Clinical evaluation of germline polymorphisms associated with capecitabine toxicity in breast cancer: TBCRC-015.

PURPOSE: Capecitabine is important in breast cancer treatment but causes diarrhea and hand-foot syndrome (HFS), affecting adherence and quality of life. We sought to identify pharmacogenomic predictors of capecitabine toxicity using a novel monitoring tool. METHODS: Patients with metastatic breast cancer were prospectively treated with capecitabine (2000 mg/m2/day, 14 days on/7 off). Patients completed in-person toxicity questionnaires (day 1/cycle) and automated phone-in assessments (days 8, 15). Correlation of genotypes with early and overall toxicity was the primary endpoint. RESULTS: Two hundred and fifty-nine patients were enrolled (14 institutions). Diarrhea and HFS occurred in 52% (17% grade 3) and 69% (9% grade 3), respectively. Only 29% of patients completed four cycles without dose reduction/interruption. In 39%, the highest toxicity grade was captured via phone. Three single nucleotide polymorphisms (SNPs) associated with diarrhea-DPYD*5 (odds ratio [OR] 4.9; P = 0.0005), a MTHFR missense SNP (OR 3.3; P = 0.02), and a SNP upstream of MTRR (OR 3.0; P = 0.03). GWAS elucidated a novel HFS SNP (OR 3.0; P = 0.0007) near TNFSF4 (OX40L), a gene implicated in autoimmunity including autoimmune skin diseases never before implicated in HFS. Genotype-gene expression analyses of skin tissues identified rs11158568 (associated with HFS via GWAS) with expression of CHURC1, a transcriptional activator controlling fibroblast growth factor (beta = - 0.74; P = 1.46 × 10-23), representing a previously unidentified mechanism for HFS. CONCLUSIONS: This is the first cancer pharmacogenomic study to use phone-in self-reporting, permitting augmented toxicity characterization. Three germline toxicity SNPs were replicated, and several novel SNPs/genes having strong functional relevance were discovered. If further validated, these markers could permit personalized capecitabine dosing.

Surveillance of women with a personal history of breast cancer by tumour subtype.

AIM: To determine if the rate and timing of a second breast cancer event (SBCE) in women with a personal history of breast cancer varies by disease subtype or breast imaging method. MATERIALS AND METHODS: A retrospective review was performed of women with a SBCE from January 2006 to December 2010 at a single institution. Data analysed included oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status of the primary and second breast cancers; mammographic and ultrasound (US) features from SBCE; and the time interval between both events. RESULTS: Of 207 patients diagnosed with a SBCE, the median age at first diagnosis was 50.6 years, range 24.8 to 80.2; at second diagnosis was 56.2 years, range 25.8 to 87.9. Eleven percent of SBCE were diagnosed >10 years after the primary cancer diagnosis. The median time between the first and second diagnosis for ER-positive patients was 2.7 years (range 0.7-17.4 years); and 1.9 years for ER-negative patients, (range 0.4-23.4 years; p<0.002). Patients with triple-negative breast cancer (TNBC) had a shorter time between diagnoses than others (p=0.0003). At 3, 5, and 10 years, 85%, 92%, and 97% of ER-negative and 54%, 81%, and 95% of ER-positive tumours, respectively, had recurred. ER-negative tumours and TNBC were more likely to be visible at US. CONCLUSION: There may be a role for customised imaging surveillance of women with a personal history of breast cancer (PHBC) after 10 years. Further studies are necessary to determine if US may be valuable in the surveillance of patients with ER-negative and TNBC tumours.

Importance of Risk Factors for Febrile Neutropenia Among Patients Receiving Chemotherapy Regimens Not Classified as High-Risk in Guidelines for Myeloid Growth Factor Use.

BACKGROUND: Clinical practice guidelines recommend prophylaxis in patients with cancer receiving a colony-stimulating factor (CSF) when the risk of febrile neutropenia (FN) is high (>20%). For patients receiving chemotherapy regimens not documented as high-risk, the decision regarding CSF prophylaxis use can be challenging, because some patients may be at high risk based on a combination of the regimen and individual risk factors. METHODS: A retrospective cohort design and US private health care claims data were used. Study subjects received chemotherapy regimens classified as "low" or "intermediate," or unclassified, in terms of FN risk, and were stratified by cancer and regimen. For each subject, the first chemotherapy course, and each cycle and FN episode within the course, were identified. FN incidence proportions were estimated by the presence and number of risk factors and chronic comorbidities. RESULTS: Across the 17 tumor/regimen combinations considered (n=160,304 in total), 74% to 98% of patients had 1 or more risk factor for FN and 41% to 89% had 2 or more. Among patients with 1 or more risk factor, FN incidence ranged from 7.2% to 29.0% across regimens, and the relative risk of FN (vs those without risk factors) ranged from 1.1 (95% CI, 0.8-1.3) to 2.2 (95% CI, 1.5-3.0). FN incidence increased in a graded and monotonic fashion with the number of risk factors and comorbidities. CONCLUSIONS: In this retrospective evaluation of patients with cancer receiving chemotherapy regimens not classified as high-risk for FN in US clinical practice, most patients had 1 or more FN risk factor and many had 2 or more. FN incidence was found to be elevated in these patients, especially those with multiple risk factors.

Inhibition of the phosphoinositide 3-kinase pathway for the treatment of patients with metastatic metaplastic breast cancer.

BACKGROUND: Mesenchymal/metaplastic breast cancers (MpBCs) are often triple-negative (TNBC), and chemo-refractory, and can harbor phosphoinositide 3-kinase (PI3kinase) alterations; thus, therapy with mTor inhibitors may demonstrate activity. PATIENTS AND METHODS: Patients with mesenchymal/MpBC treated with temsirolimus-based regimens were evaluated. Mutational analyses [polymerase chain reaction (PCR)-based DNA sequencing method, mass spectrometric detection (Sequenom MassARRAY), or next-generation sequencing] as well as loss of phosphatase and tensin homolog (PTEN) (immunohistochemistry) were performed (archived tissue when available). RESULTS: Twenty-three patients (one of whom was on two separate trials) were treated using temsirolimus-containing regimens: temsirolimus alone (n = 1 patient) or combined with the following: liposomal doxorubicin and bevacizumab (DAT, n = 18); liposomal doxorubicin (DT, n = 1); paclitaxel and bevacizumab (TAT, n = 2); paclitaxel (TT, n = 1); carboplatin and bevacizumab (CAT, n = 1). Response rate [complete response (CR) + partial response (PR)] was 25% across all regimens; 32% in the anthracycline-based regimens [DAT and DT (CR = 2, PR = 4; N = 19)]. An additional two patients achieved stable disease (SD) ≥6 months [total SD ≥6 months/CR/PR = 8 (33%)]. Molecular aberrations in the PI3K pathway were common: PIK3CA mutation = 6/15 (40%), PTEN mutation = 3/11 (27%), and PTEN loss = 2/11 (18%). A point mutation in the NF2 gene (K159fs*16; NF2 alterations can activate mTor) was found in one patient who attained CR (3+ years). Of the eight patients who achieved SD ≥6 months/CR/PR, all 4 patients with available tissue had a molecular aberration that activate the PIK3CA/Akt/mTOR axis: PIK3CA mutation = 2; PTEN loss = 1; NF2 aberration = 1. CONCLUSIONS: DAT has activity in MpBCs including complete CRs. Molecular aberrations that can activate the PI3 K/Akt/mTOR axis are common in MpBC.

The effect of filgrastim or pegfilgrastim on survival outcomes of patients with cancer receiving myelosuppressive chemotherapy.

BACKGROUND: Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is associated with higher chemotherapy relative dose intensity, which may lead to improved outcomes; however, the association between G-CSF primary prophylaxis and overall survival (OS) is not well characterized. This study assessed the effect of G-CSF primary prophylaxis on patient outcomes in randomized, controlled, registrational clinical trials of filgrastim and pegfilgrastim. PATIENTS AND METHODS: Three placebo-controlled and two non-inferiority clinical trials of filgrastim and/or pegfilgrastim in patients receiving myelosuppressive chemotherapy for lung, breast, or colorectal cancer were included. The median OS, 6- and 12-month survival rates, and hazard ratios [HRs; unadjusted Cox model with 95% confidence intervals (CIs)] were estimated for patients receiving ≥1 dose of filgrastim, pegfilgrastim, or placebo. Comparisons were based on a log-rank test. A fixed-effect meta-analysis assessed the effect of primary prophylaxis with filgrastim/pegfilgrastim on OS in the placebo-controlled trials. RESULTS: In patients with lung cancer receiving filgrastim versus placebo, the median OS was 14.1 versus 11.1 months (HR, 0.81; 95% CI 0.48-1.35; P = 0.412); in patients who crossed over to filgrastim from placebo after cycle 1, the median OS was 16.9 months (HR, 0.75; 95% CI 0.43-1.28; P = 0.286). The median OS was inestimable in at least one treatment arm in the other studies because of the small number of OS events. Where estimable, 6- and 12-month survival rates were generally greater among patients receiving filgrastim/pegfilgrastim versus placebo. In the meta-analysis of placebo-controlled studies comparing G-CSF primary prophylaxis with placebo in the as-treated analysis sets, the HR (95% CI) for OS was 0.77 (0.58-1.03). CONCLUSIONS: In this retrospective analysis, OS point estimates were greater among patients receiving filgrastim versus placebo, but the differences were not statistically significant. Further studies evaluating patient outcomes with G-CSF prophylaxis are warranted. CLINICAL TRIAL REGISTRATION: NCT00035594, NCT00094809.

Use of pegfilgrastim primary prophylaxis and risk of infection, by chemotherapy cycle and regimen, among patients with breast cancer or non-Hodgkin's lymphoma.

PURPOSE: This study aims to examine granulocyte colony-stimulating factor (G-CSF) prophylaxis by cancer type, chemotherapy regimen, and cycle in a real-world setting to assess if practice conforms to clinical guidelines, which recommend G-CSF prophylaxis every cycle when a patient's risk of febrile neutropenia (FN) is 20% or greater, and to describe the incidence of FN among patients who discontinue pegfilgrastim (peg) prophylaxis. METHODS: The cohort was selected from administrative claims data and includes adults diagnosed with non-Hodgkin's lymphoma (NHL) or breast cancer (BC) who began chemotherapy 2005-2010. RESULTS: About 83.2% of the 4,470 patients with BC treated with dose-dense doxorubicin, cyclophosphamide (ddAC), 83.6% of 2,197 patients with BC treated with docetaxel, doxorubicin, cyclophosphamide (TAC), and about 55.6% of the 2,722 patients with NHL treated with cyclophosphamide, doxorubicin, vincristine, with or without prednisone for 3-week cycles (CHOP-R Q3W) received peg prophylaxis in cycle 1. Among patients on these regimens who received peg prophylaxis in cycle 1 and were still on the regimen in cycle 4, about 90% received peg prophylaxis in that cycle. Among patients with BC or NHL who discontinued G-CSF, the incidence proportion of infection or FN varied by regimen and cycle, with a range from 0 to 14%. CONCLUSIONS: Despite clinical guidelines recommending G-CSF prophylaxis with chemotherapy regimens with a high risk of FN, many NHL and BC patients do not receive FN prophylaxis in cycle 1. However, among patients who receive G-CSF in cycle 1 and remain on the regimen, the majority appear to continue prophylaxis as indicated.

Outcome of metastatic breast cancer in selected women with or without deleterious BRCA mutations.

The aim of this study was to compare the time-to progression and overall survival (OS) in patients with metastatic breast cancer (MBC) with and without deleterious BRCA1/2 mutations. 195 women with MBC who were referred for BRCA genetic testing between 1997 and 2011 were included in the study. Logistic regression models and Cox proportional hazards models were fit to determine the associations between clinical variables and outcomes. Of 195 women with MBC, 21 % (n = 41) were positive for BRCA1/2 mutations. The number of metastatic sites at the time of metastatic disease was not different between BRCA1 versus BRCA2 carriers versus non-carriers (P = 0.77). The site of first metastasis was visceral-only in 70 % of BRCA1 carriers compared to 9 % in BRCA2 carriers and 37 % in non-carriers (P = 0.001). Median follow-up was 2.8 years. BRCA non-carriers and BRCA2 carriers had a longer time-to progression and OS compared to BRCA1 carriers (median time-to progression = 1.3 vs. 0.9 vs. 0.7 years; P = 0.31, and median OS = 4.88 vs. 4.94 vs. 1.34 years; P = 0.0065). In a multivariate model, no association was identified between BRCA positivity and time-to-event outcomes (P > 0.28). In addition, patients with triple-negative MBC carried a poorer prognosis irrespective of their BRCA status (P = 0.058 and P = 0.15 for the interaction term of BRCA status and triple-negative for time-to progression and OS, respectively). Our data indicate that BRCA1 carriers diagnosed with MBC have worse outcomes compared to BRCA2 carriers and non-carriers. However, the differences in outcome did not reach statistical significance likely due to small sample sizes.

Outcomes of a cancer-related fatigue clinic in a comprehensive cancer center.

Cancer-related fatigue (CRF) is a significant issue for cancer patients and frequently precipitates increased stress and anxiety for patients and caregivers alike. CRF may present well after the initial phase of cancer diagnosis and treatment, regardless of whether the cancer is in remission, widely metastatic, or somewhere in between. Determining whether the etiology of fatigue is potentially reversible and whether it is an effect of treatment or another unrelated cause is often perplexing. Because of the significant impact of CRF on patients at our institution, we organized a CRF clinic and began evaluating patients for fatigue in 1998. Our goal has been to initiate a more focused and, at the same time, more comprehensive effort in educating, evaluating, and treating CRF. The purpose of this report was to present a retrospective review of patients treated in our CRF clinic between 1998 and 2005, to examine the outcomes of our patients, and to briefly describe some of the challenges encountered in treating these patients. This information may help reassess and improve approaches in addressing CRF and subsequently improve fatigue in these patients.

Effects of chronic hepatitis C infection on the treatment of breast cancer patients.

BACKGROUND: Although hepatitis C (HCV) is the most common blood-borne infection in the United States, little information exists about treatment of breast cancer in the setting of chronic HCV. PATIENTS AND METHODS: The databases of the University of Texas M.D. Anderson Cancer Center (MDACC) Tumor Registry, Department of Breast Medical Oncology, and Department of Laboratory Medicine were cross-referenced for patients with breast cancer, who were also identified as having HCV. Eligible patients had a diagnosis of invasive breast cancer, breast cancer treatment at MDACC, and a diagnosis of HCV. RESULTS: During chemotherapy, 25% of patients experienced elevations in aminotransferases and 44% of patients required dose reductions/delays in chemotherapy. More than 60% of the patients who received chemotherapy demonstrated a grade 2 or greater complication. However, 92% of patients were able to complete the number of cycles specified in the initial chemotherapy plan. CONCLUSIONS: As the majority of these breast cancer patients completed the initial chemotherapy plan, this study indicates that breast cancer patients with HCV can be treated with cytotoxic therapy. Comparison with historical controls showed similar rates of hepatic toxicity in the presence (or absence) of HCV, indicating that incidence of transaminitis may not be significantly affected by HCV.

Bone biology and the role of the RANK ligand pathway.

Bone biology and the molecular basis of normal bone remodeling are important for understanding bone health, particularly for medical professionals who are treating patients with skeletal complications. Key factors in bone remodeling include RANK ligand, which stimulates bone resorption, and osteoprotegerin (OPG), which inhibits bone resorption. The ratio between these two factors regulates osteoclast formation and activity. An imbalance in the expression of RANK ligand and OPG is an underlying mechanism in cancer treatment-induced bone loss, in bone metastasis in patients with solid tumors, and in osteolysis in patients with multiple myeloma. In cancer-induced bone disease, for example, RANK ligand overwhelms the effects of OPG, leading to imbalanced bone remodeling and the "vicious cycle" of metastatic disease. Experimental therapeutics that target RANK ligand are increasingly being studied and have shown promise for decreasing tumor-related bone disease.