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The response of bone-dominant (BD) breast cancer to therapy is difficult to assess by conventional imaging. Our preliminary studies have shown that quantitative serial 2-[(18)F] fluoro-2-deoxy-D: -glucose positron emission tomography (FDG PET) correlates with therapeutic response of BD breast cancer, but the relationship to long-term outcome measures is unknown. Our goal was to evaluate the prognostic power of serial FDG PET in BD breast cancer patients undergoing treatment. We reviewed medical records of 405 consecutive breast cancer patients referred for FDG PET. Of these, 28 demonstrated metastatic BD breast cancer, were undergoing treatment, had at least 2 serial PET scans, and had abnormal FDG uptake on the first scan. Standardized uptake value (SUV) for the most conspicuous bone lesion at the initial scan, absolute change in SUV over an interval of 1-17 months, and percent change in SUV were considered as predictors of time-to-progression (TTP) and time to skeletal-related event (t-SRE). Using proportional hazards regression, smaller percentage decreases in SUV (or increases in SUV) were associated with a shorter TTP (P < 0.006). A patient with no change in SUV was twice as likely to progress compared to a patient with a 42% median decrease in SUV. A higher SUV on the initial FDG PET predicted a shorter t-SRE (hazard ratio = 1.30, P < 0.02). Changes in serial FDG PET may predict TTP in BD metastatic breast cancer patients. However, larger prospective trials are needed to validate changes in FDG PET as a surrogate endpoint for treatment response.

Hormone ablation therapy (HALT) for breast or prostate cancer accelerates the development of osteoporosis in both men and women by causing estrogen deficiency, which increases the risk for fracture by promoting bone resorption mediated by osteoclasts. Denosumab, a fully human monoclonal antibody that inhibits osteoclast formation and function, increases bone mass in patients undergoing hormone ablation therapy. In the HALT study of 1,468 men with prostate cancer on androgen-deprivation therapy, denosumab significantly reduced the risk of new vertebral fractures, increased bone mineral density (BMD), and reduced markers of bone turnover. In a study of 252 women with breast cancer undergoing adjuvant aromatase inhibitor (AI) therapy, denosumab increased BMD at 12 and 24 months, overall and in all patient subgroups. The overall rates of adverse events were similar to placebo. Clinicians should consider fracture risk assessment and therapies such as denosumab to increase bone mass in patients on hormone ablation therapy who are at high risk for fracture.

Denosumab increased lumbar spine bone mineral density (BMD) versus placebo in a 2-year, randomized, placebo-controlled, phase 3 study of patients with hormone-receptor-positive, non-metastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy. In subgroup analyses at 12 and 24 months, we evaluated factors (duration and type of aromatase inhibitor, tamoxifen use, age, time since menopause, body mass index, T-score) that might influence BMD at the lumbar spine, total hip, femoral neck, and 1/3 radius. Patients were randomized to receive placebo (n = 125) or 60 mg denosumab (n = 127) subcutaneously every 6 months. In all subgroups, 12 or 24 months' treatment with denosumab was associated with larger BMD gains than placebo across multiple skeletal sites. Most increases were statistically significant (P < 0.05). Twice-yearly administration of denosumab, regardless of patient subgroup or skeletal site, resulted in consistent increases in BMD versus placebo at 12 and 24 months.

Locally advanced breast cancer (LABC) is commonly treated with neoadjuvant chemotherapy followed by definitive surgery. The factors influencing the response of LABC to presurgical chemotherapy are incompletely understood. To characterize in vivo tumor biology in patients with LABC, we performed serial measurements of blood flow and glucose metabolism in LABC patients over the course of neoadjuvant chemotherapy and compared measurements with response. Thirty-five patients with newly diagnosed LABC underwent (18)F-FDG and (15)O-water PET imaging before therapy and after 2 mo of chemotherapy. Tumor metabolism was estimated from graphical analysis of dynamic (18)F-FDG studies and was expressed as the metabolic rate of (18)F-FDG (MRFDG). Blood flow was estimated from dynamic images after bolus (15)O-water injection using a 1-compartment model. Metabolism and blood flow data were analyzed with and without partial-volume corrections to account for changes in tumor size over the course of therapy. Changes in tumor blood flow and metabolism were compared with response to chemotherapy and with patient survival. For all patients, the mean MRFDG after 2 mo of chemotherapy decreased by 54% and the mean blood flow by 21%. Responders showed a greater decline in MRFDG than did nonresponders; however, the difference was of borderline significance (P = 0.05) after correction for partial-volume effects. Patients who responded had a decline in tumor blood flow, whereas nonresponders had an average increase (-32% vs. +48%, P < 0.005); the difference between responders and nonresponders remained significant after partial-volume correction (P < 0.01). There was also a statistically significant association between the pathologic degree of response and the percentage change in blood flow at 2 mo with and without partial-volume correction; this was not the case for MRFDG. The change in blood flow after 2 mo of therapy predicted disease-free and overall survival. Although both resistant and responsive LABC tumors have an average decline in MRFDG over the course of chemotherapy, resistant tumors have an average increase in blood flow. Patients whose tumors fail to have a decline in blood flow after 2 mo of therapy have poorer disease-free and overall survival. Further investigations are needed to elucidate the tumor biology underlying these findings.

Locally advanced breast cancer (LABC) is commonly treated with neoadjuvant chemotherapy followed by definitive surgery. The factors influencing the response of LABC to presurgical chemotherapy are incompletely understood. To characterize in vivo tumor biology in patients with LABC, we measured pretherapy blood flow and glucose metabolism in LABC, compared measurements with clinical and pathologic parameters, and examined blood flow and response to subsequent neoadjuvant chemotherapy. Thirty-seven patients with newly diagnosed LABC underwent (18)F-FDG and (15)O-water PET imaging. Thirty-one of these patients underwent neoadjuvant chemotherapy, and response was evaluated by serial measurements of tumor size and pathologic examination after definitive surgery after chemotherapy. Tumor metabolism was estimated from graphic analysis of dynamic (18)F-FDG studies and was expressed as the metabolic rate of (18)F-FDG (MRFDG). Blood flow was estimated from dynamic images after bolus (15)O-water injection using a 1-compartment model. Tumor blood flow and metabolism were compared with clinical and pathologic parameters and with response to chemotherapy. Both blood flow and metabolism were significantly higher in tumor than in normal breast. Tumor blood flow and metabolism were correlated but highly variable. There were weak associations of metabolism with patient age and tumor grade and of blood flow with estrogen receptor status. There was a statistically significant trend for patients with a high MRFDG to have a poorer response to therapy (P = 0.001). Response was not significantly correlated with any other parameters. A low ratio of MRFDG to blood flow was the best predictor of macroscopic complete response (CR) (P = 0.02 vs. non-CR). Preliminary analysis of patient follow-up showed the ratio of MRFDG to blood flow to also be predictive of disease-free survival. Despite uniformly large tumor size, blood flow and metabolism in LABC are highly variable. High glucose metabolism predicts a poor response to neoadjuvant chemotherapy, and low MRFDG relative to blood flow is a predictor of CR. Further work is needed to elucidate the biologic mechanisms underlying these findings.

The purpose of this study was to examine the specific herbs or vitamins (HV) used by patients receiving chemotherapy. Specifically, the following aspects were investigated: (1) HV use among adult cancer patients receiving chemotherapy, (2) the frequency of potential chemotherapy-HV interactions, (3) communication patterns between oncologists and their cancer patients taking HV, and (4) patients' reactions to two hypothetical scenarios of chemotherapy-HV interactions. Adult cancer patients receiving chemotherapy at a university-based outpatient clinic over a 1-month period were sent a validated eight-page questionnaire regarding the use of complementary/alternative medicine, focusing on HV use. A total of 76 patients participated; relevant medical information was obtained from study participants' charts. The chemotherapy received was compared with HV use to assess for potentially detrimental chemotherapy-HV interactions. HV use in patients receiving chemotherapy was common (78%), with 27% of the study participants being at risk of a detrimental chemotherapy-HV interaction. Most patients (>85%) would discontinue their HV or ask their medical oncologist for advice if a detrimental chemotherapy-HV interaction was suspected. Although most patients discussed HV use with their oncologist, the majority also relied on their friends and naturopathic physician for information regarding HV. Considerable potential exists for detrimental chemotherapy-HV interactions. Methods to improve communication of HV use between cancer patients receiving chemotherapy and health-care practitioners are necessary to identify and minimize the risk of these interactions.

A serious complication associated with breast cancer treatment is the increased risk for development of therapy-related myeloid neoplasms (t-MN). To determine whether dose-intensive adjuvant regimens for breast cancer induce genetic damage to hematopoietic stem cells, defined by the emergence of clonal hematopoiesis, and whether detection of clonal hematopoiesis could be used as an early marker for the subsequent development of t-MN, the Southwest Oncology Group designed a pilot clonality investigation to estimate the incidence of clonal hematopoiesis during and shortly after completion of the dose-intensive neoadjuvant regimens for high-risk breast cancer patients. Peripheral blood samples from 274 patients obtained prior to treatment, at time of surgery, and at 6 and 12 months post-surgery were examined by two different clonality assays: the HUMARA (HUMan Androgen Receptor) assay to estimate the incidence of early genetic damage by clonal proliferation, and microsatellite instability (MSI) testing to screen for LOH or defective DNA mismatch repair mechanisms. Clonal hematopoiesis was negative in 93.5% of the samples analyzed. Five patients showed a HUMARA-positive/MSI-negative pattern, and no patients showed a HUMARA-negative/MSI-positive pattern. With a median follow-up of 3.1 years, one patient in our study developed t-AML at 3 years 5 months after randomization. Our results indicate that clonal hematopoiesis assays performed within the 2 years following dose-intensive neoadjuvant therapy failed to identify an emerging clonal hematopoietic stem cell population. Longer clinical follow-up will be necessary to define better the positive predictive value of detecting clonal hematopoiesis in the HUMARA+/MSI− cases.

A serious complication associated with breast cancer treatment is the increased risk for development of therapy-related myeloid neoplasms (t-MN). To determine whether dose-intensive adjuvant regimens for breast cancer induce genetic damage to hematopoietic stem cells, defined by the emergence of clonal hematopoiesis, and whether detection of clonal hematopoiesis could be used as an early marker for the subsequent development of t-MN, the Southwest Oncology Group designed a pilot clonality investigation to estimate the incidence of clonal hematopoiesis during and shortly after completion of the dose-intensive neoadjuvant regimens for high-risk breast cancer patients. Peripheral blood samples from 274 patients obtained prior to treatment, at time of surgery, and at 6 and 12 months post-surgery were examined by two different clonality assays: the HUMARA (HUMan Androgen Receptor) assay to estimate the incidence of early genetic damage by clonal proliferation, and microsatellite instability (MSI) testing to screen for LOH or defective DNA mismatch repair mechanisms. Clonal hematopoiesis was negative in 93.5% of the samples analyzed. Five patients showed a HUMARA-positive/MSI-negative pattern, and no patients showed a HUMARA-negative/MSI-positive pattern. With a median follow-up of 3.1 years, one patient in our study developed t-AML at 3 years 5 months after randomization. Our results indicate that clonal hematopoiesis assays performed within the 2 years following dose-intensive neoadjuvant therapy failed to identify an emerging clonal hematopoietic stem cell population. Longer clinical follow-up will be necessary to define better the positive predictive value of detecting clonal hematopoiesis in the HUMARA+/MSI- cases.

The response of bone-dominant (BD) breast cancer to therapy is difficult to assess by conventional imaging. Our preliminary studies have shown that quantitative serial 2-[(18)F] fluoro-2-deoxy-D: -glucose positron emission tomography (FDG PET) correlates with therapeutic response of BD breast cancer, but the relationship to long-term outcome measures is unknown. Our goal was to evaluate the prognostic power of serial FDG PET in BD breast cancer patients undergoing treatment.BACKGROUNDThe response of bone-dominant (BD) breast cancer to therapy is difficult to assess by conventional imaging. Our preliminary studies have shown that quantitative serial 2-[(18)F] fluoro-2-deoxy-D: -glucose positron emission tomography (FDG PET) correlates with therapeutic response of BD breast cancer, but the relationship to long-term outcome measures is unknown. Our goal was to evaluate the prognostic power of serial FDG PET in BD breast cancer patients undergoing treatment.We reviewed medical records of 405 consecutive breast cancer patients referred for FDG PET. Of these, 28 demonstrated metastatic BD breast cancer, were undergoing treatment, had at least 2 serial PET scans, and had abnormal FDG uptake on the first scan. Standardized uptake value (SUV) for the most conspicuous bone lesion at the initial scan, absolute change in SUV over an interval of 1-17 months, and percent change in SUV were considered as predictors of time-to-progression (TTP) and time to skeletal-related event (t-SRE).METHODSWe reviewed medical records of 405 consecutive breast cancer patients referred for FDG PET. Of these, 28 demonstrated metastatic BD breast cancer, were undergoing treatment, had at least 2 serial PET scans, and had abnormal FDG uptake on the first scan. Standardized uptake value (SUV) for the most conspicuous bone lesion at the initial scan, absolute change in SUV over an interval of 1-17 months, and percent change in SUV were considered as predictors of time-to-progression (TTP) and time to skeletal-related event (t-SRE).Using proportional hazards regression, smaller percentage decreases in SUV (or increases in SUV) were associated with a shorter TTP (P < 0.006). A patient with no change in SUV was twice as likely to progress compared to a patient with a 42% median decrease in SUV. A higher SUV on the initial FDG PET predicted a shorter t-SRE (hazard ratio = 1.30, P < 0.02).RESULTSUsing proportional hazards regression, smaller percentage decreases in SUV (or increases in SUV) were associated with a shorter TTP (P < 0.006). A patient with no change in SUV was twice as likely to progress compared to a patient with a 42% median decrease in SUV. A higher SUV on the initial FDG PET predicted a shorter t-SRE (hazard ratio = 1.30, P < 0.02).Changes in serial FDG PET may predict TTP in BD metastatic breast cancer patients. However, larger prospective trials are needed to validate changes in FDG PET as a surrogate endpoint for treatment response.CONCLUSIONSChanges in serial FDG PET may predict TTP in BD metastatic breast cancer patients. However, larger prospective trials are needed to validate changes in FDG PET as a surrogate endpoint for treatment response.