for a median duration of 7 months (range: 1-45) and was used beyond the first-line setting in 110 (35.9%) patients. TEE were confirmed on 6 (1.97%) patients; 3 were pulmonary embolism, 2 cerebral venous sinus thrombosis (CVST), and one case of limb ischemia and all were symptomatic. Similar rates of TEE were noted prior to initiation, and after stopping ribociclib. Conclusion: In real-world settings, breast cancer patients treated with ribociclib, combined with aromatase inhibitors or fulvestrant, may not be at higher risk for thromboembolic events. However, unusual sites of thrombosis, like CVST, may raise some concerns.

Rates of Variants of Uncertain Significance Among Patients With Breast Cancer Undergoing Genetic Testing: Regional Perspectives.

Purpose: Contrary to BRCA pathogenic variants, recommendations for management of variants of uncertain significance (VUS) are not clear and focus more on the patient's family and personal history of cancer. Local and regional data on VUS are scarce. In this paper, we study patterns and frequency of VUS among breast cancer patients undergoing genetic testing. Patients and Methods: Patients with breast cancer at high risk for pathogenic variants, as per the National Comprehensive Cancer Network (NCCN) guidelines, were tested at reference laboratories. Related surgical interventions were reviewed. Results: Among a group of 1,197 patients with breast cancer who underwent genetic testing and counseling, 110 (9.2%) had VUS; most (n = 79, 71.8%) were in BRCA2. Median age (range) was 39 (25-66) years with 65 (59.1%) patients who were 40 years or younger at diagnosis. Among 103 patients with non-metastatic disease, 48 (46.6%) had breast-conserving surgery (BCS) while only 5 (4.9%) had bilateral mastectomies; all were due to bilateral disease and not prophylactic. VUS diagnosis was known prior to initial surgery in 34 (33.0%) patients; 11 (32.4%) of them had BCS only. Over the study period, only one VUS variant was upgraded to "likely positive." The recent introduction of multiple-gene panel testing had resulted in a surge in VUS rate (22.2%) in genes other than BRCA1 or BRCA2, like PALB2, CHEK2, and ATM. Conclusions: Rates of VUS are relatively high and increasing, mostly in non-BRCA1 or BRCA2, and this had no impact on the therapeutic or prophylactic surgical decisions. Adherence to guidelines is extremely important to avoid unnecessary procedures.

The practice of withholding and withdrawing life-support measures among patients with cancer in Jordan.

In Jordan, an Arabic Islamic country, decisions around withholding and/or withdrawing life support measures still present both moral and professional dilemmas. The purpose of this study was to explore the use of such measures among patients with cancer in Jordan. The medical records of 436 patients with cancer who were at least 18 years old and who died at a specialized cancer centre in Jordan in 2008 were reviewed retrospectively. Of those, 212 (48.6%) had a written decision to withhold or withdraw life support measures. Among the 436 charts reviewed, only 7 patients (1.6%) had treatment withdrawn, while 212 (48.6%) had treatment withheld. Resuscitation was the most common treatment withheld, followed by medication, and poor prognosis was the most common reason for the decision. The time period between a decision being made and the death of the patient was short, indicating that treatment plans are not being made well in advance. A cultural and religious consensus regarding such decisions is needed to help ensure that a greater proportion of terminally ill people plan their care in advance, and to aid health-care providers in advising their patients and acting in the patients' best interests.

Treatment of anemia in cancer patients undergoing chemotherapy with intravenous ferric carboxymaltose without erythropoiesis-stimulating agents.

BACKGROUND: Anemia is commonly encountered in cancer patients receiving active chemotherapy. Due to adverse events and presumed negative effects on disease-progression and survival, erythropoiesis-stimulating agents are not frequently used. In this study, we assess the efficacy and safety of intravenous ferric carboxymaltose (FCM) to treat cancer-induced anemia (CIA). PATIENTS AND METHODS: We recruited adult cancer patients on active chemotherapy with a hemoglobin (Hb) level ⩽11.0 g/dL. Based on serum ferritin (sFr) and transferrin saturation (TSAT), patients were divided into 3 groups: group I (absolute iron deficiency, n = 26) with sFr < 30 ng/mL and TSAT < 20%; group II (functional iron deficiency, n = 24) with sFr 30-800 ng/mL and TSAT < 20%; and patients with TSAT ⩾ 20% were placed in group III as "others" (n = 34). All patients were treated with intravenous FCM. Serum hepcidin and C-reactive protein were used as biomarkers to predict response. RESULTS: A total of 84 patients with a median age (SD) of 53.8 (10.6) were recruited. Baseline median Hb level was 10.2 (range: 8.3-11.0) gm/dL. At week 12, there was a significant increment in Hb level for patients in groups I and II (median increment: 2.35 and 1.5 gm/dL, respectively), with limited response observed in group III, and most of the increment noted as early as week 3 (⩾1.0 g/dL). Responders tended to have lower levels of hepcidin. No clinically significant adverse events were reported; however, asymptomatic hypophosphatemia was observed in 39 (46.4%) patients. CONCLUSIONS: Intravenous FCM is a safe and effective treatment option for the management of a subgroup of patients with CIA.The study was registered at ClinicalTrials.gov [Identifier: NCT04246021].

Clinicopathological Characteristics And Treatment Outcomes Of Breast Cancer Among Adolescents And Young Adults In A Developing Country.

PURPOSE: Compared to Western societies, breast cancer diagnosis in our region is usually made at a younger age and at a more advanced stage. Breast cancer in younger patients tends to be more aggressive, and may result in a higher likelihood of long-term treatment-related toxicity and unique psychosocial problems. This study highlights the clinicopathological features and treatment outcomes in this age-group in a developing country like ours. METHODS: Consecutive patients aged 40 years or younger with a pathologically confirmed diagnosis of breast cancer treated and followed up at our institution were included. Medical records and hospital databases were searched for patients' characteristics and treatment outcomes. RESULTS: A total of 417 patients were enrolled. Median age at diagnosis was 35 (21-40) years. On presentation, 63 (15.1%) patients had metastatic disease, 50 (79.4%) with visceral metastasis. Patients with nonmetastatic disease had poor pathological features, including node-positivity (66.9%), grade III (51.4%), lymphovascular invasion (48.6%) and positive HER2 (31.5%). Breast-conserving surgery was performed on 32.9%, and only 36.5% of women had breast-reconstruction surgery. At a median follow-up of 59 months, 5-year overall survival for the whole group was 72%: 84% for nonmetastatic and 13% for those with metastatic disease. On Cox regression, nodal metastasis (adjusted HR 3.46, 95% CI 1.48-8.10; p=0.004) and grade III disease (HR 1.97, 95% CI 1.14-3.39; p=0.015) were associated with poor outcome. CONCLUSION: Adolescents and young Jordanian adults with breast cancer present with more advanced-stage disease and more aggressive pathological features that reflect poorly on treatment outcomes.

Four cycles of adriamycin and cyclophosphamide followed by four cycles of docetaxel (NSABP-B27) with concomitant trastuzumab as neoadjuvant therapy for high-risk, early-stage, HER2-positive breast cancer patients.

BACKGROUND: The majority of breast cancer patients in Jordan are diagnosed at a young age and present with metastatic or locally advanced disease. The National Surgical Adjuvant Breast and Bowel Project Protocol B27 (NSABP-B27) (four cycles of adriamycin and cyclophosphamide [AC] followed by four cycles of docetaxel) is a standard neoadjuvant regimen in our institution. In this study, we report the efficacy of adding trastuzumab to docetaxel in this regimen for high-risk human epidermal growth factor receptor 2 (HER2)-positive early-stage disease. PATIENTS AND METHODS: Consecutive HER2-positive breast cancer patients treated with this regimen were included. Treatment was given at standard doses and schedules as reported in NSABP-B27. Trastuzumab was given with docetaxel and then continued for 1 year. RESULTS: A total of 121 patients (mean age 45.4 years) were included. The majority had high-risk features including large tumor size, positive axillary lymph nodes, and grade III disease. Three patients did not complete the planned cycles of AC due to a lack of response. Eight (6.6%) patients missed at least one cycle of docetaxel. Following neoadjuvant therapy, 119 patients underwent surgery, of whom 59 (49.6%) patients achieved pathological complete response. The response was higher in node-negative patients (64.0 vs 45.7%; P=0.03) and in hormone receptor-negative disease patients (69.7 vs 41.9%; P=0.018). Breast-conserving surgery was performed in 21.5% of the patients. The median disease-free survival (DFS) for the whole group was not reached while the 3- and 5-year DFS rates were 84.2 and 74.1%, respectively. CONCLUSION: Trastuzumab added to the NSABP-B27 regimen is a unique combination. When used in high-risk patients, as in our study, outcomes similar to reported data were achieved without unexpected toxicities.

Inferior vena cava filters in cancer patients: to filter or not to filter.

PURPOSE: Cancer and its treatment are recognized risk factors for venous thromboembolism (VTE); active cancer accounts for almost 20% of all newly diagnosed VTE. Inferior vena cava (IVC) filters are utilized to provide mechanical thromboprophylaxis to prevent pulmonary embolism (PE) or to avoid bleeding from systemic anticoagulation in high-risk situations. In this report, and utilizing a case study, we will address the appropriate utilization of such filters in cancer patients. METHODS: The case of a 43-year-old female patient with rectal cancer, who developed deep vein thrombosis following a complicated medical course, will be presented. The patient was anticoagulated with a low molecular weight heparin, but a few months later and following an episode of bleeding, an IVC filter was planned. Using the PubMed database, articles published in English language addressing issues related to IVC filters in cancer patients were accessed and will be presented. RESULTS: Many recent studies questioned the need to insert IVC filters in advanced-stage cancer patients, particularly those whose anticipated survival is short and prevention of PE may be of little clinical benefit and could be a poor utilization of resources. CONCLUSION: Systemic anticoagulation can be safely offered for the majority of cancer patients. When the risk of bleeding or pulmonary embolism is high, IVC filters can be utilized. However, placement of such filters should take into consideration the stage of disease and life expectancy of such patients.

The impact of recently published negative erythropoiesis-stimulating agent studies on the clinical management of cancer-related anemia at a single center.

BACKGROUND AND OBJECTIVES: Anemia in cancer patients is common, but often under-recognized and under-treated. Erythropoiesis stimulating agents (ESAs) are widely used to prevent and treat cancer and chemo- therapy-related anemia, but recent studies suggest a negative impact on disease progression and survival associated with their use. This retrospective study describes the prevalence of anemia in cancer patients and recent trends in its management given the negative studies. PATIENTS AND METHODS: All consecutive adult cancer patients (n=959) admitted to regular medical units over one year were reviewed. Patients with a hemoglobin (Hb) value <12 g/dL on admission were considered anemic. Information on the primary tumor, main reasons for admission and treatment given were collected. RESULTS: At the time of enrollment, anemia was detected in 755 (78.7%) patients. The mean Hb value for anemic patients was 9.5 g/dL. Prevalence and severity of anemia varied according to tumor type and reason for admission. The majority (68.6%) of the anemic patients were not offered treatment. The mean Hb value at which treatment was started was 8.0 g/dL. Anemia treatment was related to its severity; treatment rates were 94.4%, 32.9%, and 5.0% in patients with severe, moderate and mild anemia, respectively (P<.0001). Blood transfusion was used the most while ESAs were rarely used. Length of hospital stay was affected by the presence of anemia (7.2 days in anemic patients vs. 4.85 days in nonanemic patients) (P<.001). CONCLUSIONS: Blood transfusion was used the most for cancer-related anemia, while ESAs were rarely used. The majority of patients with moderate anemia were not treated, including patients on active chemotherapy. Better guidelines addressing anemia management in this subgroup of patients are highly needed.