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1.  Pathologic complete response rates in triple-negative, HER2-positive, and hormone receptor-positive breast cancers after anthracycline-free neoadjuvant chemotherapy with carboplatin and paclitaxel with or without trastuzumab 
Breast (Edinburgh, Scotland)  2014;24(1):18-23.
Background
Pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) in the breast and lymph nodes in patients with locally advanced or inflammatory breast cancer (LABC) is associated with improved disease-free and overall survival. Increasingly, studies are testing the efficacy of platinum-containing NCT in LABC, particularly in patients with human epidermal growth factor receptor 2 (HER2)-positive (HER2+) and triple-negative breast cancers (TNBC).
Methods
In this retrospective study, we reviewed patients’ medical records and collected demographics, tumor HER2 and hormone receptor (HR) status, grade, and treatment-associated toxicities in patients with LABC previously treated with neoadjuvant carboplatin and trastuzumab (HER2+ disease) at City of Hope between April 2009 and December 2011. All patients provided written informed consent before study inclusion. The primary endpoint was pCR (no invasive disease in breast and lymph nodes); the secondary endpoint was pCR-breast (no invasive disease in breast only). Recurrence-free survival (RFS) was estimated using the Kaplan-Meier method.
Results
Thirty eight consecutive patients with 39 tumors (one patient with two primaries) were included in the study. Patients completed a median of four cycles of NCT. Eighteen of 39 (46%) tumors were HER2+; 8/18 (44%) had a pCR and 10/18 (56%) had a pCR-breast. Thirteen of 18 HER2+ tumors were HR+ (72%); 4/13 (31%) had a pCR and 5/13 (38%) had a pCR-breast. Ten of 39 (26%) tumors were TNBC; 6/10 (60%) had a pCR and 7/10 (70%) had a pCR-breast. Recurrence-free survival at 25-months median follow-up was 86% (95% CI 0.75-0.98); no recurrences were observed in patients with a pCR.
Conclusions
This regimen achieved a high rate of pCR in HER2+ and TNBC tumors. Further studies comparing platinum-containing and anthracycline-free regimens versus anthracycline-containing regimens in patients with locally advanced HER2+ breast cancer and TNBC are warranted.
doi:10.1016/j.breast.2014.10.008
PMCID: PMC4596816  PMID: 25467313
Locally advanced breast cancer (LABC); Inflammatory breast cancer; Neoadjuvant chemotherapy (NCT); Pathologic complete response (pCR); Human epidermal growth factor receptor 2 (HER2); Triple-negative breast cancer (TNBC); Carboplatin; Paclitaxel
2.  Biosimilars: Extrapolating the evidence. A roundtable discussion 
EJC Supplements  2016;13(2):1-2.
doi:10.1016/j.ejcsup.2015.12.001
PMCID: PMC4724664  PMID: 26903777
3.  Impact of Neoadjuvant Chemotherapy in Stage II–III Triple Negative Breast Cancer on Eligibility for Breast-conserving Surgery and Breast Conservation Rates 
Annals of surgery  2015;262(3):434-439.
Objective
To assess the efficacy of neoadjuvant systemic therapy (NST) at increasing the rate of successful breast-conserving therapy (BCT) in triple negative breast cancer.
Background
Inducing tumor regression to permit BCT is often cited to support administration of NST. To quantify this benefit, we conducted a surgical companion study to CALGB40603, a randomized phase II, 2×2 factorial trial of neoadjuvant paclitaxel ± carboplatin ± bevacizumab (B) followed by doxorubicin plus cyclophosphamide ± B in stage II–III triple negative breast cancer.
Methods
Before and after NST, treating surgeons evaluated BCT candidacy by clinico-radiographic criteria; surgery performed was at surgeon and patient discretion. We measured (1) conversion rates from BCT-ineligible to BCT-eligible, (2) surgical choices in BCT candidates, and (3) rates of successful BCT with tumor-free margins.
Results
Four hundred four patients were assessable for surgical outcomes. Two hundred nineteen (54%) were BCT candidates before NST. One hundred ninety-seven (90%) remained BCT candidates after NST, of whom 138 (70%) chose BCT, which was successful in 130 (94%). Of 185 (46%) who were not BCT candidates before NST, 78 (42%) converted to candidates with NST. Of these, 53 (68%) chose BCT with a 91% (48/53) success rate. The overall BCT-eligibility rate rose from 54% to 68% (275/404) with NST. Addition of carboplatin, B, or both increased conversion rates.
Conclusions
This is the first study to document prospectively a 42% conversion rate from BCT-ineligible to BCT-eligible, resulting in a 14% absolute increase in BCT eligibility. BCT was successful in 93% of patients who opted for it, but 31% of BCT-eligible patients still chose mastectomy.
doi:10.1097/SLA.0000000000001417
PMCID: PMC4710511  PMID: 26222764
breast-conserving therapy; mastectomy; neoadjuvant therapy; surgery; triple negative breast cancer
4.  Age-Related Changes in Nanoparticle Albumin-Bound Paclitaxel Pharmacokinetics and Pharmacodynamics: Influence of Chronological Versus Functional Age 
The Oncologist  2014;20(1):37-44.
This study evaluated age-related changes in pharmacokinetic and pharmacodynamic parameters of nanoparticle albumin-bound paclitaxel in patients with metastatic breast cancer. A borderline significant relationship exists between age and 24-hour area under the curve, and there is an association between toxicity risk score and grade ≥3 chemotherapy toxicity and pharmacokinetic variables. The treatment is well tolerated across all age groups.
Purpose.
This study evaluated age-related changes in pharmacokinetic and pharmacodynamic parameters of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in patients with metastatic breast cancer.
Methods.
Forty patients received nab-paclitaxel (100 mg/m2 weekly for 3 weeks followed by a 1-week break) as first- or second-line chemotherapy. Blood samples were collected for analysis, and response was assessed every two cycles. Planned statistical analyses included linear regression to examine the relationship between age and pharmacokinetic variables (ln clearance [CL] and ln area under the curve [AUC]) and two-sided two-sample t tests to evaluate age differences in pharmacodynamic variables. The association between chemotherapy toxicity risk scores and pharmacokinetic and pharmacodynamic variables including grade ≥3 toxicity were examined post hoc.
Results.
Of 40 patients enrolled, 39 (98%) were evaluable (mean age: 60 years; range: 30–81 years). A partial response was achieved in 31%, and 38% had stable disease. There was a borderline positive association between age and 24-hour ln AUC (slope = 0.011; SE = 0.006; p = .055). Grade 3 toxicity was experienced by 26% (8% hematologic, 18% nonhematologic). There were no differences in age based on the presence of grade 3 toxicity (p = .75), dose reductions (p = .38), or dose omissions (p = .15). A significant association was noted between chemotherapy toxicity risk score category and presence of grade 3 toxicity (toxicity rate by risk score category: low, 5 of 30 patients; medium, 3 of 6 patients; high, 2 of 3 patients; p = .041).
Conclusion.
A borderline significant relationship exists between age and 24-hour AUC, but no differences were noted for pharmacodynamic variables (grade 3 toxicity, dose reductions, or dose omissions) based on age. There is an association between toxicity risk score and grade ≥3 chemotherapy toxicity and pharmacokinetic variables. The treatment is well tolerated across all age groups.
doi:10.1634/theoncologist.2014-0202
PMCID: PMC4294604  PMID: 25492923
Older adult; Pharmacokinetics; Pharmacodynamics; Geriatric oncology; Taxane
5.  TGFβ Induces ‘BRCAness’ and Sensitivity to PARP Inhibition in Breast Cancer by Regulating DNA Repair Genes 
Molecular cancer research : MCR  2014;12(11):1597-1609.
Transforming growth factor β (TGFβ) proteins are multitasking cytokines, whose high levels at tumor sites generally correlate with poor prognosis in human cancer patients. Previously it was reported that TGFβ downregulates the expression of ataxia telangiectasia mutated (ATM) and mutS homolog 2 (MSH2) in breast cancer (BC) cells through a miRNA-mediated mechanism. In this study, expression of a panel of DNA repair genes was examined, identifying breast cancer 1, early onset (BRCA1) as a target downregulated by TGFβ through the miR-181 family. Correlations between the expression levels of TGFβ1 and the miR-181/BRCA1 axis were observed in primary breast tumor specimens. By downregulating BRCA1, ATM, and MSH2, TGFβ orchestrates DNA damage response (DDR) in certain BC cells to induce a ‘BRCAness’ phenotype, including impaired DNA repair efficiency and synthetic lethality to the inhibition of poly (ADP-ribose) polymerase (PARP). Xenograft tumors with active TGFβ signaling exhibited resistance to the DNA-damaging agent doxorubicin but increased sensitivity to the PARP inhibitor ABT-888. Combination of doxorubicin with ABT-888 significantly improved the treatment efficacy in TGFβ-active tumors. Thus, TGFβ can induce ‘BRCAness’ in certain BCs carrying wild-type BRCA genes and enhance the responsiveness to PARP inhibition, and the molecular mechanism behind this is characterized. Implications: These findings enable better selection of sporadic breast cancer patients for PARP interventions, which have exhibited beneficial effects in patients carrying BRCA mutations.
doi:10.1158/1541-7786.MCR-14-0201
PMCID: PMC4233161  PMID: 25103497
Transforming growth factor β (TGFβ); breast cancer; DNA repair; poly (ADP-ribose) polymerase (PARP); breast cancer 1; early onset (BRCA1)
6.  Breast cancer-secreted miR-122 reprograms glucose metabolism in pre-metastatic niche to promote metastasis 
Nature cell biology  2015;17(2):183-194.
Reprogrammed glucose metabolism as a result of increased glycolysis and glucose uptake is a hallmark of cancer. Here we show that cancer cells can suppress glucose uptake by non-tumour cells in the pre-metastatic niche, by secreting vesicles that carry high levels of the miR-122 microRNA. High miR-122 levels in the circulation have been associated with metastasis in breast cancer patients and we show that cancer-cell-secreted miR-122 facilitates metastasis by increasing nutrient availability in the pre-metastatic niche. Mechanistically cancer-cell-derived miR-122 suppresses glucose uptake by niche cells in vitro and in vivo by downregulating the glycolytic enzyme pyruvate kinase (PKM). In vivo inhibition of miR-122 restores glucose uptake in distant organs, including brain and lungs, and decreases the incidence of metastasis. These results demonstrate that by modifying glucose utilization by recipient pre-metastatic niche cells, cancer-derived extracellular miR-122 is able to reprogram systemic energy metabolism to facilitate disease progression.
doi:10.1038/ncb3094
PMCID: PMC4380143  PMID: 25621950
7.  Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis 
Cancer cell  2014;25(4):501-515.
SUMMARY
Cancer-secreted miRNAs are emerging mediators of cancer–host crosstalk. Here we show that miR-105, which is characteristically expressed and secreted by metastatic breast cancer cells, is a potent regulator of migration through targeting the tight junction protein ZO-1. In endothelial monolayers, exosome-mediated transfer of cancer-secreted miR-105 efficiently destroys tight junctions and the integrity of these natural barriers against metastasis. Overexpression of miR-105 in non-metastatic cancer cells induces metastasis and vascular permeability in distant organs, whereas inhibition of miR-105 in highly metastatic tumors alleviates these effects. MiR-105 can be detected in the circulation at the pre-metastatic stage, and its levels in the blood and tumor are associated with ZO-1 expression and metastatic progression in early-stage breast cancer.
doi:10.1016/j.ccr.2014.03.007
PMCID: PMC4016197  PMID: 24735924
8.  The Effect of Aromatase Inhibition on the Cognitive Function of Older Patients with Breast Cancer 
Clinical breast cancer  2013;14(2):132-140.
Purpose
To evaluate the association between aromatase inhibitor (AI) therapy and cognitive function (over a 6-month time period) in a cohort of patients age ≥ 60 compared with an age-matched healthy control group, and to evaluate changes in regional cerebral metabolism as measured by positron emission tomography (PET) scans of the brain done in a subset of the patient cohort.
Patients and Methods
Thirty-five patients (32 evaluable) and 35 healthy controls were recruited to this study. Patients with breast cancer completed a neuropsychological battery, self-reported memory questionnaire, and geriatric assessment prior to initiation of AI therapy and again 6 months later. Age-matched healthy control participants completed the same assessments at the same time points as the patient group.
Results
No significant decline in cognitive function was seen among individuals receiving an AI from pre-treatment to 6 months later compared with healthy controls. In the PET cohort over the same period, both standardized volume of interest (sVOI) and statistical parametric mapping (SPM) analyses detected specific changes in metabolic activity between baseline and follow-up uniquely in the AI patients, uniquely, most significantly in medial temporal lobes.
Conclusion
While patients undergoing AI treatment demonstrated few changes in neuropsychologic performance compared with healthy controls over a 6-month period during this interval, regionally specific changes in cerebral metabolic activity were identified in the patient group. Additional longitudinal follow-up is needed to understand the potential clinical implications of these findings.
doi:10.1016/j.clbc.2013.10.010
PMCID: PMC4103787  PMID: 24291380
cognitive function; older adults; breast cancer; aromatase inhibitors; PET scan
9.  Dose Escalation of Total Marrow Irradiation with Concurrent Chemotherapy in Patients with Advanced Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation 
Purpose
We have demonstrated that toxicities are acceptable with total marrow irradiation (TMI) 16 Gy without chemotherapy or TMI 12 Gy and the reduced intensity regimen of fludarabine/melphalan in patients undergoing hematopoietic cell transplantation (HCT). This study reports on TMI combined with higher intensity chemotherapy regimens on two phase I trials in patients with advanced AML/ALL who would do poorly on standard intent-to-cure HCT regimens.
Methods
Trial 1: TMI on days -10 to -6, VP16 day -5 (60 mg/kg), and cyclophoshamide (CY) day -3 (100 mg/kg). TMI dose (Gy) was 12 (n=3), 13.5 (n=3) and 15 (n=6) at 1.5 Gy BID. Trial 2: Busulfan (BU) days -12 to -8 (800 uM min), TMI days -8 to -4, and VP16 day -3 (30 mg/kg). TMI dose (Gy) was 12 (n=18) and 13.5 (n=2) at 1.5 Gy BID.
Results
Trial 1: 12 patients; median age 33; 6 induction failure (IF), 6 first relapse (1RL); 9 with marrow blasts (10–98%), 5 with circulating blasts (24–85%) and 2 with chloromas. No dose limiting toxicities were observed. Eleven achieved CR at day 30. With a median follow-up 14.75 months, 5 remain in complete remission from 13.5–37.7 months. Trial 2: 20 patients; median age 41; 13 IF, 5 1RL, 2 in 2nd relapse; 19 with marrow blasts (3–100%) and 13 with peripheral blasts (6–63%). Grade 4 dose limiting toxicities were seen at 13.5 Gy (stomatitis and hepatotoxicity). Stomatitis was the most frequent toxicity in both trials.
Conclusions
TMI dose escalation to 15 Gy is possible when combined with CY/VP16 and is associated with acceptable toxicities and encouraging outcomes. TMI dose escalation is not possible with BU/VP16 due to dose-limiting toxicities. Future efforts will focus on whether further dose escalation with CY/VP16 is safe with the goal of improving disease control in this high risk population.
doi:10.1016/j.ijrobp.2012.03.033
PMCID: PMC4312108  PMID: 22592050
total marrow irradiation; bone marrow transplantation; total body irradiation; tomotherapy; acute leukemia
10.  miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway 
eLife  2014;3:e01977.
MicroRNAs (miRNAs) are important regulators of stem and progenitor cell functions. We previously reported that miR-142 and miR-150 are upregulated in human breast cancer stem cells (BCSCs) as compared to the non-tumorigenic breast cancer cells. In this study, we report that miR-142 efficiently recruits the APC mRNA to an RNA-induced silencing complex, activates the canonical WNT signaling pathway in an APC-suppression dependent manner, and activates the expression of miR-150. Enforced expression of miR-142 or miR-150 in normal mouse mammary stem cells resulted in the regeneration of hyperproliferative mammary glands in vivo. Knockdown of endogenous miR-142 effectively suppressed organoid formation by BCSCs and slowed tumor growth initiated by human BCSCs in vivo. These results suggest that in some tumors, miR-142 regulates the properties of BCSCs at least in part by activating the WNT signaling pathway and miR-150 expression.
DOI: http://dx.doi.org/10.7554/eLife.01977.001
eLife digest
Messenger RNA molecules take the information encoded in a gene's DNA sequence and turn it into instructions for building a protein. However, if certain smaller molecules of RNA—called microRNAs—bind to a messenger RNA molecule, they ‘silence’ it, which prevents the information in the messenger RNA from being translated to make a protein.
Despite their small size, microRNAs are very powerful. These molecules are able to simultaneously inhibit the translation of hundreds of messenger RNAs and perform many roles, including controlling cell growth and maintaining populations of stem cells. Furthermore, microRNAs have been linked to different aspects of the growth of cancerous cells. Certain microRNAs appear to suppress tumors by regulating the growth of the stem cells found there, while others appear to be ‘hyperactive’ in cancers—including breast cancer, colon cancer, and blood cancer.
In 2009, researchers compared the amount of microRNA in breast cancer stem cells that are highly capable of forming tumors with the amount in other cancer cells within the same tumor. Amongst other differences, two microRNAs (called miR-142 and miR-150) were found to be hyperactive in human breast cancer stem cells. One of them, miR-142, is known to target a gene called APC that inhibits the renewal of normal stem cells. Mutations in the APC gene have been linked to colon cancer, and scientists have suggested that the mutations inactivate APC in cancer cells to promote unregulated cell growth. Breast tumors rarely have mutations in the APC gene, but Isobe et al. wondered whether microRNAs that target this gene might also promote the growth of these tumor cells.
Isobe et al.—including several of the researchers involved in the 2009 work—show that miR-142 does target the APC gene in human breast cancer stem cells, and silences it. With the gene silenced, a cancer-promoting pathway turns on and more miR-150 is made. Increasing the amount of either miR-142 or miR-150 causes excessive cell growth in breast tissue and can form abnormal breast tissue in mice. Reducing the amount of miR-142 in human breast cancer stem cells slows the growth of breast tumors.
Although they only make up a small population of human breast cancer cells, focusing on breast cancer stem cells could uncover the cancer-promoting pathways that are activated in human breast cancers.
DOI: http://dx.doi.org/10.7554/eLife.01977.002
doi:10.7554/eLife.01977
PMCID: PMC4235011  PMID: 25406066
breast cancer; cancer stem cells; miR-142; miR-150; APC; WNT signaling pathway; human; mouse
11.  Barriers to Treatment in Patients With Locally Advanced Breast Cancer 
Delays between presentation and treatment could have a significant effect on breast cancer mortality. The authors hypothesized that patient, physician, and system barriers are all responsible for treatment delays. Therefore, a study was conducted to define prevalent barriers to treatment from the patient’s perspective. A modified 43-item Likert-scale questionnaire was administered to patients with clinical stage III locally advanced breast cancer (LABC) who had experienced a delay in treatment of 3 months or more. Between October 2008 and January 2010, 153 patients presented with LABC; 43 patients (28.1%) met eligibility, and 40 completed the questionnaire. Among the patient barriers reported, 38% of patients delayed care for fear of losing their breast and 47% awaited previously scheduled routine appointments instead of seeking care. Among the physician barriers reported, 20% of physicians of initial contact did not believe the breast lump/symptom was related to cancer and 15% did not believe it needed a biopsy. Among the system barriers reported, the most prevalent were delays in performing diagnostic tests and obtaining insurance authorization for tests, treatment, or physician visits. Substantial delays were seen in 28.1% of patients from presentation to when they sought therapy at City of Hope Comprehensive Cancer Center. The high prevalence of patient barriers versus physician/system barriers suggests that increased educational efforts for patients and health care professionals are needed.
PMCID: PMC4159358  PMID: 24142820
12.  Analysis of Circulating Tumor Cells in Breast Cancer 
Over the past few decades, substantial progress has been made in the diagnosis and treatment of breast cancer. Early identification of relapsed and metastatic disease has been a primary focus of ongoing research. Circulating tumor cells (CTCs) are implicated as harbingers of metastases. With advances in detection technologies, CTCs offer the option for real-time liquid biopsies. Methods to identify CTCs in the bloodstream by physical or biochemical properties, although feasible, still require improvements to promote widespread, reproducible use. Sufficient data support enumeration and assessment of changes in the number of CTCs as prognostic indicators, but controversy around their predictive utility for selecting treatments remains. As the technology to detect CTCs and characterize their heterogeneous molecular profile evolves, additional information will likely be obtained to guide targeted and individualized therapies.
PMCID: PMC4159355  PMID: 23946176
13.  Enrollment onto breast cancer therapeutic clinical trials: A tertiary cancer center experience 
Applied nursing research : ANR  2013;26(3):133-135.
Background
Advances in breast cancer prevention, diagnosis, and treatment are in part the result of patient involvement in clinical trials. Despite increases in new clinical research initiatives and trials open to accrual, only 2–3% of women with breast cancer enroll. There is a need to identify the barriers interfering patient accrual.
Methods
Data were extracted from patients with breast cancer seen for treatment in 2009 retrospectively. Descriptive analysis of patient demographic on enrollment were performed using logistic regression analyses.
Results
Of 418 patients evaluated for treatment, 163 had a trial available; 138 of these were eligible. Eighty (58%) participated in a clinical trial; the remainder declined (24%) or were not presented for a trial by their treating physicians (76%). Age, preferred language, marital status, family history, or race/ethnicity did not predict for enrollment on a therapeutic clinical trial. Patients with stage II or III breast cancer were more likely to be enrolled on a trial compared to patients with stage 0 or I (odds ratio 2.89, 9.17; p=.02, .0005 respectively).
Conclusions
Enrollment of breast cancer patients on therapeutic clinical trials was relatively high (58% eligible, 19% overall). Prospective studies observing breast cancer stage, clinical trial design, and inclusion of community based physician practices would add breadth to the understanding of poor accrual to breast cancer clinical trials.
doi:10.1016/j.apnr.2013.01.003
PMCID: PMC3748286  PMID: 23490340
Breast cancer; Clinical trials; Cancer prevention; Clinical trial accrual; Trial barriers; Accrual
14.  Breast Cancer, Version 3.2013 
These NCCN Guidelines Insights highlight the important updates specific to the management of HER2-positive metastatic breast cancer in the 2013 version of the NCCN Clinical Practice Guidelines in Oncology for Breast Cancer. These include new first-line and subsequent therapy options for patients with HER2-positive metastatic breast cancer.
PMCID: PMC3991132  PMID: 23847214
15.  Second primary malignancies after autologous hematopoietic cell transplantation for multiple myeloma 
Recent studies demonstrate an increased risk of second primary malignancies (SPM) in multiple myeloma (MM) patients on maintenance lenalidomide following autologous stem cell transplantation (ASCT). There may be other risk factors driving SPM post-ASCT in MM, so we explored this possibility through analysis of our large transplant database in conjunction with our long-term followup program. We conducted a retrospective cohort study of 841 consecutive MM patients who underwent ASCT from 1989–2009 at City of Hope, as well as a nested case-control analysis evaluating the role of all therapeutic exposures before, during and after ASCT. Median length of follow-up for the entire cohort was 3.4 years (range 0.3–19.9). Sixty cases with seventy SPM were identified. The overall cumulative incidence of SPM was 7.4% at five years and 15.9% at ten years if non-melanoma skin cancers (NMSCs) were included, and 5.3% at 5 years and 11.2% at 10 years if NMSCs were excluded. Multivariate analysis of the entire cohort revealed association of both older age (≥55yrs) (RR 2.3 p<0.004) and race (non-Hispanic white) (RR 2.4 p=0.01) with an increased risk of SPM. Furthermore, thalidomide exposure demonstrated a trend towards increased risk (OR=3.5, p=0.15); however, not enough patients were treated with lenalidomide to accurately assess the risk of this agent. Exclusion of NMSCs retained the association with these variables, but was accompanied with loss of statistical significance. This large single-institution analysis identified race and older age to be associated with increased risk of developing SPM. The trend toward increased risk with thalidomide exposure suggests a class effect from immunomodulatory drugs that may not be restricted to lenalidomide.
doi:10.1016/j.bbmt.2012.09.023
PMCID: PMC3553262  PMID: 23073267
second primary malignancy; transplantation; myeloma
16.  Image Guided Total Marrow Irradiation (TMI) Using Helical TomoTherapy in Patients with Multiple Myeloma and Acute Leukemia Undergoing Hematopoietic Cell Transplantation (HCT) 
Purpose
TBI plays an important role in patients undergoing HCT, but is associated with significant toxicities. Targeted TBI using helical tomotherapy (HT) results in reduced doses to normal organs, which predict for reduced toxicities compared to standard TBI.
Methods and Materials
Thirteen patients with multiple myeloma (MM) were treated on an autologous tandem transplant Phase I trial with high dose melphalan, followed 6 weeks later by TMI to skeletal bone. Doses levels were 10, 12, 14, and 16 Gy at 2 Gy QD/BID. On a separate allogeneic HCT trial, 8 patients (5 AML, 1 ALL, 1 NHL, 1 MM) were treated with TMI+TLI + splenic RT to 12 Gy (1.5 Gy BID) combined with fludarabine/melphalan.
Results
For the 13 patients on the tandem autoHCT trial, median age was 54 (42–66). Median organ doses were 15–65% that of the GTV dose. Grade 1–2 acute toxicities were primarily observed. Six reported no vomiting, 9 no mucositis, 6 no fatigue, and 8 no diarrhea. For the 8 patients on the alloHCT trial, the median age was 52 (24–61). Grade 2–3 nausea, vomiting, mucositis and diarrhea were observed. On both trials no grade 4 non-hematologic toxicity was observed and all patients engrafted successfully.
Conclusions
This study demonstrates that TMI using HT is clinically feasible. Reduced acute toxicities observed compare favorably to those seen with standard TBI. Initial results are encouraging and warrant further evaluation as a method to dose escalate with acceptable toxicity or to offer TBI containing regimens to patients unable to tolerate standard approaches.
doi:10.1016/j.ijrobp.2008.04.071
PMCID: PMC3896447  PMID: 18786784
helical tomotherapy; IMRT; bone marrow transplantation; multiple myeloma; leukemia
17.  Late Relapses Following Reduced Intensity Allogeneic Transplantation in Patients with Multiple Myeloma: a long-term follow-up study 
British journal of haematology  2012;160(2):199-206.
SUMMARY
We analysed the long-term outcomes of 60 multiple myeloma patients who underwent reduced intensity allogeneic stem cell transplantation between August 2000 and March 2008. Regimens included fludarabine and melphalan conditioning (flu-mel regimen) for allogeneic haematopoietic cell transplant (HCT) or a planned tandem regimen consisting of high-dose melphalan conditioning for autograft followed by low-dose total body irradiation conditioning for allogeneic HCT (auto-allo regimen). Donors included human leucocyte antigen-matched siblings (n=55) or matched unrelated donors (n=5). With a median follow-up of 9.8 years, 7-year overall survival (OS) and progression-free survival (PFS) were 60% and 31%, respectively. By multivariate Cox regression analysis, disease status of complete response (CR) or partial response (PR) at transplant and the presence of chronic graft-versus-host disease were significantly associated with improved OS. Only disease status was significantly associated with improved PFS. We noted a surprising number of very late relapses, with six patients (10%) relapsing between 6 and 12 years post-transplant. Among the six late relapse patients, all were transplanted within 14 months of diagnosis, 5 had normal karyotypes, and 5 were in CR/PR. Our data provide additional evidence that, while survival may be extended by reduced intensity allogeneic transplant, ultimately, it may not offer a cure.
doi:10.1111/bjh.12123
PMCID: PMC3542410  PMID: 23151215
multiple myeloma; reduced intensity; allogeneic; tandem auto-allo; transplantation
18.  A phase II study of docetaxel and vinorelbine plus filgrastim for HER-2 negative, stage IV breast cancer: SWOG S0102 
Docetaxel and vinorelbine have demonstrated Single-agent activity in breast cancer. Preclinical studies suggest potential synergy between these antitubulin chemotherapy agents. This study evaluates these drugs in combination in metastatic breast cancer. Taxane-naive patients with HER-2 negative, stage IV breast cancer without prior chemotherapy for metastatic disease, were eligible. Docetaxel (60 mg/m2) was given intravenously on Day 1, vinorelbine (27.5 mg/m2) intravenously on Days 8 and 15, and filgrastim on Days 2–21 of a 21-day cycle. The primary study outcome was one-year overall survival (OS), with secondary outcomes of progression-free survival (PFS), response rate (RR), and toxicity. Of 95 patients registered, 92 were eligible and received treatment. One-year OS was 74 % (95 % CI 64–82 %) with a median OS of 22.3 months (95 % CI 18.8–31.4 months). One-year PFS was 34 % (95 % CI 24–43 %) with median of 7.2 months (95 % CI 6.4–10.3). OS at 2 and 3 years were 49 % (95 % CI 38–59 %) and 30 % (95 % CI 21–40 %), respectively. OS was poorer for women with estrogen-receptor negative disease (n = 32) compared to estrogen-receptor positive (n = 60) (log-rank p = 0.031), but PFS was not significantly different (p = 0.11). RR was 59 % among the 74 patients with measurable disease. Grade 3 and 4 adverse events were 48 and 16 %, respectively. Grade 4 neutropenia was 12 % and grade 3/4 febrile neutropenia was 3 %. Common grade 3/4 nonhematologic toxicities were fatigue (14 %), pneumonitis (10 %), and dyspnea (9 %). The combination of docetaxel and vinorelbine is an active first-line chemotherapy in HER-2 nonoverexpressing, metastatic breast cancer. This combination is associated with significant hematologic and nonhematologic toxicity. The safety profile and expense of the filgrastim limit recommendations for routine use.
doi:10.1007/s10549-013-2797-2
PMCID: PMC3889983  PMID: 24352574
Breast cancer; Vinorelbine; Docetaxel; Metastatic
19.  Conditional Survival and Cause-specific Mortality after Autologous Hematopoietic Cell Transplantation for Hematological Malignancies 
Leukemia  2012;27(5):1139-1145.
The probability of survival is conventionally calculated from autologous hematopoietic cell transplantation (aHCT). Conditional survival takes into account the changing probability of survival with time survived, but is not known for aHCT populations. We determined disease-, and cause-specific conditional survival for 2388 patients treated with aHCT over a period of 20 years at a single institution. A total of 1054 deaths (44% of the cohort) were observed: 78% attributed to recurrent disease; 9% to subsequent malignancies; and 6% to cardiopulmonary disease. Estimated probability of relative survival was 62% at 5 and 50% at 10 years from aHCT. On the other hand, 5-year relative survival was 70%, 75%, 81%, and 88% after having survived 1, 2, 5, and 10 years after aHCT, respectively. The cohort was at a 13.9-fold increased risk of death compared with the general population (95%CI=13.1–14.8). The risk of death approached that of the general population for 10-year survivors (SMR=1.4, 95%CI=0.9–1.9), with the exception of female Hodgkin lymphoma patients transplanted before 1995 at age 40 years or younger (SMR=6.0, 95%CI=1.9–14.0). Among those who had survived 10 years, non-relapse-related mortality rates exceeded relapse-related mortality rates. This study provides clinically relevant survival estimates after aHCT, and helps inform interventional strategies.
doi:10.1038/leu.2012.311
PMCID: PMC3776451  PMID: 23183426
conditional survival; autologous HCT; cause-specific mortality
20.  Metastatic Breast Cancer, Version 1.2012 
These NCCN Guidelines Insights highlight the important updates/changes specific to the management of metastatic breast cancer in the 2012 version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer. These changes/updates include the issue of retesting of biomarkers (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2) on recurrent disease, new information regarding first-line combination endocrine therapy for metastatic disease, a new section on monitoring of patients with metastatic disease, and new information on endocrine therapy combined with an mTOR inhibitor as a subsequent therapeutic option.
PMCID: PMC3753191  PMID: 22773798
21.  Total Marrow Irradiation: A New Ablative Regimen as Part of Tandem Autologous Stem Cell Transplantation for Patients with Multiple Myeloma 
Purpose
To establish feasibility, maximum tolerated dose, and potential efficacy of ablative dose total marrow irradiation (TMI) delivered by helical tomotherapy, in patients with multiple myeloma (MM).
Experimental Design
Patients with responding or stable MM received tandem autologous transplants (TASCT), first with melphalan 200 mg/m2, and ≥ 60 days later, with TMI. TMI doses were to be escalated from 1000 cGy, by increments of 200 cGy. All patients received thalidomide and dexamethasone maintenance.
Results
Twenty two of 25 enrolled patients (79%) received TASCT: TMI was administered a median of 63.5 days (44–119) after melphalan. Dose limiting toxicities at level 5 (1800 cGy) included reversible grade 3 pneumonitis, congestive heart failure, and enteritis (1), and grade 3 hypotension (1). The estimated median radiation dose to normal organs was 11–81% of the prescribed marrow dose. Late toxicities included reversible enteritis (1), and lower extremity deep venous thrombosis during maintenance therapy (2). The complete and very good partial response rates were 55% and 27%, following TASCT and maintenance therapy. At a median of 35 months of follow-up (21-50+ months) progression-free and overall survival for all patients are 49 % (95% CI 0.27-0.71) and 82% (0.67-1.00).
Conclusion
Ablative dose TMI as part of TASCT is feasible, and the complete response rate is encouraging. Careful monitoring of late toxicities is needed. Further assessment of this modality is justified at the 1600 cGy maximum tolerated dose level in MM patients who are candidates for ASCT.
doi:10.1158/1078-0432.CCR-10-1912
PMCID: PMC3717559  PMID: 21047977
multiple myeloma; total marrow irradiation; tandem autologous transplantation
22.  CCL2 mediates crosstalk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells 
Cancer Research  2012;72(11):2768-2779.
Cancer stem cells (CSCs) play critical roles in cancer initiation, progression, and therapeutic refractoriness. Although many studies have focused on the genes and pathways involved in stemness, characterization of the factors in the tumor microenvironment that regulate CSCs is lacking. In this study, we investigated the effects of stromal fibroblasts on breast cancer (BC) stem cells. We found that compared to normal fibroblasts, primary cancer-associated fibroblasts (CAFs) and fibroblasts activated by co-cultured BC cells produce higher levels of chemokine (C-C motif) ligand 2 (CCL2), which stimulates the stem cell-specific, sphere-forming phenotype in BC cells and CSC self-renewal. Increased CCL2 expression in activated fibroblasts required STAT3 activation by diverse BC-secreted cytokines, and in turn, induced NOTCH1 expression and the CSC features in BC cells, constituting a “cancer-stroma-cancer” signaling circuit. In a xenograft model of paired fibroblasts and BC tumor cells, loss of CCL2 significantly inhibited tumorigenesis and NOTCH1 expression. In addition, upregulation of both NOTCH1 and CCL2 was associated with poor differentiation in primary BCs, further supporting the observation that NOTCH1 is regulated by CCL2. Our findings therefore suggest that CCL2 represents a potential therapeutic target that can block the cancer-host communication that prompts CSC-mediated disease progression.
doi:10.1158/0008-5472.CAN-11-3567
PMCID: PMC3367125  PMID: 22472119
breast cancer; cancer stem cells; chemokine (C-C motif) ligand 2; tumor microenvironment; stromal fibroblasts
23.  Role of SMC1 in Overcoming Drug Resistance in Triple Negative Breast Cancer 
PLoS ONE  2013;8(5):e64338.
Triple-negative breast cancer (TNBC) is one of the hardest subtypes of breast cancer to treat due to the heterogeneity of the disease and absence of well-defined molecular targets. Emerging evidence has shown the role of cohesin in the formation and progression of various cancers including colon and lung cancer but the role of cohesin in breast cancer remains elusive. Our data showed that structural maintenance of chromosome 1 (SMC1), a subunit of the cohesin protein complex, is differentially overexpressed both at RNA and protein level in a panel of TNBC cell lines as compared to normal epithelial or luminal breast cancer cells, suggesting that the amplified product of this normal gene may play role in tumorigenesis in TNBC. In addition, our results show that induced overexpression of SMC1 through transient transfection enhanced cell migration and anchorage independent growth while its suppression with targeted small interfering RNA (siRNA) reduced the migration ability of TNBC cells. Increased expression of SMC1 also lead to increase in the mesenchymal marker vimentin and decrease in the normal epithelial marker, E-cadherin. Immunocytochemical studies along with flow cytometry and cell fractionation showed the localization of SMC1 in the nucleus, cytoplasm and also in the plasma membrane. The knockdown of SMC1 by siRNA sensitized the TNBC cells towards a PARP inhibitor (ABT-888) and IC50 was approximately three fold less than ABT-888 alone. The cytotoxic effect of combination of SMC1 suppression and ABT-888 was also confirmed by the colony propagation assay. Taken together, these studies report for the first time that SMC1 is overexpressed in TNBC cells where it plays a role in cell migration and drug sensitivity, and thus provides a potential therapeutic target for this highly invasive breast cancer subtype.
doi:10.1371/journal.pone.0064338
PMCID: PMC3661439  PMID: 23717600
24.  Tandem Autologous versus Single Autologous Transplantation Followed by Allogeneic Hematopoietic Cell Transplantation for Patients with Multiple Myeloma: Results from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 Trial 
The lancet oncology  2011;12(13):1195-1203.
Background
Autologous hematopoietic cell transplantation (HCT) improves survival in patients with multiple myeloma, but disease progression remains a challenge. Allogeneic HCT (alloHCT) has the potential to reduce disease progression through graft-versus-myeloma effects. The aim of the BMT CTN 0102 trial was to compare outcomes of autologous HCT (autoHCT) followed by alloHCT with non-myeloablative conditioning (auto-allo) to tandem autoHCT (auto-auto) in patients with standard risk myeloma. Patients in the auto-auto arm were randomized to one year of thalidomide and dexamethasone (Thal-Dex) maintenance therapy or observation (Obs).
Methods
Patients with multiple myeloma within 10 months from initiation of induction therapy were classified as standard (SRD) or high risk (HRD) disease based on cytogenetics and beta-2-microglobulin levels. Assignment to auto-allo HCT was based on availability of an HLA-matched sibling donor. Primary endpoint was three-year progression-free survival (PFS) according to intent-to-treat analysis.
Results
710 patients were enrolled completed a minimum of 3-year follow up. Among 625 SRD patients, 189 and 436 were assigned to auto-allo and auto-auto, respectively. Seventeen percent (33/189) of SR patients in the auto-allo arm and 16% (70/436) in the auto-auto arm did not receive a second transplant. Thal-Dex was not completed in 77% (168/217) of assigned patients. PFS and overall survival (OS) did not differ between the Thal-Dex (49%, 80%) and Obs (41%, 81%) cohorts and these two arms were pooled for analysis. Three year PFS was 43% and 46% (p=0·671) and three-year OS was 77% and 80 % (p=0·191) with auto-allo and auto-auto, respectively. Corresponding progression/relapse rates were 46% and 50% (p=0·402); treatment-related mortality rates were 11% and 4% (p<0·001), respectively. Auto/allo patients with chronic graft-vs-host disease had a decreased risk of relapse. Most common grade 3 to 5 adverse events in auto-allo was hypebilirubenemia (21/189) and in the auto-auto was peripheral neuropathy (52/436). Among 85 HRD patients (37 auto-allo), three PFS was 40% and 33% (p=0·743) and three-year OS was 59% and 67% (p=0·460) with auto-allo and auto-auto, respectively.
Conclusion
Thal-Dex maintenance was associated with poor compliance and did not improve PFS or OS. At three years there was no improvement in PFS or OS with auto-allo compared to auto-auto transplantation in patients with standard risk myeloma. Decisions to proceed with alloHCT after an autoHCT in patients with standard risk myeloma should take into consideration results of the current trial. Future investigation of alloHCT in myeloma should focus to minimize TRM and maximize graft-versus myeloma effects. This trial was registered in Clinicaltrials.gov (NCT00075829) and was funded by the National Heart, Lung and Blood Institute and National Cancer Institute.
doi:10.1016/S1470-2045(11)70243-1
PMCID: PMC3611089  PMID: 21962393

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