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With the development of HER2-directed therapies, identifying non-invasive imaging biomarkers of HER2 status in breast cancer brain metastases has become increasingly important, particularly given the risks of tissue sampling within the brain and the possibility of a change in receptor expression from the primary tumor to the brain metastasis. The purpose of this study was to evaluate whether lesion contour and composition on MR could help identify the HER2 status of breast cancer brain metastases.We derived a cohort of 34 women with a mean age of 55 years (range: 31-81 years) with a total of 47 distinct histologically proven breast cancer brain metastases with preoperative contrast-enhanced brain MR and HER2 immunohistochemistry and/or fluorescent in-situ hybridization (FISH) of the resected/biopsied brain specimens from 2018 to 2021. Two fellowship-trained neuroradiologists evaluated the lesion contour and lesion composition of each lesion. Logistic regression analyses were performed.In a logistic regression model, an irregular contour had an odds ratio of 170 (p = 0.007) in differentiating HER2-positive from HER2-negative lesions. In a logistic regression model, when compared to a predominantly cystic lesion composition, a solid lesion composition had an odds ratio of 17 (p = 0.016) in differentiating HER2-positive from HER2-negative lesions.Lesion contour and lesion composition on MR were significantly associated with the HER2 status of breast cancer brain metastases. Current assessment of HER2 status requires tissue sampling and immunochemical and/or FISH analyses. A non-invasive imaging biomarker that may help predict HER2 status may be of great clinical value.

Introduction Phase II clinical trials including geriatric assessment (GA) measures are critical for improving the evidence base for older adults with cancer. We assessed the efficacy and tolerability of nab-paclitaxel in older adults with metastatic breast cancer (MBC). Patients and Methods Patients aged ≥ 65 years with MBC and ≤ 1 previous line of chemotherapy received 100 mg of nab-paclitaxel on days 1, 8, and 15 of a 28-day cycle. A GA was completed pre-chemotherapy, and the validated Cancer and Aging Research Group (CARG) chemotherapy toxicity risk score was calculated. Relationships between tolerability (number of courses, hospitalizations, dose reductions, and toxicity) and risk score were assessed using general linear models, Student t tests, and the Fisher test. Response rate and progression-free survival were evaluated using the Kaplan-Meier method. Results Forty patients (mean age, 73 years; range, 65-87 years) were included. The median number of cycles was 6, 75% (n = 30) of patients had ≥ 1 dose hold, and 50% (n = 20) had ≥ 1 dose reduction. Fifty-eight percent (n = 23) had treatment-related ≥ grade 3 toxicities, and 30% (n = 12) were hospitalized owing to toxicity. Thirty-five percent (n = 14) responded, and the median progression-free survival was 6.5 months (95% confidence interval, 5.5 months to undefined). Patients with intermediate/high toxicity risk scores had higher risk of grade ≥ 3 toxicity than those with low risk scores (odds ratio, 5.8; 95% confidence interval, 1.3-33.1; P = .01). A higher mean risk score was associated with higher likelihood of dose reductions and hospitalizations. Conclusions Among older adults with MBC receiving weekly nab-paclitaxel, more than one-half experienced ≥ grade 3 chemotherapy toxicity. However, a GA-based risk score could predict treatment tolerability.

Summary Although obesity is known to be critical for cancer development, how obesity negatively impacts antitumor immune responses remains largely unknown. Here, we show that increased fatty acid oxidation (FAO) driven by activated STAT3 in CD8+ T effector cells is critical for obesity-associated breast tumor progression. Ablating T cell Stat3 or treatment with an FAO inhibitor in obese mice spontaneously developing breast tumor reduces FAO, increases glycolysis and CD8+ T effector cell functions, leading to inhibition of breast tumor development. Moreover, PD-1 ligation in CD8+ T cells activates STAT3 to increase FAO, inhibiting CD8+ T effector cell glycolysis and functions. Finally, leptin enriched in mammary adipocytes and fat tissues downregulates CD8+ T cell effector functions through activating STAT3-FAO and inhibiting glycolysis. We identify a critical role of increased oxidation of fatty acids driven by leptin and PD-1 through STAT3 in inhibiting CD8+ T effector cell glycolysis and in promoting obesity-associated breast tumorigenesis.

Endocrine therapy in the setting of breast cancer has undoubtedly advanced clinical outcomes in this disease, but treatment with endocrine therapy is accompanied by a wide spectrum of side effects. It is of prime importance to understand and characterize these toxicities to facilitate clinical decision-making. Somewhat surprisingly, there is a relative paucity of data pertaining to cognitive changes associated with endocrine therapy. In this article we review cognitive associated with two classes of endocrine therapy: (1) selective estrogen receptor modulators (SERMs; tamoxifen and raloxifene) and (2) aromatase inhibitors (AIs; anastrozole, letrozole, and exemestane). Companion studies to the Multiple Outcome of Raloxifene Evaluation (MORE), the Study of Tamoxifen and Raloxifene (STAR) and National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trials provide relevant data to understand the effect of SERMs on cognition. In contrast, substudies of the Arimidex, Taxmoxifen Alone or in Combination (ATAC), Tamoxifen and Exemestane Adjuvant Multinational (TEAM) and Breast International Group (BIG) 1–98 trials juxtapose cognitive effects of AIs against those of tamoxifen. These and other studies are examined herein to provide a comprehensive overview of the effect of endocrine therapy on cognition.

Summary Background Treatment with bisphosphonates decreases bone loss and can increase disease-free survival in patients with breast cancer. The aim of our study was to assess the effect of zoledronic acid on clearance of disseminated tumour cells (DTCs) from the bone marrow in women undergoing neoadjuvant chemotherapy for breast cancer. Methods Patients were recruited for this open-label, phase 2 randomised trial between March 17, 2003, and May 19, 2006, at a single centre. Eligible patients had clinical stage II–III (≥T2 and/or ≥N1) newly diagnosed breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, and normal cardiac, renal, and liver function. 120 women were randomly assigned, using allocation concealment, to receive 4 mg zoledronic acid intravenously every 3 weeks (n=60), or no zoledronic acid (n=60), for 1 year concomitant with four cycles of neoadjuvant epirubicin (75 mg/m 2 ) plus docetaxel (75 mg/m 2 ) and two cycles of adjuvant epirubicin plus docetaxel. The primary endpoint was the number of patients with detectable DTCs at 3 months. Final analysis was done 1 year after the last patient was enrolled. Analyses were done for all patients with available data at 3 months. This study is registered with ClinicalTrials.gov, number NCT00242203. Findings Of the 120 patients initially enrolled, one withdrew after signing consent and one patient's baseline bone marrow was not available. Both of these patients were in the control group. At 3 months, 109 bone-marrow samples were available for analysis. In the zoledronic acid group, bone marrow was not collected from one patient because of disease progression, one patient was taken off study because of severe diarrhoea, and two patients had not consented at the time of surgery. In the control group, bone marrow was not collected from two patients because of disease progression, one patient withdrew consent, and three patients were not consented at the time of surgery. At baseline, DTCs were detected in 26 of 60 patients in the zoledronic acid group and 28 of 58 patients in the control group. At 3 months, 17 of 56 patients receiving zoledronic acid versus 25 of 53 patients who did not receive zoledronic acid had detectable DTCs (p=0·054). The most common grade 3–4 toxicities were infection (five of 60 patients in the zoledronic acid group and six of 59 in the control group) and thrombosis (five of 60 in the zoledronic acid and two of 59 in the control group). There was one documented case of osteonecrosis in the zoledronic acid group. Interpretation Zoledronic acid administered with chemotherapy resulted in a decreased proportion of patients with DTCs detected in the bone marrow at the time of surgery. Our study supports the hypothesis that the antimetastatic effects of zoledronic acid may be through effects on DTCs. Funding Novartis Pharmaceuticals and Pfizer Inc.

Increasing evidence suggests mutations in human breast cancer cells that induce inappropriate expression of the 18-kDa cytokine pleiotrophin (PTN, Ptn) initiate progression of breast cancers to a more malignant phenotype. Pleiotrophin signals through inactivating its receptor, the receptor protein tyrosine phosphatase (RPTP)beta/zeta, leading to increased tyrosine phosphorylation of different substrate proteins of RPTPbeta/zeta, including beta-catenin, beta-adducin, Fyn, GIT1/Cat-1, and P190RhoGAP. PTN signaling thus has wide impact on different important cellular systems. Recently, PTN was found to activate anaplastic lymphoma kinase (ALK) through the PTN/RPTPbeta/zeta signaling pathway; this discovery potentially is very important, since constitutive ALK activity of nucleophosmin (NPM)-ALK fusion protein is causative of anaplastic large cell lymphomas, and, activated ALK is found in other malignant cancers. Recently ALK was identified in each of 63 human breast cancers from 22 subjects. We now demonstrate that RPTPbeta/zeta is expressed in each of these same 63 human breast cancers that previously were found to express ALK and in 10 additional samples of human breast cancer. RPTPbeta/zeta furthermore was localized not only in its normal association with the cell membrane but also scattered in cytoplasm and in nuclei in different breast cancer cells and, in the case of infiltrating ductal carcinomas, the distribution of RPTPbeta/zeta changes as the breast cancer become more malignant. The data suggest that the PTN/RPTPbeta/zeta signaling pathway may be constitutively activated and potentially function to constitutively activate ALK in human breast cancer.

Purpose The purpose of this study was to determine the incidence of metastatic bone disease (MBD), the frequency of intravenous (I.V.) bisphosphonate use and its impact on skeletal-related events (SREs), and opioid use. Patients and Methods Patients diagnosed with MBD between 2000 and 2004 were identified using 2 Thomson MarketScan® Research Databases. A total of 6783 patients, 1431 with breast cancer, fulfilled the criteria. Pain was assessed as the number of days on opioids, the strength of which was categorized according to the World Health Organization 3-step ladder for pain. Results Use of I.V. bisphosphonates steadily increased for all cancers from 17% in 2000 to 38% in 2004. For all patients, 61% received mild opioids and 35% received moderate to severe opioids at baseline. Use of I.V. bisphosphonates within the first 90 days after diagnosis of MBD was associated with a 63% decrease in SREs and reduction in use of moderate to severe opioids. Among patients with breast cancer, 10.6% received oral bisphosphonates before diagnosis of MBD, and 33.8% had pain at baseline. There was a 5.4% reduction in the use of moderate to severe opioids. Conclusion Our data support the role of I.V. bisphosphonates in decreasing SRE and improving the quality of life for patients with MBD; the result is less pain and fewer SREs. More than 73% of all patients and 53% of patients with breast cancer never receive I.V. bisphosphonate treatment. Educational measures are warranted to increase the awareness by patients and physicians of the value of I.V. bisphosphonates in MBD.

Pleiotrophin (PTN, Ptn) is an 18kDa cytokine expressed in human breast cancers. Since inappropriate expression of Ptn stimulates progression of breast cancer in transgenic mice and a dominant negative PTN reverses the transformed phenotype of human breast cancer cells that inappropriately express Ptn, it is suggested that constitutive PTN signaling in breast cancer cells that inappropriately express Ptn activates pathways that promote a more aggressive breast cancer phenotype. Pleiotrophin signals by inactivating its receptor, the receptor protein tyrosine phosphatase (RPTP)beta/zeta, and, recently, PTN was found to activate anaplastic lymphoma kinase (ALK) through the PTN/RPTPbeta/zeta signaling pathway in PTN-stimulated cells, not through a direct interaction of PTN with ALK and thus not through the PTN-enforced dimerization of ALK. Since full-length ALK is activated in different malignant cancers and activated ALK is a potent oncogenic protein, we examined human breast cancers to test the possibility that ALK may be expressed in breast cancers and potentially activated through the PTN/RPTPbeta/zeta signaling pathway; we now demonstrate that ALK is strongly expressed in different histological subtypes of human breast cancer; furthermore, ALK is expressed in both nuclei and cytoplasm and, in the ;;dotted" pattern characteristic of ALK fusion proteins in anaplastic large cell lymphoma. This study thus supports the possibility that activated ALK may be important in human breast cancers and potentially activated either through the PTN/RPTPbeta/zeta signaling pathway, or, alternatively, as an activated fusion protein to stimulate progression of breast cancer in humans.

Purpose: To conduct a dose escalation clinical study with topotecan and concurrent standard dose thoracic irradiation to assess its feasibility and toxicity in the treatment of patients with locally advanced, inoperable nonsmall cell lung cancer (NSCLCA). Methods and Materials: Between April 1993 and August 1994, 12 patients with inoperable, loco-regionally advanced NSCLCA were entered in a prospective dose escalation trial and assigned to receive concurrent thoracic radiotherapy and topotecan. Patients received thoracic irradiation to a total tumor dose of 60 Gy in 30 fractions. Initial fields were to encompass the gross disease plus the mediastinum. Topotecan was delivered by bolus injection days 1 through 5, and days 22 through 26, beginning on the same day as the radiation therapy. The initial dose level was 0.5 mg/m 2 . Two additional dose levels of 0.75 mg/m 2 and 1.0 mg/m 2 were tested. Results: Six patients were accessioned to the 0.5 mg/m 2 dose level, three patients to the 0.75 mg/m 2 dose level, and three patients to the 1.0 mg/m 2 dose level. At the 0.5 mg/m 2 dose level, zero of six patients had ≥Grade 4 hematologic toxicity. One of the six had Grade 3 esophagitis. At the 0.75 mg/m 2 dose level, two of three patients had ≥Grade 3 nonhematologic toxicity including anorexia, fatigue, nausea, vomiting, and weakness; zero patients experienced ≥Grade 4 hematologic toxicity. At the 1.0 mg/m 2 dose level one of three patients had ≥Grade 3 esophagitis, and two of three patients experienced Grade 4 neutropenia. With a follow-up of 12 to 24 months, two patients are alive and free of disease, three patients are alive with disease (two with distant metastasis, one with local disease and distant metastasis), and the remaining seven patients are dead of disease. Conclusions: The combination of topotecan and thoracic radiotherapy for nonsmall lung cancer, in the manner given by this protocol, could be safely given at a dose level of only 0.5 mg/m 2 days 1 to 5 and 22 to 26 with 60 Gy of external beam radiotherapy. Higher doses of topotecan were associated with high hematologic and gastrointestinal toxicity. Distant metastasis was the primary pattern of failure.

Malignancies arising from the gastrointestinal tract represent a diversity of histologies and natural history. The role of chemotherapy in the multidisciplinary approach to these malignancies is reviewed in this article.

Anemia is a common problem in elderly patients. The National Health and Nutrition Examination Survey (NHANES III) reported that the incidence of anemia steadily increases after age 50. Anemia is found in 10% and 11% ofwomen andmen respectively who were older than age 65, and in 20% of individuals≥85 years. In this sameseries, the causes of anemia inpatients over 65 years were equally attributed to nutritional deficiency, anemia of inflammation, and “unexplained” causes. Anemia in the geriatric population has unique significance because it is an independent predictor ofmorbidity,mortality, and frailty. Consistently an inverse relationship between the number of co-morbid medical conditions and anemia is observed. The anemia associated with malignancy is complex and multifactorial. It may be caused by blood loss, marrow infiltration, erythrophagocytosis, or inflammation. The treatment of anemia in geriatric oncology patients is likely to be evenmore complex. In younger patients with cancer, the impetus to correct anemia has largely been driven by a desire to improve patients' quality of life. Using the FACT to assess fatigue in a mixed population of cancer patients, Cella demonstrated an inverse association between the level of hemoglobin and the selfreporting of fatigue. In elderly patients the imperative to correct anemia is further driven by the physiologic consequences of low oxygen carrying capacity on already compromised cardiac, pulmonary, and renal reserves. Either transfusion of red blood cells or the administration of erythropoietin stimulating agents (ESAs) has been used to correct anemia in individuals with cancer. The tenuous fluid and electrolyte balance experienced by elderly patients make transfusion a somewhat less desirable approach.

Seventy-eight patients with cancer experienced 88 episodes of fever while neutropenic and were randomly assigned to receive empiric antibiotic therapy with cefoperazone 2 g intravenously every 12 hours and mezlocillin 4 g intravenously every six hours or imipenem/cilastatin 500 mg intravenously over 30 to 60 minutes every six hours. Within 96 hours of starting antibiotic treatment, 24 patients (57 percent) treated with cefoperazone and mezlocillin and 34 patients (74 percent) receiving imipenem/cilastatin became afebrile. One half of the patients in each arm required changes in the antibiotic regimen because of side effects, persistent fever with a site suspicious for infection, resistant organisms, or breakthrough bacteremias. Forty patients (95 percent) receiving cefoperazone and mezlocillin and 43 patients (93 percent) receiving imipenem/cilastatin recovered from the neutropenic episode. Two patients in each regimen group died of their underlying disease. One patient in the imipenem/cilastatin arm died of Pseudomonas aeruginosa sepsis. Although the two regimens are comparable in efficacy, the incidence of side effects favored the cefoperazone and mezlocillin group. No seizures or bleeding were seen in either arm; however, 19 patients (41 percent) receiving imipenem/cilastatin required pretreatment antiemetic drugs for nausea.