Use Of Trastuzumab Research Articles

Continuation of trastuzumab beyond disease progression in HER2-positive metastatic gastric cancer: the MD Anderson experience.

Despite the wide spread use of trastuzumab in human epidermal growth factor receptor 2 (HER2) overexpressing metastatic gastric cancer patients, its optimal duration of administration beyond first-line disease progression is unknown. In HER2 overexpressing metastatic breast cancer, trastuzumab continuation beyond first-line disease progression has shown improvement in time to progression (TTP) without an increased risk of treatment related toxicity. HER2-overexpressing metastatic gastric cancer patients were identified from our database between January 2010 and December 2014. We retrospectively reviewed the medical records of 43 patients who received trastuzumab in combination with chemotherapy as first-line and continued trastuzumab beyond disease progression. Forty-three cases were identified, 27 males (62.8%), median age of the patients was 58 years. Thirty-five (81.4%) presented with stage 4 as their initial presentation. Eighty one percent had 3+ HER2 overexpression by immunohistochemistry (IHC) and 18% had 2+ HER2 overexpression confirmed by fluorescence in situ hybridization (FISH). Thirteen (52%) were moderately differentiated, 16 (37.1%) were poorly differentiated. The most common sites of metastasis were liver 35 (81.4%) and lung 14 (32.5%). The most commonly used first-line regimen was oxaliplatin, 5-fluorouracil (5-FU), and trastuzumab in 22 (51.1%) patients. Twenty-five (58.1%) patients received irinotecan, 5-FU and trastuzumab in the second-line. Progression-free survival (PFS) was 5 months (95% CI: 4.01-5.99 months). Five patients are still alive and excluded from calculating the median overall survival (OS) which was 11 months (range, 5-53 months) for the remaining 20 subjects of this second-line group. Trastuzumab was not discontinued due to side effects in any of the study population. In conclusion, this retrospective analysis suggests that continuation of trastuzumab beyond disease progression in patients with HER2-overexpressing metastatic gastric cancer is feasible and safe. Randomized studies are warranted.

Neratinib in HER-2-positive breast cancer: results to date and clinical usefulness.

The management of HER-2-positive breast cancer has improved significantly with the use of targeted agents to the HER-2 signaling pathway. Despite the improved survival achieved with the use of trastuzumab and chemotherapy in both the adjuvant and metastatic setting, patients may still recur or progress; whilst preclinical data demonstrate that these cancer cells remain addicted to the HER-2 oncogene. Neratinib, an oral small molecule tyrosine-kinase inhibitor has efficacy in the metastatic and adjuvant setting of patients who have previously received trastuzumab-based treatment. Diarrhea, being a class effect of tyrosine-kinase inhibitor, is the most common side effect seen following neratinib administration, but recent data suggests that a prophylactic loperamide regimen can reduce the incidence of grade 3 diarrhea. Phase I through to III clinical trials of neratinib will be reviewed, with discussion of the postulated mechanism underlying diarrheal events and its management.

Which is more important for doctors in a middle-income country, a national guideline or the medical literature? An adherence survey of trastuzumab use for breast cancer in Iran

IntroductionMost national standard therapeutic guidelines in the world recommend a 52-week trastuzumab regimen for breast cancer treatment. In contrast, the national guideline published by the Iranian Ministry of Health recommends a nine-week regimen. Since guidelines are not necessarily followed in daily practice, we assessed the extent to which current routine practice in Iran as a middle-income country matches the recommendations found in these guidelines. Methods128 Iranian oncologists were asked to complete an online anonymous questionnaire. Concurrently, a 3-year retrospective claims database analysis was conducted using data from the Social Security Organization, a health insurer which covers approximately 50% of the Iranian population, to enable comparisons with the questionnaire results. ResultsWith a 41% (52/128) response rate, doctors reported a relatively high absolute adherence (86%) to the guideline for HER2 receptor testing but a low rate of absolute adherence (6%) to the guideline for duration of trastuzumab treatment. Doctors indicated that the planned duration was 9 weeks in only 33% of patients; in most cases, the plan was 52-week treatment. Patients with a 9-week treatment plan received trastuzumab for 8.6 weeks on average while patients with 52-week plans received treatment for 29.2 weeks. The general trends found in the survey were confirmed in the claims database analysis of 1295 HER2-positive patients. ConclusionsResource-sensitive guidelines may be beneficial in middle-income countries where limited budgets cannot accommodate all innovative technologies. However, Iranian physicians appear to rely more on the medical literature than on national guidelines regarding trastuzumab use. Policymakers, doctors and other stakeholders need to reach some consensus about the optimal way to treat patients. A national guideline needs to be accompanied with country-specific economic evaluations.

Synthesis and stability test of radioimmunoconjugate 177Lu-DOTA-F(ab′)2-trastuzumab for theranostic agent of HER2 positive breast cancer

The use of trastuzumab as intact IgG labeling radionuclide for HER2 positive breast cancer theranostic agent is not ideal because it is slowly eliminated from the blood and normal tissues resulting in low tumor/blood (T/B) and tumor/normal tissue (T/NT) ratios. To overcome this limitation, we developed the trastuzumab F(ab′)2 fragments and radiolabeling of the fragments by β and γ-particle of Lutetium-177. F(ab)2 fragments were produced by digestion of trastuzumab IgG (Herceptin) with pepsin for 18 h at 37 °C. The F(ab′)2 fragment fractionated in PD-10 column, followed by the conjugation with 2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA) as a metal chelator and radiolabeling with 177LuCl3. Molecular weight of fragments was calculated by LCMS (Liquid Chromatography Mass Spectroscopy) and the radiochemical purity was evaluated by ITLC-SG (Instan Thin Layer Chromatography). Our study showed that the purity of F(ab′)2 fragment generated by PD-10 fractions was >98% and the molecular weight of F(ab′)2 was 98.35 kDa. The average numbers of pSCN-Bn-DOTA chelates per antibody fragment were 5.03 ± 1.5 and the optimum conjugation reactions was performed at molar ratio 20:1 (chelator to antibody). The stability test of the radioimmunoconjugate in the human serum albumin (HSA) at 37 °C showed the radiochemical purity was 91.96 ± 0.26% after 96 h storage. This indicated that the radioimmunoconjugate is relatively stable when applied to the human body's physiological condition.

Abstract 4719: Varlitinib demonstrates potent antitumor efficacy in patient-derived gastric cancer xenograft models

Abstract Varlitinib is a potent, reversible pan-HER inhibitor of the ATP-binding site of EGFR (IC50 = 7 nM), HER2 (IC50 = 2 nM) and HER4 (IC50 = 4 nM). Gastric Cancer is the fifth most common cancer worldwide, with 952,000 cases diagnosed in 2012, constituting 6.8% of total cancer diagnosis. Prognosis for gastric cancer is poor, with the overall 5-year survival rate for gastric cancer in the US at ∼29%. Current clinical guidelines recommend use of trastuzumab combined with chemotherapy for HER2+ (amplified) patients with advanced gastric cancer. However the majority of patients (∼80%) do not have HER2 amplification. Studies have implicated dysregulation of HER signaling in gastric cancer and there is strong scientific rationale for testing of pan-HER therapies in Gastric Cancer. We tested the anti-tumour activity of Varlitinib as a single agent in patient-derived gastric cancer xenograft in SCID mice (GC22-0808 & GC11-0414) with over-expression of HER proteins. Varlitinib is very active in tumour growth inhibition studies, causing dose-dependent inhibition with tumour stasis observed at dosing of 50 mg/kg BID and tumour regression observed at dosing of 100 mg/kg BID. Tumour protein lysates after two-day treatment with Varlitinib and vehicle were also analysed to elucidate the mechanism of action. Multiple proliferation and anti-apoptosis pathways were inhibited by Varlitinib, including AKT, PI3K and Survivin pathways. In view of the robust anti-tumour activity inhibiting multiple survival and proliferation pathways, as well as the safe tolerabilty profile of Varlitinib, ASLAN has initiated Phase 2 clinical trials of Varlitinib in gastric cancer. Citation Format: A. G. Lisa Ooi, Bertil E. Lindmark, Mark McHale, Huynh T. Hung, Richard Ong. Varlitinib demonstrates potent antitumor efficacy in patient-derived gastric cancer xenograft models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4719.

Intrathecal trastuzumab for leptomeningeal carcinomatosis in patients with human epidermal growth factor receptor 2 positive breast cancer

There has been recent increase in incidence of leptomeningeal carcinomatosis, possibly due to widespread use of adjuvant trastuzumab and its known poor CNS penetration. Currently there are limited therapeutic options for these patients and outcome is poor. We report two cases of women with HER2 positive breast cancer who developed leptomeningeal carcinomatosis for which they were treated with intrathecal trastuzumab in combination with systemic therapy. Both patients had rapid symptomatic benefit and radiological response and remained progression free for at least seven months. Intrathecal trastuzumab can be considered a reasonable therapeutic option for these difficult to treat patients.

Guideline Adherence Regarding the Use of Expensive Drugs in Daily Practice: The Examples of Trastuzumab in Breast Cancer and Bortezomib in Multiple Myeloma

Background: The present study was designed to obtain insights into guideline adherence regarding the use of expensive drugs in The Netherlands in daily practice and into the patients' perspective on the decision-making process. Material and Methods: A retrospective review of medical charts regarding the use of trastuzumab in early and metastatic breast cancer (EBC/MBC) and bortezomib in multiple myeloma (MM) was conducted. Prescription according to clinical practice guidelines was assessed. The review was supplemented with patient interviews. Results: Of 702 adjuvant-treated EBC patients, 97% had a documented human epidermal growth factor receptor 2 (HER2) testing (23% HER2 positive). 92% (147/160) of the HER2-positive EBC patients were treated with trastuzumab. Of 594 MBC patients, 81% had a documented HER2 testing (19% HER2 positive). 82% (75/91) of the HER2-positive MBC patients were treated with trastuzumab. Of 68 MM patients, 50% were treated with bortezomib. Reasons not to treat were consistent with the guidelines. Patients were generally satisfied with the decision-making process; improvements in patient education were suggested (e.g., repeating the information given, adding information on side effects). Conclusions: Guidelines were generally well followed with respect to trastuzumab and bortezomib, indicating that funding did not influence the treatment decisions of physicians. In view of the growing numbers of both cancer patients and expensive new anticancer drugs, and increasing budget constraints, it is unclear whether the present-day policies will guarantee a similar level of guideline adherence. Patient involvement in decision-making could be increased by improving the patient education on treatment.

Anthracycline- and trastuzumab-induced cardiotoxicity: a retrospective study.

Some chemotherapeutic agents cause cardiotoxic effects including reduction in left ventricular ejection fraction (LVEF) and occasionally congestive heart failure. Anthracyclines and HER2 monoclonal antibodies are common offenders, but clinical practice data on LVEF changes, risk factors and acute recovery is lacking. We retrospectively examined the electronic medical record at an academic medical center for receipt of anthracyclines and/or trastuzumab from 2000 to 2013 in cancer patients. Patient characteristics and serial LVEF assessments were collected. Patients with and without LVEF decline were analyzed by univariate and multivariate analysis. A total of 549 patients were identified with anthracycline/trastuzumab use and 216 had multiple LVEF assessments. Only 27 of the 216 patients who had multiple LVEF assessments at multiple occasions suffered a clinically significant LVEF fall (12.5%), and symptomatic CHF was rare (0.5%). Compared to unaffected patients, those with a fall in LVEF were more likely to have hypertension, hyperlipidemia or coronary artery disease (CAD). Concomitant trastuzumab and anthracycline use was a risk factor (36 vs 9.5% for anthracycline alone, p<0.001). The median time from start of chemotherapy to reduced LVEF was 202days (5-3008). On multivariate analysis, hypertension and use of trastuzumab remained independent predictors of LVEF fall. Acute recovery in LVEF was observed in 44% of patients. LVEF changes from cancer therapies are frequent and hard to predict. Hypertension, hyperlipidemia and CAD are associated with LVEF decline. Acute recovery of LVEF is observed in those experiencing treatment-related cardiotoxicity. Attention to timely interruption of cardiotoxic chemo is recommended.

Therapeutic potential and critical analysis of trastuzumab and bevacizumab in combination with different chemotherapeutic agents against metastatic breast/colorectal cancer affecting various endpoints.

Researchers are working day and night across the globe to eradicate or at least lessen the menace of cancer faced by the mankind. The two very frequently occurring cancers faced by the human beings are metastatic breast cancer and metastatic colorectal cancer. The various chemotherapeutic agents like anthracycline, cyclophosphamide, paclitaxel, irinotecan, fluorouracil and leucovorin etc., have been used impressively for long. But the obstinate character of metastatic breast cancer and metastatic colorectal cancer needs more to tackle the threat. So, the scientists found the use of monoclonal antibodies trastuzumab (Herceptin(®)) and bevacizumab (Avastin(®)) for the same. The current study critically investigates the therapeutic potential of trastuzumab and bevacizumab in combination with various chemotherapeutic agents against metastatic breast cancer and metastatic colorectal cancer. To the best of our knowledge, this is the very first critical analysis showing percent wise increase in various positive endpoints like median time to disease progression, median survival, and progression free survival etc. for the treatment of metastatic breast/colorectal cancer using trastuzumab and bevacizumab in combination with different chemotherapeutic agents and provides the rational for the success and failure of the selected monoclonal antibodies.

Novel cancer stem cell targets during epithelial to mesenchymal transition in PTEN-deficient trastuzumab-resistant breast cancer.

Continued use of trastuzumab in PTEN-deficient HER2+ breast cancer induces the epithelial-to-mesenchymal transition (EMT), transforms HER2+ to triple negative breast cancer, and expands breast cancer stem cells (BCSCs). Using cancer cell lines with two distinct states, epithelial and mesenchymal, we identified novel targets during EMT in PTEN-deficient trastuzumab-resistant breast cancer. Differential gene expression and distinct responses to a small molecule in BT474 (HER2+ trastuzumab-sensitive) and the PTEN-deficient trastuzumab-resistant derivative (BT474-PTEN-LTT) provided the selection tools to identify targets during EMT. siRNA knockdown and small molecule inhibition confirmed MEOX1 as one of the critical molecular targets to regulate both BCSCs and mesenchymal-like cell proliferation. MEOX1 was associated with poor survival, lymph node metastasis, and stage of breast cancer patients. These findings suggest that MEOX1 is a clinically relevant novel target in BCSCs and mesenchymal-like cancer cells in PTEN-deficient trastuzumab resistant breast cancer and may serve as target for future drug development.

Factors associated with non use of adjuvant trastuzumab in older patients with HER2+ breast cancer.

601Background: Although adjuvant trastuzumab for human epidermal growth factor (HER2)+ breast cancer (BC) is highly efficacious regardless of age, the real world use of trastuzumab for older patients is not known. Methods: We used Surveillance, Epidemiology and End Results (SEER) Medicare data to identify patients aged ≥66 with stage I-III HER2+ BC diagnosed in 2010-2011(when HER2 was available). Multivariable logistic regression examined characteristics associated with trastuzumab non use. Results: Among 1900 women, 77% were ≤ age 80, 76% had a comorbidity score=0, 6% had history of congestive heart failure (CHF), 72% had hormone receptor (HR)+BC, and 15% had stage III disease. Overall, 51% did not receive adjuvant trastuzumab and 30% did not receive any systemic therapy. Older age, CHF, favorable disease characteristics (lower stage, HR+), black race, and low socio-economic status were strongly associated with non use of trastuzumab (Table). Even among patients with higher risk cancers, a substantial pr...

Continuation of trastuzumab beyond disease progression in patients with metastatic gastric cancer: A retrospective analysis of 25 cases—The MD Anderson experience.

e15560Background: Despite the widespread use of trastuzumab in the management of patients with Human Epidermal growth factor receptors (HER2) - overexpressing metastatic gastric cancer, its optimal...

PI3K upregulation as a negative predictive factor of survival in HER2 amplified gastric cancer treated with Trastuzumab.

e15567Background: Use of Trastuzumab accrues significant clinical benefit in the HER2 positive metastatic Gastric Cancer (GC) population. However, many patients do not respond to therapy or develop...

Potential resource and cost saving analysis of subcutaneous versus intravenous administration for rituximab in non-Hodgkin&amp;#39;s lymphoma and for trastuzumab in breast cancer in 17 Italian hospitals based on a systematic survey

IntroductionSubcutaneous versions of different oncology therapies have been available for patients for a few years, yet patient-relevant and hospital benefits have not been assessed in real life.MethodsIn order to analyze the impact of subcutaneous administrations for rituximab or trastuzumab in comparison to the respective intravenous mode a primary research in Italy was executed. The study’s primary objectives were to analyze the resource and cost implications from different perspectives (patient, medical staff) in the real world. The route of administration was discussed and aligned with the participating centers in order to capture all relevant therapy parts. After the successful execution of a pilot study 19 centers in six regions in Italy were recruited to participate.ResultsSignificant time savings might be achieved with the subcutaneous mode through significantly lower patient preparation time including less time preparing the actual dosing for each individual patient. The total time difference is 3.3 hours with rituximab in hematology (non-Hodgkin’s lymphoma), which adds up to 23.55 hours for a full course of treatment per patient (overall preparation time: 40.1 hours intravenous [95% confidence interval (CI): ±0.47] vs 16.6 hours subcutaneous [95% CI: ±0.2]). In early breast cancer (trastuzumab), the time saving might be 3.3 hours for the first cycle and the total time saving for patient preparation might be 17.2 hours (overall preparation time: 38.8 hours intravenous [95% CI: ±9.42] vs 21.6 hours subcutaneous [95% CI: ±9.9]). Furthermore, in both settings, the time of medical staff was reduced and could hence be used elsewhere. Finally, in case wastage was experienced with intravenous therapies, there were potential significant reductions in wastage through the subcutaneous administration (93%–100%) with cost savings of €6,057 with rituximab subcutaneous and €28,399 with trastuzumab subcutaneous administration for the full treatment course.ConclusionThere are significant resource and cost savings due to subcutaneous administration with rituximab and trastuzumab in Italy based on a systematic survey. With the availability of a subcutaneous use of rituximab and trastuzumab, hospitals, patients and payers in general still have the current standard of care therapies available in the approved indications for a more efficient use of time and resources.

Progesterone Receptors, Pathological Complete Response and Early Outcome for Locally Advanced Breast Cancer - a Single Centre Study. (PPLB - 01).

Neoadjuvant chemotherapy (NACT) for locally advanced breast cancer (LABC), apart from increasing breast conservation rates, also provides an opportunity to assess tumour response to chemotherapy, with Pathological Complete Response (pCR) described as an independent prognostic factor and a surrogate marker for better outcome and survival. Our primary aim was to identify clinical and pathological factors associated with pCR following NACT in patients with LABC treated at our institution. Our secondary aim was to analyze the impact of pCR and associated factors on disease free survival (DFS) and overall survival (OS). A retrospective analysis of LABC patients treated with NACT between Jun 2011 and Dec 2013. Clinical and histological variables were analyzed for association with pCR (no invasive or in situ carcinoma in breast or axillary lymph nodes). Kaplan-Meier curves and Cox regression model was used for survival analysis. All values were twosided, and statistical significance was defined as p<0.05. 240 patients were included. The median tumor size was 6cm, with T4 disease in 49.8%. 45% of tumors were of low grade (G1+G2) and 53.8% of high grade (G3). Estrogen Receptor (ER) was positive in 70.8%, progesterone receptor (PR) in 53.3% and Her2 in 38.8%. The preferred NACT regimen was sequential anthracycline and taxane and 88.8% of patients received this regimen. Of 93 potential Her2 Positive patients, only 23 received trastuzumab. Overall 23.2% patients had pCR. At median follow up of 21months (range, 3-42), 16.3% of patients had recurrent disease, and 6.7% had died. High tumor grade (p=0.04), PR negative status (p<0.01) and trastuzumab treatment (p=0.01) were significant predictors of pCR in univariate analysis. On multivariate analysis PR negativity (OR 3.2, 95% CI=1.6 to 6.04, p=0.001) and Trastuzumab use (OR 0.24, 95% CI=0.1 to 0.6, p=0.004) were significant. Patients with pCR had positive associations with survival (p<.02,OS& .02,DFS) and interestingly PR positivity had positive association with DFS (p=0.02) in Kaplan-Meier curves. On Cox regression, PR positivity (HR=0.3, p<0.01) and pCR (HR=0.2, p<0.01) correlated with DFS, though not with early OS. for the PR positive patients were paradoxical. Though less likely to have pCR (15%, vs 32% if PR negative), they had better DFS (p=0.02), and achieving pCR had no survival benefit in this group. In contrast, PR negative patients, irrespective of ER status, had a high pCR rate, and achieving pCR had survival advantage (p<0.05,DFS& p<0.02,OS). PR negative patients without pCR had the worst DFS (p<0.01) among all. High grade and Trastuzumab treatment as predictors of pCR, and pCR as a surrogate marker for survival are well recognized, and are supported by our findings. In present cohort, PR negativity showed prognostic importance independent of ER status. However these results were derived from sub-group, post-hoc analysis of data from a pre-existing cohort, without 'a-priori' hypothesis for survival analysis in relation to PR. These "hypothesis generating" results need confirmation by a well-designed prospective cohort or a randomized trial.

Pertuzumab for the treatment of breast cancer: a safety review

ABSTRACTIntroduction: Approximately twenty to thirty percent of newly diagnosed breast cancers are human epidermal growth factor receptor 2 (HER2) positive. The use of trastuzumab, and more recently pertuzumab, has significantly improved the progression free survival (PFS) and overall survival (OS) in this patient population. However, pertuzumab has side effects that can impact treatment tolerability and quality of life.Areas covered: This review describes the safety and tolerability of pertuzumab, a monoclonal antibody targeted at HER2 approved by the United States Food and Drug Administration (FDA) for use in the neoadjuvant and first line metastatic settings.Expert opinion: The combination of trastuzumab, pertuzumab, and chemotherapy is approved in the neoadjuvant and first line metastatic settings and should be strongly considered by providers. Further studies are needed to look at side effect prevention, novel pertuzumab containing regimens, and re-treating patients with pertuzumab.

Disparities in Use of Human Epidermal Growth Hormone Receptor 2-Targeted Therapy for Early-Stage Breast Cancer.

Trastuzumab is a key component of adjuvant therapy for stage I to III human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The rates and patterns of trastuzumab use have never been described in a population-based sample. The recent addition of HER2 information to the SEER-Medicare database offers an opportunity to examine patterns of trastuzumab use and to evaluate possible disparities in receipt of trastuzumab. We examined a national cohort of Medicare beneficiaries with incident stage I to III HER2-positive breast cancer diagnosed in 2010 and 2011 (n = 1,362). We used insurance claims data to track any use of trastuzumab in the 12 months after diagnosis as well as to identify chemotherapy drugs used in partnership with trastuzumab. We used modified Poisson regression analysis to evaluate the independent effect of race on likelihood of receiving trastuzumab by controlling for clinical need, comorbidity, and community-level socioeconomic status. Overall, 50% of white women and 40% of black women received some trastuzumab therapy. Among women with stage III disease, 74% of whites and 56% of blacks received trastuzumab. After adjustment for tumor characteristics, poverty, and comorbidity, black women were 25% less likely to receive trastuzumab within 1 year of diagnosis than white women (risk ratio, 0.745; 95% CI, 0.60 to 0.93). Approxemately one half of patients 65 years of age and older with stage I to III breast cancer do not receive trastuzumab-based therapy, which includes many with locally advanced disease. Significant racial disparities exist in the receipt of this highly effective therapy. Further research that identifies barriers to use and increases uptake of trastuzumab could potentially improve recurrence and survival outcomes in this population, particularly among minority women.

Locoregional recurrence following breast cancer surgery in the trastuzumab era: A systematic review by subtype

Increasing evidence suggests that molecular subtype influences locoregional recurrence (LRR) of breast cancer. Previous systematic reviews that evaluated the quantitative influence of subtype on LRR predated the use of Trastuzumab. This study assessed the impact of subtype on LRR in a contemporary treatment era. A comprehensive search for all published studies assessing LRR according to breast cancer subtype was performed. Only studies with patients treated with Trastuzumab were included. Relevant data were extracted from each study for systematic review. Primary outcome was LRR related to breast cancer subtype. In total, 11,219 patients were identified from seven studies. Overall LRR rate was 3.44%. The lowest LRR rates were in luminal A (1.7%), and the highest rates were in triple-negative (7.4%) subtypes. There were significantly lower risks of LRR in patients with luminal A subtype compared with luminal B [odds ratio (OR) 0.54, 95% confidence interval (CI) 0.38–0.76; p < 0.0004], HER2/neu-overexpressing (OR 0.32, 95% CI 0.24–0.45; p < 0.0001) and triple-negative breast cancers (OR 0.25, 95% CI 0.19–0.32; p < 0.0001). There were significant differences in LRR between the luminal B and HER2/neu-overexpressing breast cancers (OR 0.61, 95% CI 0.41–0.89; p = 0.0145). The reduced risk in HER2/neu overexpressing compared with triple-negative breast cancers approached statistical significance (OR 0.75, 95% CI 0.55–1.03; p = 0.0933). Significant variations in LRR occur across breast cancer subtypes, with lowest rates in luminal cancers and highest rates in triple-negative breast cancers. Low levels of LRR highlight advances in breast cancer management in the contemporary era.

Co-Targeting of JNK and HUNK in Resistant HER2-Positive Breast Cancer

Strategies for successful primary treatment of HER2-positive breast cancer include use of the HER2 inhibitors trastuzumab or lapatinib in combination with standard chemotherapy. While successful, many patients develop resistance to these HER2 inhibitors indicating an unmet need. Consequently, current research efforts are geared toward understanding mechanisms of resistance and the signaling modalities that regulate these mechanisms. We have undertaken a study to examine whether signaling molecules downstream of epidermal growth factor receptor, which often act as compensatory signaling outlets to circumvent HER2 inhibition, can be co-targeted to overcome resistance. We identified JNK signaling as a potential area of intervention and now show that inhibiting JNK using the pan-JNK inhibitor, SP600125, is effective in the HER2-positive, resistant JIMT-1 xenograft mammary tumor model. We also investigate potential combination strategies to bolster the effects of JNK inhibition and find that co-targeting of JNK and the protein kinase HUNK can prohibit tumor growth of resistant HER2-positive mammary tumors in vivo.

Risk of Congestive Heart Failure in Early Breast Cancer Patients Undergoing Adjuvant Treatment With Trastuzumab: A Meta-Analysis.

The use of trastuzumab has proven to be a successful strategy in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer; however, it is associated with an increased risk of cardiac dysfunction. We performed an up-to-date, comprehensive meta-analysis to clarify the risk of congestive heart failure (CHF) in patients with early breast cancer receiving different durations of adjuvant trastuzumab with the longest-term follow-up. Eligible studies included randomized control trials of HER2-positive early breast cancer patients with or without trastuzumab in adjuvant chemotherapy. Adequate reporting of CHF data were required for inclusion. Statistical analyses were conducted to calculate the overall incidence, relative risk (RR), and 95% confidence interval (CI) by use of a fixed-effects model. Six randomized control trials including 18,111 patients were identified. The overall incidence of high-grade CHF in patients treated with trastuzumab versus placebo was 1.44% (95% CI, 0.79%-2.64%) and the RR was 3.19 (95% CI, 2.03-5.02; p < .00001). In subgroup analysis, the difference in CHF incidence failed to achieve significance. The RR for 8 mg/kg trastuzumab (high dose) was greater than that for 4 mg/kg (low dose) (RR, 6.79, 95% CI, 2.03-22.72, p = .0001; versus RR, 2.64; 95% CI, 1.61-4.32; p = .002). Additionally, higher RRs were observed for patients receiving trastuzumab for 1 year (RR, 3.29; 95% CI, 2.07-5.25) and 2 years (RR, 9.54; 95%CI, 2.19-41.43), but not 9 weeks (RR, 0.50; 95% CI, 0.05-5.49) compared with control groups. No evidence of publication bias was observed. Adjuvant trastuzumab therapy was strongly associated with an increased risk of significant CHF in patients with early breast cancer, particularly in 2-year use. This comprehensive meta-analysis evaluated the risk of congestive heart failure with a usage profile of adjuvant trastuzumab in patients with early breast cancer. Before initiating treatment with trastuzumab, a risk-benefit analysis for individual patients should be critically evaluated, considering that the prognosis is closely related to drug dose and duration of use. Cardiac function should be monitored throughout the treatment period and also during follow-up. Thus, early identification of trastuzumab-related cardiac dysfunction can allow effective medical intervention, elimination of symptoms, recovery of function, and continuation of trastuzumab therapy.