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1.  Trastuzumab treatment for breast cancer during pregnancy 
Canadian Family Physician  2008;54(1):31-32.
QUESTION One of my patients has been diagnosed with breast cancer and started treatment with trastuzumab. She has recently discovered that she is pregnant and wishes to continue the pregnancy. What are the consequences of trastuzumab treatment during pregnancy and can she continue her pregnancy?
ANSWER Human data regarding the safety of trastuzumab during pregnancy are scarce. Only 3 case reports could be located in the published literature. Anhydramnios was observed in a case where the exposure to trastuzumab occurred during the second trimester, which reversed after discontinuation of the drug without any apparent consequences to the baby. Evidence is insufficient to provide any recommendations, but in light of the case reports, pregnancies exposed to trastuzumab during the second trimester should be closely followed with particular attention to amniotic fluid volume.
PMCID: PMC2329906  PMID: 18208949
2.  Complementary role of magnetic resonance imaging after ultrasound examination in assessing fetal renal agenesis: a case report 
Introduction
Ultrasonography is used routinely during pregnancy to screen and detect fetal abnormalities. However, there are some conditions like anhydramnios (a prevalent state in renal agenesis) or maternal obesity that may limit the diagnostic accuracy of ultrasonography. Magnetic resonance imaging has proven to be useful when ultrasound alone is insufficient to make a correct diagnosis.
Case presentation
We present the case of a 22-year-old Caucasian woman who was admitted to our unit at the 26th week of gestation for a detailed anatomy scan. Anhydramnios and failure to visualize the kidneys, bladder and renal vessels were confirmed with the use of sonography in our department. Since the lack of amniotic fluid limited the acoustic window for fetal ultrasonography, a magnetic resonance imaging scan was requested to confirm suspected renal agenesis. A fetal magnetic resonance imaging scan was performed and confirmed the suspected diagnosis. A baby boy was born by breech vaginal delivery after spontaneous onset of labor at the 34th week of gestation. The boy weighed 1690g, with Apgar scores of 6 and 4 at two and five minutes respectively, and died one hour after delivery. The diagnosis of bilateral renal agenesis was confirmed on autopsy.
Conclusions
The aim of this study was to evaluate the potential contribution of magnetic resonance imaging in diagnostic procedure after inconclusive ultrasound examination during the assessment of fetal urinary tract abnormalities in the third trimester.
doi:10.1186/1752-1947-8-96
PMCID: PMC3976151  PMID: 24618008
Magnetic resonance imaging; Fetus; Renal agenesis
3.  A case report of trastuzumab dose in gastric cancer 
Introduction
Trastuzumab (Herceptin®, F. Hoffman-La Roche) is now approved for the treatment of metastatic HER2-positive gastric cancer based on the improved survival observed on the phase III Trastuzumab for Gastric Adenocarcinoma (ToGA) study. Standard dosing of trastuzumab is currently extrapolated from breast cancer data: a 3-week schedule (8 mg/kg load, 6 mg/kg q 3 weeks) or a weekly schedule (4 mg/kg load, 2 mg/kg q week).
Case study
Our case study examines an HER2-positive metastatic gastric cancer patient that required a higher than currently recommended standard dose of trastuzumab to achieve treatment response.
Discussion
Several mechanisms may explain these findings and include higher clearance of trastuzumab, higher tumor burden, and pharmacologic resistance in metastatic gastric cancer versus breast cancer. The question of trastuzumab dosing in gastric cancer is currently being evaluated in a phase III clinical trial.
doi:10.3978/j.issn.2078-6891.2013.015
PMCID: PMC3819770  PMID: 24294514
Trastuzumab; metastatic gastric cancer; pharmacokinetics
4.  Sustained complete remission of human epidermal growth factor receptor 2-positive metastatic breast cancer in the liver during long-term trastuzumab (Herceptin) maintenance therapy in a woman: a case report 
Introduction
This case report and short review discusses how long trastuzumab should be continued in metastatic breast cancer, the safety issues in case of pregnancy and the risk of relapse with trastuzumab cessation.
Case presentation
We present the case of a 34-year-old Caucasian woman with human epidermal growth factor receptor 2-positive metastatic breast cancer in the liver who achieved prolonged complete remission within six months of receiving trastuzumab (Herceptin) in combination with vinorelbine and gemcitabine. The patient remains in complete remission seven years later and continues to receive trastuzumab as maintenance therapy.
Conclusion
Trastuzumab-based therapies have greatly improved the survival rates of patients with human epidermal growth factor receptor 2- positive metastatic breast cancer. Despite such improvements, the safety of trastuzumab administration during pregnancy is yet to be defined.
doi:10.1186/1752-1947-4-401
PMCID: PMC3004934  PMID: 21143954
5.  Amniotic fluid insulin and C-peptide as predictive markers for fetal macrosomia, birth injuries, and delivery complications? 
Background
Gestational diabetes mellitus (GDM) occurs in 3–5% of all pregnancies. GDM increases both maternal and fetal risks, causes fetal macrosomia, and hence increases the rates of caesarean sections and delivery complications such as shoulder dystocia. An early predictive marker and consequent early treatment could be beneficial, so amniotic fluid insulin and C-peptide have been examined in several studies. Increased amniotic fluid insulin in early amniocentesis between the 14th and 20th gestational week predicted a later GDM. A potential direct association with fetal macrosomia remains to be determined.
Material/Methods
This retrospective study investigated amniotic fluid insulin/C-peptide from amniocenteses between 14 and 20 weeks of gestation in correlation with fetal birth weight, type of delivery, and complications. To focus on effects of fetal hyperinsulinism apart from therapeutic confounders, we included patients who did not participate in GDM screening. Insulin and C-peptide were measured in 144 samples of frozen amniotic fluid. Birth weight, type of delivery, complications, and birth injuries were noted.
Results
Birth weights ranged from 760 g to 4410 g with a mean weight of 3424 g at an average of 40 weeks gestation. The mean amniotic fluid insulin was 4.36 μU/ml and the mean C-peptide concentration was 0.076 ng/ml. There was no correlation between amniotic fluid insulin or C peptide and birth weight, type of delivery, complications, and birth injuries.
Conclusions
Amniotic fluid insulin and C-peptide are unsuitable as predictive marker for fetal macrosomia, type of delivery, complications, or birth injuries.
doi:10.12659/MSM.889503
PMCID: PMC3907493  PMID: 24423633
amniocentesis; gestational diabetes; macrosomia; amniotic fluid; insulin; C-peptide
6.  Adjuvant Trastuzumab in HER2-Positive Breast Cancer 
The New England Journal of Medicine  2011;365(14):1273-1283.
BACKGROUND
Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab.
METHODS
We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety.
RESULTS
At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study.
CONCLUSIONS
The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk–benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006 ClinicalTrials.gov number, NCT00021255.)
doi:10.1056/NEJMoa0910383
PMCID: PMC3268553  PMID: 21991949
7.  Delayed Paclitaxel-Trastuzumab-Induced Interstitial Pneumonitis in Breast Cancer 
Case Reports in Oncology  2011;4(1):186-191.
Pneumonitis is a rare but serious complication associated with paclitaxel and/or trastuzumab treatment. We report a 51-year-old female patient with locally advanced breast cancer who presented with shortness of breath, fever, dry cough and pulmonary infiltrates. She had been treated without complications for 10 weeks with paclitaxel (Taxol®) and trastuzumab (Herceptin®) as neoadjuvant therapy, with complete clinical and pathological response. Infections and cardiomyopathy were excluded as causes of her symptoms. Bronchoscopy and biopsy were performed and a diagnosis of drug-induced interstitial pneumonitis was made. After treatment with steroids, the patient showed a significant response in less than 24 h; she was discharged home without the need for oxygen less than 48 h after therapy initiation. Although no causative association could be found between either trastuzumab or paclitaxel and this patient's pulmonary syndrome, the potential for such toxicity should be considered, especially as paclitaxel/trastuzumab is a vey common combination therapy for breast cancer.
doi:10.1159/000326063
PMCID: PMC3080783  PMID: 21516267
Paclitaxel; Trastuzumab; Interstitial pneumonitis; Drug-induced infiltrative lung disease; Breast cancer
8.  Toxic optic neuropathy in the setting of docetaxel chemotherapy: a case report 
BMC Ophthalmology  2014;14:18.
Background
To describe the first reported case of toxic optic neuropathy secondary to docetaxel (Taxotere®) chemotherapy.
Case presentation
A 53-year-old female presented with predominantly unilateral visual loss, but extensive bilateral visual field defects and bilateral optic nerve head swelling 2 weeks after first dose of docetaxel (Taxotere®) and trastuzumab (Herceptin®) chemotherapy for a left sided node-positive, HER2 positive breast cancer. Extensive investigation ruled out other causes of optic neuropathy. She was treated with high dose corticosteroids intravenously for 1 week then a tapering oral dose over 8 weeks. Visual field defects gradually resolved and visual acuity improved. Docetaxel chemotherapy was discontinued but targeted therapy with trastuzumab continued without further complication.
Conclusion
Docetaxel can cause a toxic optic neuropathy possibly due to an ischemic or neurotoxic mechanism at the optic nerve head. With cessation of docetaxel therapy and treatment with systemic corticosteroids, visual recovery can occur without significant residual visual deficit.
doi:10.1186/1471-2415-14-18
PMCID: PMC3941969  PMID: 24564293
Toxic optic neuropathy; Toxic; Optic neuropathy; Docetaxel; Chemotherapy
9.  Effectiveness of neoadjuvant trastuzumab and chemotherapy in HER2-overexpressing breast cancer 
Purpose
Trastuzumab and chemotherapy is the current standard of care in HER2+ early or locally advanced breast cancer, but there are scanty literature data of its real world effectiveness.
Methods
We retrospectively reviewed 205 patients with HER2+ breast cancer diagnosed in 10 Italian Medical Oncology Units between July 2003 and October 2011. All patients received neoadjuvant systemic therapy (NST) with trastuzumab in association with chemotherapy. Many different chemotherapy regimens were used, even if 90 % of patients received schemes including anthracyclines and 99 % received taxanes. NST was administered for more than 21 weeks (median: 24) in 130/205 (63.4 %) patients, while trastuzumab was given for more than 12 weeks (median: 12 weeks) in 101/205 (49.3 %) patients. pCR/0 was defined as ypT0+ypN0, and pCR/is as ypT0/is+ypN0.
Results
pCR/0 was obtained in 24.8 % and pCR/is in 46.8 % of the patients. At multivariate logistic regression, nonluminal/HER2+ tumors (P < 0.0001) and more than 12 weeks of neoadjuvant trastuzumab treatment (P = 0.03) were independent predictors of pCR/0. Median disease-free survival (DFS) and cancer-specific survival (CSS) have not been reached at the time of analysis. At multivariate analysis, nonluminal/HER2+ subclass (DFS: P = 0.01 and CSS: P = 0.01) and pathological stage II–III at surgery (DFS: P < 0.0001 and CSS: P = 0.001) were the only variables significantly associated with a worse long-term outcome.
Conclusions
Our data set the relevance of molecular subclasses and residual tumor burden after neoadjuvant as the most relevant prognostic factors for survival in this cohort of patients.
doi:10.1007/s00432-013-1436-y
PMCID: PMC3678021  PMID: 23604446
Breast cancer; Pathological complete response; HER2; Neoadjuvant; Trastuzumab; Survival
10.  Addition of GM-CSF to trastuzumab stabilises disease in trastuzumab-resistant HER2+ metastatic breast cancer patients 
British Journal of Cancer  2010;103(9):1331-1334.
Background:
One of the proposed mechanisms of trastuzumab-induced regression of human epidermal growth factor receptor 2-positive (HER2+) tumours includes facilitation of antibody-dependent cell-mediated cytotoxicity (ADCC). Granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates ADCC. We presented our pilot study of adding GM-CSF to trastuzumab in patients with trastuzumab-resistant HER2+ metastatic breast cancer.
Methods:
Patients with HER2+ metastatic breast cancer that progressed after trastuzumab +/− chemotherapy were continued on trastuzumab 2 mg kg–1 intravenous weekly and GM-CSF 250 μg m–2 subcutaneous daily. Patients were assessed for response every 8 weeks. Treatment was continued until disease progression or intolerable toxicity.
Results:
Seventeen patients were evaluable (median age 48 years, range 27–75 years). The median number of metastatic sites was 2 (range 1–3); the most common site was the liver (n=10). The median number of prior regimens for metastatic disease was 2 (range 1–5). No objective disease response was observed, but five patients (29%) had stable disease for a median duration of 15.8 (range 10–53.9) weeks. The most common adverse event was rash at the injection site. No grade 4 or irreversible adverse event was seen.
Conclusion:
The addition of GM-CSF to trastuzumab alone had a modest clinical benefit and acceptable safety profile in heavily pretreated patients with trastuzumab-resistant HER2+ metastatic breast cancer.
doi:10.1038/sj.bjc.6605918
PMCID: PMC2990606  PMID: 20877352
granulocyte-macrophage colony-stimulating factor; HER2; metastatic breast cancer; trastuzumab
11.  Postterm pregnancy 
Facts, Views & Vision in ObGyn  2012;4(3):175-187.
Postterm pregnancy is a pregnancy that extends to 42 weeks of gestation or beyond. Fetal, neonatal and maternal complications associated with this condition have always been underestimated. It is not well understood why some women become postterm although in obesity, hormonal and genetic factors have been implicated. The management of postterm pregnancy constitutes a challenge to clinicians; knowing who to induce, who will respond to induction and who will require a caesarean section (CS). The current definition and management of postterm pregnancy have been challenged in several studies as the emerging evidence demonstrates that the incidence of complications associated with postterm pregnancy also increase prior to 42 weeks of gestation. For example the incidence of stillbirth increases from 39 weeks onwards with a sharp rise after 40 weeks of gestation. Induction of labour before 42 weeks of gestation has the potential to prevent these complications; however, both patients and clinicians alike are concerned about risks associated with induction of labour such as failure of induction and increases in CS rates. There is a strong body of evidence however that demonstrates that induction of labour at term and prior to 42 weeks of gestation (particularly between 40 & 42 weeks) is associated with a reduction in perinatal complications without an associated increase in CS rates. It seems therefore that a policy of induction of labour at 41 weeks in postterm women could be beneficial with potential improvement in perinatal outcome and a reduction in maternal complications.
PMCID: PMC3991404  PMID: 24753906
Body mass index; induction of labour; perinatal complications; postterm pregnancy; ultrasound
12.  Health-Related Quality of Life With Adjuvant Docetaxel- and Trastuzumab-Based Regimens in Patients with Node-Positive and High-Risk Node-Negative, HER2-Positive Early Breast Cancer: Results from the BCIRG 006 Study 
The Oncologist  2013;18(7):812-818.
In the BCIRG 006 trial, eligible patients were randomly assigned to either four cycles of adjuvant doxorubicin and cyclophosphamide followed by four cycles of docetaxel or one of two trastuzumab-containing regimens: adjuvant doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab administered for 1 year or six cycles of docetaxel plus carboplatin combined with trastuzumab administered for 1 year. Health-related quality-of-life outcomes for adjuvant docetaxel and trastuzumab-based regimens were favorable and support docetaxel plus carboplatin combined with trastuzumab as a more tolerable treatment option.
Background.
This study aims to describe and compare health-related quality of life (HRQL) in patients with node-positive and high-risk node-negative HER2-positive early breast cancer receiving adjuvant docetaxel and trastuzumab-based or docetaxel-based regimens alone.
Methods.
Eligible patients (n = 3,222) were randomly assigned to either four cycles of adjuvant doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC→T) or one of two trastuzumab-containing regimens: adjuvant doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab administered for 1 year (AC→TH) or six cycles of docetaxel plus carboplatin combined with trastuzumab administered for 1 year (TCH). The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and BR-23 were administered at baseline, the start of cycle 4 (mid), and the end of chemotherapy (EOC), as well as at 6, 12, and 24 months after chemotherapy.
Results.
Compliance rates for the EORTC questionnaires were acceptable at 72%–93% of eligible patients out to the 12-month assessment. Systemic side effect (SE) change scores were significantly improved for TCH-treated patients compared with AC→TH and AC→T at EOC, suggesting improved tolerability. Physical functioning (PF) was only slightly worse at midpoint for those receiving TCH, compared with patients who were just starting on taxane in an AC→TH regimen, but was otherwise similar between arms. All treatment arms recovered from the deterioration in SE, PF, and Global Health Scale scores by 1 year and median future perspective change scores continued to improve throughout treatment and follow-up.
Conclusion.
HRQL outcomes for adjuvant docetaxel and trastuzumab-based regimens are favorable and support TCH as a more tolerable treatment option.
doi:10.1634/theoncologist.2013-0091
PMCID: PMC3720634  PMID: 23814044
Breast cancer; BCIRG 006; Docetaxel; Trastuzumab; Chemotherapy; Quality of life; Anthracycline-induced cardiotoxicity; Adjuvant therapy
13.  Efficacy of Neoadjuvant Therapy with Trastuzumab Concurrent with Anthracycline- and Non-anthracycline-based Regimens for HER2-Positive Breast Cancer 
Cancer  2011;118(9):2385-2393.
Background
To evaluate the pathologic complete response (pCR) rates and relapse-free survival (RFS) and overall survival (OS) of patients receiving neoadjuvant systemic therapy (NST) with trastuzumab in combination with an anthracycline- or a non-anthracycline-based regimen.
Methods
In this retrospective non-randomized study, we reviewed records of 300 patients with HER2-positive breast cancer treated with either sequential paclitaxel and trastuzumab and FEC75 in combination with trastuzumab (PH-FECH) or docetaxel, carboplatin and trastuzumab (TCH). The Kaplan-Meier product-limit method was used to estimate RFS and OS rates. Logistic regression models and Cox proportional hazards models were fit to determine the associations between NST, pCR and survival.
Results
There was no significant difference in the decline in cardiac ejection fraction, however, patients who received PH-FECH had less cardiac comorbidities at baseline (P = 0.002). pCR rates were 60.6% and 43.3% for patients who received PH-FECH(n=235) and TCH(n=65), respectively (P=0.016). Patients who received PH-FECH were 1.45 times more likely to have a pCR (Odds ratio [OR]:1.45; 95% confidence interval (CI):1.06-1.98; P=0.02). Three-year RFS rates were 93% and 71% (P<0.001), and 3-year OS rates were 96% and 86% (P=0.008) for patients who received PH-FECH and TCH, respectively. Patients who received PH-FECH had a lower risk of recurrence (Hazard ratio [HR]:0.27; 95% CI:0.12-0.60; P=0.001) and death (HR:0.37; 95% CI:0.12-1.13; P=0.08) than those treated with TCH.
Conclusion
The type of NST in HER2-positive breast cancer is predictive of pCR rate independent of disease and patient characteristics. While TCH is active, PH-FECH shows a higher pCR rate and RFS advantage.
doi:10.1002/cncr.26555
PMCID: PMC3274632  PMID: 21953213
HER2-positive breast cancer; neoadjuvant therapy; trastuzumab; anthracyclines; pCR; survival
14.  Integrating Molecular Mechanisms and Clinical Evidence in the Management of Trastuzumab Resistant or Refractory HER-2+ Metastatic Breast Cancer 
The Oncologist  2011;16(11):1535-1546.
To facilitate crosstrial comparisons and the understanding of resistance mechanisms, unifying definitions of trastuzumab resistance and trastuzumab refractoriness are provided. Mechanisms of resistance are reviewed.
Human epidermal growth factor receptor (HER)-2+ breast cancer is a distinct molecular and clinical entity, the prognosis of which is improved by trastuzumab. However, primary resistance to trastuzumab is observed in >50% of patients with HER-2+ advanced breast cancer, and the majority of patients who initially respond to treatment eventually develop disease progression. To facilitate crosstrial comparisons and the understanding of resistance mechanisms, we propose a unifying definition of trastuzumab resistance as progression at first radiological reassessment at 8–12 weeks or within 3 months after first-line trastuzumab in the metastatic setting or new recurrences diagnosed during or within 12 months after adjuvant trastuzumab. In contrast, we define trastuzumab-refractory breast cancer as disease progression after two or more lines of trastuzumab-containing regimens that initially achieved disease response or stabilization at first radiological assessment. We review mechanisms of trastuzumab resistance mediated by p95HER-2 overexpression, phosphoinositide 3-kinase pathway activation, and signaling pathway activation driven by HER-3, epidermal growth factor receptor, and insulin-like growth factor 1 receptor. We distinguish in vitro from in vivo evidence, highlighting that most data describing trastuzumab resistance are derived from preclinical studies or small retrospective patient cohorts, and discuss targeted therapeutic approaches to overcome resistance. Prospective analysis through clinical trials with robust tissue collection procedures, prior to and following acquisition of resistance, integrated with next-generation tumor genome sequencing technologies, is identified as a priority area for development. The identification of predictive biomarkers is of paramount importance to optimize health economic costs and enhance stratification of anti-HER-2 targeted therapies.
doi:10.1634/theoncologist.2011-0165
PMCID: PMC3233287  PMID: 22020213
Breast cancer; ErbB-2; mTOR; PI3 kinase; AKT; Trastuzumab
15.  Outcome impact of PIK3CA mutations in HER2-positive breast cancer patients treated with trastuzumab 
British Journal of Cancer  2013;108(9):1807-1809.
Background:
Phosphatidylinositol 3-kinase (PI3K) pathway activation has been suggested to negatively influence response to anti-HER2 therapy in breast cancer patients. The present study focused on mutations of the PIK3CA gene, encoding one of the two PI3K subunits.
Methods:
PIK3CA mutations were assessed by direct sequencing in 80 HER2-positive patients treated with 1 year of trastuzumab. All patients preoperatively received four cycles of anthracycline-based chemotherapy, followed by four cycles of docetaxel and 1 year of trastuzumab, starting either before surgery with the first cycle of docetaxel and continuing after surgery (neoadjuvant trastuzumab arm, n=43), or only after surgery (adjuvant trastuzumab arm, n=37).
Results:
PIK3CA mutations were found in 17 tumours (21.3%). Better disease-free survival (DFS) was observed in patients with PIK3CA wild-type compared with mutated tumours (P=0.0063). By combining PIK3CA status and treatment arms, four separate prognostic groups with significantly different DFS (P=0.0013) were identified.
Conclusion:
These results confirm that the outcome of HER2-positive patients treated with trastuzumab is significantly worse in patients with PIK3CA-mutated compared with wild-type tumours.
doi:10.1038/bjc.2013.164
PMCID: PMC3658522  PMID: 23612454
breast cancer; HER2; neoadjuvant therapy; PIK3CA; trastuzumab
16.  Loss of Phosphatase and Tensin Homolog or Phosphoinositol-3 Kinase Activation and Response to Trastuzumab or Lapatinib in Human Epidermal Growth Factor Receptor 2–Overexpressing Locally Advanced Breast Cancers 
Journal of Clinical Oncology  2010;29(2):166-173.
Purpose
Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be associated with trastuzumab resistance. Trastuzumab, the humanized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and lapatinib, an epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, are both established treatments for HER2-overexpressing breast cancers. Understanding of the cellular response to HER2-targeted therapies is needed to tailor treatments and to identify patients less likely to benefit.
Methods
We evaluated the effect of trastuzumab or lapatinib in three HER2-overexpressing cell lines. We confirmed the in vitro observations in two neoadjuvant clinical trials in patients with HER2 overexpression; 35 patients received trastuzumab as a single agent for the first 3 weeks, then docetaxel every 3 weeks for 12 weeks (trastuzumab regimen), whereas 49 patients received lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel for 12 weeks before primary surgery (lapatinib regimen). Apoptosis, Ki67, p-MAPK, p-AKT, and PTEN were assessed by immunohistochemistry. Genomic DNA was sequenced for PIK3CA mutations.
Results
Under low PTEN conditions, in vitro data indicate that lapatinib alone and in combination with trastuzumab was effective in decreasing p-MAPK and p-AKT levels, whereas trastuzumab was ineffective. In the clinical trials, we confirmed that low PTEN or activating mutation in PIK3CA conferred resistance to the trastuzumab regimen (P = .015), whereas low PTEN tumors were associated with a high pathologic complete response rate (P = .007).
Conclusion
Activation of PI3 kinase pathway is associated with trastuzumab resistance, whereas low PTEN predicted for response to lapatinib. These observations support clinical trials with the combination of both agents.
doi:10.1200/JCO.2009.27.7814
PMCID: PMC3058274  PMID: 21135276
17.  Cardiac safety results from a phase II, open-label, multicenter, pilot study of two docetaxel-based regimens plus bevacizumab for the adjuvant treatment of subjects with node-positive or high-risk node-negative breast cancer 
SpringerPlus  2014;3:244.
Purpose
Adding antiangiogenic therapy to standard chemotherapy has improved response rates and progression-free survival in metastatic breast cancer (BC) patients. This phase II study evaluated cardiac safety of bevacizumab with/without trastuzumab with two docetaxel-based regimens in early BC.
Methods
127 women with non-metastatic node-positive or high-risk node-negative BC were enrolled. Women with human epidermal growth factor receptor 2 (HER2)-negative BC (n = 93) received docetaxel/doxorubicin/cyclophosphamide (TAC) + bevacizumab, while women with HER2-positive disease (n = 34) received docetaxel/carboplatin/trastuzumab (TCH) + bevacizumab, every 3 weeks for six cycles. Maintenance therapy with bevacizumab alone or bevacizumab plus trastuzumab, respectively, was given every 3 weeks for 52 weeks. The primary objective was to evaluate cardiac safety, as measured by the incidence of ≥ grade 3 clinical congestive heart failure (CHF); the secondary objective was assessment of safety and toxicity.
Results
At least one cardiac adverse event (AE; CHF, cardiomyopathy, or left ventricular dysfunction) was reported in 26.1% of TAC (n = 92) and 17.6% of TCH subjects (n = 34); there were no cardiac deaths. ≥ Grade 3 clinical CHF was observed in 4.3% in the TAC plus bevacizumab stratum and 0% in the TCH plus bevacizumab stratum. A ≥ grade 3 treatment-emergent AE (any kind) related to study treatment was observed in 59.8% in the TAC with bevacizumab and 52.9% in the TCH plus bevacizumab stratum.
Conclusion
Adding bevacizumab to a docetaxel-based regimen with trastuzumab did not appear to increase cardiotoxicity.
Trial registration
ClinicalTrials.gov Identifier: NCT00446030, registered March 8, 2007.
doi:10.1186/2193-1801-3-244
PMCID: PMC4031367  PMID: 24860718
Adverse events; Anthracyclines; Antiangiogenic; Congestive heart failure; Trastuzumab
18.  Weekly paclitaxel plus trastuzumab in metastatic breast cancer pretreated with anthracyclines-a phase II multipractice study 
BMC Cancer  2012;12:165.
Background
The 3-weekly combination of trastuzumab and paclitaxel has been approved for the treatment of advanced breast cancer based on a large pivotal study. However, mono and combination chemotherapy trials suggest that weekly paclitaxel has a better therapeutic index, especially in the palliative setting. The present trial examined the efficacy and safety of weekly paclitaxel over a limited duration combined with continued trastuzumab in HER2+ patients.
Methods
Patients with histologically confirmed metastatic breast cancer overexpressing HER2 were eligible if pretreated with anthracycline in either the adjuvant or palliative setting. Treatment consisted of weekly trastuzumab (2 mg/kg/week for up to one year after a loading dose of 4 mg/kg in week 1) and paclitaxel (90 mg/m², administered in weeks 1–6 and 8–13).
Results
Twenty-seven German centers enrolled 121 patients. The median number of metastatic sites was two (range 1–5); 38% of patients had received chemotherapy for advanced disease. After a median 42 weeks of trastuzumab treatment, limited by disease progression in roughly half the patients, a best objective response rate (complete response + partial response) of 76% was achieved, including complete remissions in 29%. 74% of patients lived without tumor progression at six months. Median progression-free and overall survival were 9.4 (95% confidence interval [CI]: 8.1–11.3) and 22 months (95% CI: 17–46). After alopecia, Common Toxicity Criteria grade ≥2 toxicity was predominantly hematological (leukopenia [31%] and anemia [41%]); however, thrombocytopenia occurred in only 5%. Neurotoxicity was remarkably low. Two cardiac events (grades 2 and 3) were presumed treatment-related.
Conclusions
Weekly paclitaxel plus trastuzumab allows an increased dose density and offers an attractive and effective alternative to the conventional schedule. Limiting the duration of cytotoxic therapy to 3 months seems to be an option to reduce neurotoxicity without impairing long-term outcome.
doi:10.1186/1471-2407-12-165
PMCID: PMC3443018  PMID: 22559145
19.  The Clinical Significance of Eosinophils in the Amniotic Fluid in Preterm Labor 
Objective
White blood cells are not traditionally considered to be normally present in amniotic fluid. This study was conducted after the observation that a patient with preterm labor and intact membranes had eosinophils as a predominant cell in the amniotic fluid, and had an episode of asthma during the index pregnancy. The goal of this study was to determine whether women presenting with preterm labor with eosinophils in the amniotic fluid had a different outcome than those without eosinophils as the predominant white blood cell in the amniotic cavity.
Methods
This retrospective case-control study included women who presented with preterm labor and intact membranes between 24 and 34 weeks of gestation. Patients underwent an amniocentesis shortly after admission for the assessment of the microbiologic status of the amniotic cavity and/or fetal lung maturity. Amniotic fluid was cultured for aerobic and anaerobic bacteria as well as genital mycoplasmas. Cytologic studies included amniotic fluid white blood cell count and differential, which was performed on cytocentrifuged specimens. Patients with microbial invasion of the amniotic cavity and/or a white blood cell count >20 cells/mm3 were excluded from the study. Cases were defined as women in whom the differential contained >20% of eosinophils. Controls were selected among women with an amniotic fluid eosinophil count ≤20% and matched for gestational age at amniocentesis. The analysis was conducted with non-parametric statistics.
Results
The study population consisted of 10 cases and 50 controls. Gestational age and cervical dilatation at admission were similar in both groups. Cases had a lower gestational age at delivery than controls [34.6 weeks, inter-quartile range (IQR) 32–37.3 weeks vs. 38.0 weeks, IQR 35–40 weeks, respectively; p=0.018]. The prevalence of preterm delivery ≤35 weeks was higher among patients who had >20% eosinophils than in the control group [50% (5/10) vs. 18% (9/50), respectively; p=0.029]. Similar results were observed for delivery at <37 weeks [Cases: 70% (7/10) vs. Controls: 36% (18/50); p=0.046].
Conclusions
Women with preterm labor and intact membranes who have a large proportion of eosinophils in the amniotic fluid are at an increased risk for spontaneous preterm delivery. These patients may have had an episode of preterm labor related to a type I hypersensitivity reaction.
doi:10.3109/14767050903168465
PMCID: PMC3470475  PMID: 19900034
Premature birth; preterm birth; prematurity; premature labor; mast cells; amniotic fluid cells; amniotic fluid white blood cells; allergy; allergy-induced preterm labor; atopy; pregnancy; type I hypersensitivity reaction; parturition; labor; eosinophil granule proteins
20.  FETAL RENAL ARTERY IMPEDANCE AS ASESSED BY DOPPLER ULTRASOUND IN PREGNANCIES COMPLICATED BY INTRA-AMNIOTIC INFLAMMATION AND PRETERM BIRTH 
OBJECTIVE
To evaluate the fetal renal artery impedance in the context of inflammation-associated preterm birth (PTB).
STUDY DESIGN
We conducted a prospective Doppler assessment of the fetal renal artery impedance in 70 singleton fetuses. The study group consisted of 56 premature fetuses (28.1 [25.3–30.6] weeks at enrollment). Gestational age (GA) reference ranges were generated based on fetuses with uncomplicated pregnancies (n=14). Doppler studies included renal artery pulsatility index (PI), resistance index (RI), systolic/diastolic (S/D) ratio and presence-or-absence of end-diastolic blood flow. We assessed amniotic fluid (AF) inflammation by proteomic profiling (SELDI-TOF). Data were interpreted in relationship to amniotic fluid index (AFI), cord blood interleukin-6 (IL-6) and erythropoietin (EPO) levels. The cardiovascular and metabolic profiles of the neonates were investigated in the first 24 hours of life.
RESULTS
Fetuses delivered by mothers with intra-amniotic inflammation had higher cord blood IL-6 but not EPO levels. Fetal inflammation did not affect either renal artery PI,RI,S/D ratio or end-diastolic blood flow. Neonates delivered in the context of intraamniotic inflammation had higher serum blood urea nitrogen levels, which correlated significantly with AF IL-6 levels. The renal artery RI and SD ratio were inversely correlated with the AFI independent of GA, cord blood IL-6 and status of the membranes.
CONCLUSION
The fetus is capable of sustaining normal renal artery impedance despite inflammation. Resistance in the renal vascular bed affects urine output independent of inflammation.
doi:10.1016/j.ajog.2008.11.001
PMCID: PMC3791328  PMID: 19185102
21.  Gamma-glutamyl transferase activity in fetal serum, maternal serum, and amniotic fluid during gestation. 
Journal of Clinical Pathology  1984;37(6):700-703.
Gamma-glutamyl transferase activity was measured in fetal serum, maternal serum, and amniotic fluid in 173 pregnancies from 15 to 40 weeks' gestation. Fetal serum was obtained in the second trimester by fetoscopy and in the third trimester by umbilical cord puncture at caesarian section or vaginal delivery. Enzyme activities in maternal blood (10 IU/1, SD 2) and fetal blood (88 IU/1, SD 20) remained relatively constant throughout gestation, whereas in the amniotic fluid there was a significant decrease at term from the value in the second trimester (p less than 0.001). Electrophoretic separation of the enzyme showed one isoenzyme in the fetal blood and at least two in the amniotic fluid. The fetal isoenzyme had the same mobility as the major isoenzyme in the amniotic fluid.
PMCID: PMC498850  PMID: 6144697
22.  Preterm prelabour amniorrhexis: intrauterine infection and interval between membrane rupture and delivery. 
This study aimed to determine if fetal bacteraemia and amniotic fluid infection at the time of membrane rupture reduces the interval between membrane rupture and the onset of labour in pregnancies complicated by preterm prelabour amniorrhexis. Sixty nine pregnancies with preterm prelabour amniorrhexis at 12-36 weeks' gestation that were managed expectantly had spontaneous onset of labour. In all cases cordocentesis and amniocentesis were performed and fetal blood and amniotic fluid were cultured for aerobic and anaerobic bacteria. In the group with negative fetal blood and amniotic fluid cultures (group 1) the median interval from amniorrhexis to delivery was 41 days (range 1-161) and there was an inverse correlation between gestational age at amniorrhexis and delivery interval. In the group with negative fetal blood but positive amniotic fluid cultures (group 2) the median amniorrhexis to delivery interval was nine days (range 1-37), and in the group with positive fetal blood cultures (group 3) the interval was two days (range 1-5). These findings suggest that pregnancies complicated by preterm prelabour amniorrhexis and fetal bacteraemia undergo spontaneous labour within five days of membrane rupture, and if labour does not occur then infection is unlikely.
PMCID: PMC2528402  PMID: 7743284
23.  Polyhydramnios as a Predictor of Adverse Pregnancy Outcomes 
Objectives:
This study aimed to ascertain the frequency of polyhydramnios in singleton pregnancies, to determine the associated risk factors, and assess the adverse maternal and perinatal outcomes.
Methods:
A retrospective cohort study of all singleton pregnancies complicated with polyhydramnios after 28 weeks of gestation was carried out in Nizwa Hospital’s Obstetrics & Gynecology Department, Oman, from January 2002 to December 2007. Of 25,979 pregnant women reviewed, 477 were found to have polyhydramnios. The control group consisted of 900 pregnant women. Cases of polyhydramnios were diagnosed as mild, moderate, or severe based on their highest amniotic fluid index. Cases were compared with controls in terms of demographic data; prevalence of diabetes, macrosomia, or Caesarean deliveries; frequency of fetal anomalies, and perinatal mortality rate.
Results:
Polyhydramnios was diagnosed in 1.8% of pregnancies. It was mild in 382 (80%), moderate in 84 (17.6%), and severe in 12 (2.4%). A total of 72 (15.3 %) cases of polyhydramnios were complicated by diabetes (gestational or established diabetes mellitus) as compared to 10% of the control group and 39 (8.1%) neonates had congenital anomalies. Polyhydramnios was associated with advanced maternal age; 58 (12.2%) of subjects were over 40 years old. The perinatal mortality rate with polyhydramnios was 42 per 1,000 births compared to 14 per 1000 births in the control group.
Conclusion:
These data demonstrate that polyhydramnios is associated with an increased risk of adverse perinatal outcomes, and there is a significant positive relation with maternal age, diabetes, fetal anomalies, and fetal macrosomia.
PMCID: PMC3616801  PMID: 23573383
Amniotic fluid index; Caesarean delivery; Macrosomia; Perinatal outcome; Oman
24.  Radiation Recall Reaction Induced by Adjuvant Trastuzumab (Herceptin) 
Case Reports in Medicine  2009;2009:307894.
Although concerns of radiation sensitization have been raised with concurrent trastuzumab (Herceptin) administration, there has been no published case of radiation recall reaction associated with trastuzumab. This case describes a clinical presentation consistent with a radiation recall reaction following administration of adjuvant trastuzumab after neoadjuvant FEC-D chemotherapy and locoregional radiotherapy for HER2-positive, locally advanced breast cancer in a premenopausal woman. Although the mechanism and etiology of radiation recall dermatitis remain unclear, this case raises further hypotheses regarding a possible drug dose-dependence and possible predisposing risk factor for the development of radiation recall reactions.
doi:10.1155/2009/307894
PMCID: PMC2739423  PMID: 19746202
25.  Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? 
British Journal of Cancer  2006;94(2):259-267.
This study evaluated by immunohistochemistry (IHC) immune cell response during neoadjuvant primary systemic therapy (PST) with trastuzumab in patients with HER2-positive primary breast cancer. In all, 23 patients with IHC 3+ primary breast cancer were treated with trastuzumab plus docetaxel. Pathological complete and partial responses were documented for nine (39%) and 14 (61%) patients, respectively. Case-matched controls comprised patients treated with docetaxel-based PST without trastuzumab (D; n=23) or PST without docetaxel or trastuzumab (non-taxane, non-trastuzumab, NT–NT; n=23). All surgical specimens were blind-analysed by two independent pathologists, with immunohistochemical evaluation of B and T lymphocytes, macrophages, dendritic cells and natural killer (NK) cells. Potential cytolytic cells were stained for Granzyme B and TiA1. HER2 expression was also evaluated in residual tumour cells. Trastuzumab treatment was associated with significantly increased numbers of tumour-associated NK cells and increased lymphocyte expression of Granzyme B and TiA1 compared with controls. This study supports an in vivo role for immune (particularly NK cell) responses in the mechanism of trastuzumab action in breast cancer. These results suggest that trastuzumab plus taxanes lead to enhanced NK cell activity, which may partially account for the synergistic activity of trastuzumab and docetaxel in breast cancer.
doi:10.1038/sj.bjc.6602930
PMCID: PMC2361112  PMID: 16404427
primary systemic therapy; trastuzumab; ADCC; MoA

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