Supplementary Figures 1 - 5 from Bispecific Antibody to ErbB2 Overcomes Trastuzumab Resistance through Comprehensive Blockade of ErbB2 Heterodimerization
Bohua LiYanchun MengLei ZhengXunmin ZhangQing TongWenlong TanShi HuHui LiYang ChenJinjing SongGe ZhangLei ZhaoDapeng ZhangSheng HouWeizhu QianYajun Guo
0
Citation
0
Reference
10
Related Paper
Abstract:
<p>PDF file - 362K, Competitive binding assay (S1); TPL inhibits ErbB2 signaling in breast cancer cell lines (S2); ErbB2 knockdown inhibits ErbB2 signaling and results in growth inhibition in the MDA-MB-231 cell line (S3); TPL inhibited MDA-MB-231 breast cancer cell growth in a dose-dependent manner both in vitro and in vivo (S4); The effects of siRNA knockdown of EGFR or ErbB3 on the BT-474TraR cell line (S5).</p>Keywords:
ERBB3
Trastuzumab is the first Food and Drug Administration (FDA)‐approved therapeutic targeting a HER‐family receptor tyrosine kinase (HER2/ErbB2/neu). Although trastuzumab is effective in the treatment of HER2‐positive breast cancer, a substantial proportion of patients will not respond to trastuzumab‐based regimens (primary resistance), and those who do respond will often lose clinical benefits (i.e., secondary resistance). Although multiple mechanisms underlying the development of secondary trastuzumab resistance have been identified, few studies have specifically examined the basis of primary trastuzumab resistance. Here, we review these studies, which together demonstrate that trastuzumab induces phenotypic changes in tumor cells, even when they are not growth inhibited by trastuzumab, including changes in gene expression. These changes have important clinical implications, including the sensitization of malignant cells to other therapeutic drugs. In light of these observations, we propose that the conventional definition of resistance as it pertains to trastuzumab and, perhaps, to other targeted therapeutics, may require revision. The results of these studies will be useful in informing the direction of future basic and clinical research focused on overcoming primary trastuzumab resistance.
Acquired resistance
Cite
Citations (74)
ErbB
ERBB3
Lapatinib
Cite
Citations (39)
Cite
Citations (0)
乳癌(BC ) 在 ≥ 被诊断；65 个岁女人在关于盒子的一半。专家们当前建议，那全身的治疗基于他们的全面条件和预期寿命与 BC 被提供给老病人，好处将超过治疗的风险，这能相当被期望。为年轻题目，相似对人的表皮的生长因素 receptor-2 (HER-2 ) 的 monoclonal 抗体， trastuzumab，代表一种有效治疗学的选择什么时候 BC 在表示上这受体。不幸地， trastuzumab 的管理与左室的机能障碍和长期的心失败(CHF ) 的出现被联系，因为有 homeostatic 的干扰，可能在心 HER-2 工作。基于登记的、回顾的分析在在没为 BC 给任何治疗的那些与 10%-15% 相比收到 trastuzumab 的老女人在 25% 附近报导了 CHF 的发生，并且 CHF 的风险被估计了在 > 更高双重；60-65 岁 trastuzumab 用户对非用户。极其先进的年龄和先存在的心脏病被显示了预先安排到 trastuzumab cardiotoxicity。因此，为有 trastuzumab 的治疗的更老的病人的选择应该主要基于他们的一般地位和 comorbidities 的存在；特别与 anthracyclines，以前的化疗应该也被考虑。一旦治疗开始了，努力应该被作保证常规心脏的监视。选择 biomarkers 的角色，例如心脏的 troponin，或新成像技术(三尺寸，织物 Doppler echocardiography，磁性的回声成像) 是有希望的，但是必须进一步在特别被调查老。而且，另外的研究被需要以便更好理解 trastuzumab 由影响旧心的机制。
Cardiotoxicity
Cite
Citations (0)
The backbone of treatment for women with metastatic HER2-overexpressing breast tumors is trastuzumab. But what should be done for women with advanced breast cancer who experience disease progression while on trastuzumab? In the past, doctors tended to discontinue that medication and try other treatments. But an increasing number of studies show that continuing trastuzumab therapy while adding other drugs—some old and some new—offers better disease control. In one study reported at the CTRC-AACR San Antonio Breast Cancer Symposium, a one-two punch from pertuzumab and trastuzumab was found to be effective in patients who progressed on sequential treatment with each monoclonal antibody alone. Another showed that maintaining trastuzumab therapy while adding lapatinib provides greater disease control than lapatinib treatment alone. A third showed that the combination of trastuzumab and the mammalian target of rapamycin (mTOR) inhibitor ridaforolimus has antitumor activity in heavily pretreated trastuzumab-resistant HER-positive metastatic breast cancer patients. Also, researchers found that single-agent trastuzumab-DM1 is effective in heavily pretreated women who received more than two years of prior HER2-directed therapy. Pertuzumab+Trastuzumab Active after Failed Sequential Therapy SABCS Abstract 5114 and 5088 The combination of pertuzumab and trastuzumab shows efficacy in patients with HER2-positive metastatic breast cancer whose disease has progressed on sequential treatment with each monoclonal antibody alone, researchers reported at the CTRC-AACR San Antonio Breast Cancer Symposium. Overexpression of the HER2 gene is found in 20% to 30% of breast tumors, noted Jose Baselga, MD, Chairman of the Medical Oncology Service and Director of the Division of Medical Oncology, Hematology, and Radiation Oncology at the Vall d'Hebron University Hospital in Barcelona. Two humanized monoclonal antibodies, trastuzumab and pertuzumab, have thus been developed, targeting different epitopes of HER2, he said. Trastuzumab binds to the juxta-membrane eptiope, inhibiting ligand-independent HER2 signaling. Pertuzumab represents the first in a new class of investigational agents known as HER-dimerization inhibitors. It is designed to bind to the HER2 receptor and inhibits the ability of HER2 to interact with other HER family members (HER1/EGFR, HER2, HER3, and HER4). In the first two cohorts of the current Phase II trial (article now available online ahead of print in the Journal of Clinical Oncology), the combination of pertuzumab plus trastuzumab was highly effective is patients who had disease progression on trastuzumab. The results were so promising, Dr. Baselga said, that he and his co-researchers amended the protocol to allow recruitment of a third cohort of patients who are receiving pertuzumab as monotherapy. Combo Therapy Best At the meeting, Dr. Baselga reported on the third cohort of 29 patients with HER2-positive metastatic breast cancer who were administered pertuzumab monotherapy after progressing on trastuzumab plus chemotherapy. Of those, one patient did not progress and remains on pertuzumab monotherapy. Another 12 patients discontinued treatment, and 16 patients with documented progressive disease on pertuzumab monotherapy were also administered trastuzumab. Trastuzumab was given as either a 4 mg/kg loading dose followed by 2 mg/kg weekly or an 8 mg/kg loading dose followed by 6 mg/kg every three weeks. Pertuzumab was given an 840 mg loading dose, followed by 420 mg every three weeks. Of the 19 patients on pertuzumab monotherapy, one (3.4%) had a partial response and two (6.9%) had stable disease for eight or more cycles, leading to an objective response rate of 3.4% and a clinical benefit rate of 10.3%, Dr. Baselga reported. Of the 16 patients who received the monoclonal antibody doublet, 14 have achieved the overall best response endpoint of eight cycles of assessment, he said. Three (21.4%) achieved a partial response and three (21.4%) had stable disease for eight or more cycles, for a clinical benefit rate of 43.8%. Eight (57.1%) patients experienced progressive disease. “In total, three patients remain on combination therapy. One had not reached the overall best response endpoint at eight cycles and showed stable disease at last tumor assessment. One patient died of hepatorenal failure due to progressive disease before an efficacy assessment was carried out,” Dr. Baselga said. Safety Profile The most frequent adverse events were diarrhea (48% of patients on monotherapy and 31% of patients on combination therapy) and nausea (34% of patients in monotherapy and 31% of patients on combination therapy). Three patients showed a Grade 2 drop in left ventricular ejection fraction (LVEF)—two during pertuzumab monotherapy and one during combination therapy. All the LVEF decreases were asymptomatic. Cardiac Safety Trial Also at the meeting, researchers reported results of a retrospective analysis showing that the cardiac safety profile of pertuzumab appears to be similar to that of trastuzumab. The analysis involved 569 patients who received pertuzumab: 302 as a single agent, 175 in combination with cytotoxic chemotherapy, and 92 in combination with trastuzumab or erlotinib. Overall, 5.7% of patients experienced a significant drop in LVEF. Of these, four (0.7%) patients developed symptomatic heart failure.JOSE BASELGA, MD: “The clinical benefit rate in patients on combination therapy is very impressive. The doublet is very active without significant toxicity.”The rate of asymptomatic LVEF decrease was similar regardless of whether pertuzumab was given as monotherapy or in combination with chemotherapy or trastuzumab or erlotinib, reported Thomas M. Suter, MD, Associate Professor of Medicine at the Swiss Cardiovascular Center of the University of Berne. “In carefully selected patients, the combination of pertuzumab and trastuzumab does not appear to increase the rate of cardiac events,” he said. Funding for the poster study was provided by Genentech. Phase III Trial Underway Dr. Baselga said that the combination of trastuzumab, pertuzumab, and docetaxel is now being evaluated as first-line treatment of metastatic breast cancer patients in the Phase III CLEOPATRA (Clinical Evaluation Of Pertuzumab and Trastuzumab) trial, Dr. Baselga said. The primary objective of the study, which is now recruiting patients, is to compare progression-free survival rates in patients randomized in a one-to-one fashion to either trastuzumab plus docetaxel and placebo or trastuzumab plus docetaxel and pertuzumab. Secondary objectives include the comparison of overall survival rates, objective response rates, and the duration of response between the two arms, and to evaluate safety and quality of life. The investigators will also evaluate biomarkers and correlate them with clinical outcomes. Key eligibility criteria include age 18 years or older; confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease; formalin-fixed and paraffin-embedded tissue for central testing; overexpression of HER2; baseline LVEF of at least 50%, and an Eastern Cooperative Oncology Group performance status of 0/1. If this study is successful, this combination of trastuzumab plus pertuzumab and chemotherapy has the potential to become a new standard of care in HER2-positive metastatic breast cancer, Dr. Baselga said. Additionally, a large randomized Phase II trial is investigating trastuzumab, pertuzumab, and capecitabine in patients who have disease progression after first-line trastuzumab therapy, he said. Discussion Asked for her opinion, Edith A. Perez, MD, Director of the Breast Cancer Program and Professor of Medicine in the Division of Hematology/Oncology at the Mayo Clinic in Jacksonville, FL, called the clinical benefit rate in patients on the combination therapy “very impressive” and said that it was promising that the doublet is very active without significant toxicity.” Adding Lapatinib & Continuing Trastuzumab Better than Lapatinib Alone, Reinforcing Trastuzumab Use Beyond Progression SABCS Abstract 61 In women with metastatic HER2-overexpressing breast tumors that progress on trastuzumab, maintaining trastuzumab therapy while adding lapatinib provides greater disease control than lapatinib treatment alone, researchers report. “We observed a 26% reduction in the risk of death among women on the combination therapy,” said Kimberly L. Blackwell, MD, Director of the Clinical Trials Program in Breast Cancer at Duke University Medical Center. “The updated intention-to-treat overall survival data indicated that there was a 4.5-month improvement in overall survival in favor of early randomization to combination therapy over lapatinib alone. This is highly statistically significant,” she said during her oral presentation at the CTRC-AACR San Antonio Breast Cancer Symposium. Dual Hit to HER2 The addition of lapatinib to trastuzumab therapy provides a dual hit to the HER2 receptor that is overexpressed in these women, Dr. Blackwell said. Trastuzumab is a humanized monoclonal antibody against HER2, while lapatinib is an oral small-molecule epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor. Dual targeting of the HER2 receptor is believed to disrupt downstream signaling pathways and, in turn, interfere with cancer cell proliferation and cell survival, she said.KIMBERLY L. BLACKWELL, MD: “To put this into clinical perspective, the 4.5 month improvement in this population of heavily pretreated HER2-positive patients is similar to that seen with other biological agents and chemotherapy in first-line therapy without the side effects seen with traditional chemotherapy.”“In breast cancer, the targeting of [HER2] overexpression has led to many clinical benefits. Because [they attack the HER2 receptor differently], it was very appealing to combine these two agents without using a chemotherapy backbone.” At the San Antonio meeting, Dr. Blackwell updated the survival data of the EGF104900 study, a randomized clinical trial of patients with HER2-positve breast cancer who have recently had disease progression on trastuzumab. Documented Progression with Anthracyclines, Taxanes, & Trastuzumab The study involved 296 metastatic breast cancer patients with documented HER2-positive tumors and documented progression on anthracycline, taxane, and trastuzumab regimens. The participants’ last treatment regimen had to have included trastuzumab. The patients were a median age 51 and had good performance status; they had a median of four to five chemotherapy regimens prior to entering the trial. The women were randomized to oral lapatinib (1,500 mg per day) or oral lapatinib (1,000 mg per day) plus intravenous trastuzumab (2–4 mg/kg weekly). Patients were allowed to cross over to combination therapy if they had disease progression on single-agent lapatinib. A total of 77 (52%) of the 148 patients assigned to lapatinib monotherapy eventually did receive combination therapy—about half of them before the eight-week staging assessment. “The median number of trastuzumab regimens for advanced breast cancer was three different regimens in each arm,” Dr. Blackwell said. Half of the patients had estrogen receptor-negative tumors. “Three-fourths of the patients had known visceral disease, and unlike many of the studies that were done with HER2-targeted agents in the early days, we allowed for known brain metastases, and these were equally matched in the two arms.” Specifically, 20 of the 148 women in the monotherapy arm and 16 of the 148 women in the combination arm had brain metastases. Study Results The median survival time of the women taking lapatinib and trastuzumab was 14 months compared with 9.5 months for lapatinib alone, Dr. Blackwell reported. After one year of treatment, 41% of women who were treated with lapatinib monotherapy were alive vs 56% of the women treated with lapatinib. “The absolute survival difference remained at 10% at six months in favor of the combination therapy. This means that 15 more women out of 100 are alive at a year because they received combination therapy,” Dr. Blackwell said. “The survival benefit was seen in spite of the fact that over half the patients crossed over to receive dual blockade.” She said that after updating cardiac and safety events, the combination treatment did not appear to signal any unexpected concerns: “There has only been one cardiac-related death. That occurred in the combination arm and it was attributable to a fatal pulmonary embolism,” she said. The only Grade 3–4 adverse event that occurred in 5% or more of the patients was diarrhea, occurring in 8% of patients in the combination arm and 7% of those in the lapatinib arm. ‘Amazing That No Significant Safety Signal’ “As a clinician, I think it's amazing there was not a significant safety signal. And considering the heavily pretreated nature of these patients, the fact that we really did not see an increase in side effects with the combination of agents is remarkable,” Dr. Blackwell said. “To put this into clinical perspective, the 4.5 month improvement in this population of heavily pretreated HER2-positive patients is similar to that seen with other biological agents and chemotherapy in first-line therapy without the side effects seen with traditional chemotherapy.” ALTTO: 2 Study Designs The findings offer strong support for the Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) study, whose total accrual goal is 8,000 patients, she said. The multicenter open-label trial is employing two study designs: In Design 1, which is now closed to enrollment, all neoadjuvant and adjuvant chemotherapy is completed prior to administration of trastuzumab and/or lapatinib. In Design 2, all anthracycline-based neoadjuvant and adjuvant chemotherapy is completed prior to administration of trastuzumab and/or lapatinib, while paclitaxel is given concurrently with the drug(s). In both designs, the trial will compare four treatment options: Trastuzumab alone for 52 weeks; lapatinib alone for 52 weeks; trastuzumab for 12 weeks, followed by a 6-week break, followed by lapatinib for 34 weeks; and lapatinib in combination with trastuzumab for 52 weeks. ‘Significant for Many Reasons’ Asked to comment on the findings, Edith A. Perez, MD, Professor of Medicine in the Division of Hematology/Oncology at the Mayo Clinic in Jacksonville, FL, said, “In the US, there's a tendency of doctors to take women off trastuzumab once it fails to help, but this shows significant benefit to continuing with it and adding a second targeted agent. “The results of this trial are significant for many reasons,” she continued. “This is the first time that someone has shown that continuing with trastuzumab through progression and adding a second type of HER2-therapy leads to a significant survival improvement. It really validates the concept that trastuzumab is an important drug to maintain.” The study was funded by GlaxoSmithKline PLC. Kathleen Pritchard: Already Shown? During the question-and-answer period, Kathleen I. Pritchard, MD, Head of Clinical Trials & Epidemiology at Toronto Sunnybrook Regional Cancer Centre, said, “With all due respect, I think we have already shown that continuing trastuzumab in this setting is useful. There is evidence to suggest that just trastuzumab [would be effective]. It would have been good to have a trastuzumab-alone arm.” Dr. Blackwell replied that since the patients in the study had just progressed on trastuzumab, “that design was not considered feasible.” Dr. Pritchard countered that she found that unfortunate. Another member of the audience asked if the findings justify the routine use of trastuzumab and lapatinib in patients who progress on trastuzumab. Dr. Blackwell said that in her own practice, she will consider the combination for patients who had documented benefit from HER2-directed therapy. Trastuzumab+Ridaforolimus Effective in Heavily Pretreated Patients SABCS Abstract 3091 A combination of trastuzumab and the mammalian target of rapamycin (mTOR) inhibitor ridaforolimus is well tolerated, with encouraging antitumor activity in heavily pretreated trastuzumab-resistant HER-positive metastatic breast cancer patients, researchers reported at the CTRC-AACR San Antonio Breast Cancer Symposium. “We saw better than expected [progression-free] survival in this group of heavily pretreated women. And there really were no safety issues,” said Denise A. Yardley, MD, Director of Breast Cancer Research at the Sarah Cannon Research Institute. Dr. Yardley said that mTOR, a key regulator in cell growth and division, is an attractive target for cancer therapy since activation of the mTOR pathway is observed in a substantial proportion of breast cancers that are associated with reduced PTEN activity. In patients with advanced HER2-positive breast cancer, PTEN loss is implicated in 50% of cases of trastuzumab resistance, she said. The new study aimed to determine if combining ridaforolimus with trastuzumab might be efficacious in breast cancer patients with acquired trastuzumab resistance. Two-Stage Design The single-arm, two-stage Phase II trial included patients with HER2-positive metastatic breast cancer who had developed resistance to trastuzumab, defined as disease progression on trastuzumab treatment with no more than two prior trastuzumab regimens. All the patients were given ridaforolimus, administered orally at 40 mg once daily for five consecutive days a week. They also received trastuzumab at a loading dose of 4 mg/kg, followed by 2 mg/kg/wk. The treatment cycle for both agents was four weeks. In Stage 1 of the trial, patients were assessed for safety after at least one cycle of therapy, and the objective response rate was assessed every two cycles according to modified RECIST guidelines. The study design stipulated that if one or more patients exhibited an objective response, patients would proceed to Stage 2, where they would continue on study treatment until disease progression. The final cohort included 34 patients with a median age of 54. Fifty-nine percent had three or more prior chemotherapy regimens, and 56% had two or more prior trastuzumab regimens. Dr. Yardley described one patient: After diagnosis, the woman underwent treatment with four cycles of doxorubicin and cyclophosphamide, followed by tamoxifen, then anastrozole. After developing bone metastases, the patient was started on first-line paclitaxel plus trastuzumab, followed by exemestane plus trastuzumab. The woman eventually had disease progression on trastuzumab plus exemestane, Dr. Yardley said. Subsequent treatments included radiation, temozolomide, ixabepilone, gem-citabine, and vinorelbine. The patient developed liver metastases while on vinorelbine and entered the study a month later. “These are heavily, heavily pretreated patients,” Dr. Yardley said. Safety Profile as Expected Adverse effects were within the expected safety profile of either drug, she said, citing stomatitis/mucositis, hyperglycemia, and neutropenia. One patient died due to a large intestine perforation, which was assessed by investigators as being possibly related to ridaforolimus. One patient suffered Grade 4 stomatitis. Grade 3 events included four cases of stomatitis, and two cases each of mucosal inflammation, asthenia, fatigue, and pneumonitis. There was one case of Grade 3 nausea and one case of Grade 3 dysphasia. In addition to the patient who died, four patients discontinued therapy before the first disease assessment, three due to adverse events. Of the remaining patients, five showed partial responses, 13 had stable disease, and 11 continued to progress. The preliminary median progression-free survival time was 16.4 weeks, and at the time of the report, eight patients remained on study treatment. The study was funded by Merck. Response Rate Higher than Expected “We wanted to show a response rate of at least 5% and it was 15%,” Dr. Yardley said.” Combining ridaforolimus with trastuzumab or other HER2-directed therapies is worthy of further evaluation.” Asked her opinion for this article, Minetta C. Liu, MD, Associate Professor of Medicine in the Division of Hematology/ Oncology at Lombardi Comprehensive Cancer Center, explained that as effective as trastuzumab has proven to be, some patients do eventually develop resistance. “The question is: Can we improve on its clinical activity by continuing therapy and adding another agent? This combination shows early promise, but further research is needed.” T-DM1 Shrinks Tumors after Multiple Previous Treatments SABCS Abstract 701 Single-agent trastuzumab-DM1 has robust anti-tumor activity in a heavily pretreated population of patients with metastatic breast cancer who had failed to respond to a median of seven other drugs and who received more than two years of prior HER2-directed therapy, according to results of a Phase II trial reported at the CTRC-AACR San Antonio Breast Cancer Symposium. One-third of women whose tumors had progressed after treatment with an anthracycline, a taxane, capecitabine, trastuzumab, and lapatinib had an objective response to T-DM1, said Ian E. Krop, MD, Assistant Professor of Medicine at Harvard Medical School and a medical oncologist at the Breast Oncology Center at Dana-Farber Cancer Institute. At the 2008 San Antonio Breast Cancer Symposium (Abstract 33), T-DM1 was shown to have potent anti-tumor activity in trastuzumab- and lapatinib-pretreated patients. “This study confirms those results [and extends them] to a different population of patients with very refractory disease,” Dr. Krop said. Antibody-Drug Conjugate He explained that T-DM1 is an antibody-drug conjugate, designed for the targeted intracellular delivery of the anti-microtubule derivative DM1 via trastuzumab. The DM1 molecules form a very stable bond with trastuzumab so that DM1 is not released until trastuzumab finds cells that have HER2 overexpression. “The cytotoxic drug goes right to the cancer cells so it's not floating around and causing other problems. And trastuzumab still does all the things that trastuzumab does,” Dr. Krop told attendees crowded around his late-breaking poster prior to his early morning oral poster presentation. The study involved 110 patients with HER2-positive metastatic breast cancer with prior exposure to an anthracycline, a taxane, capecitabine, trastuzumab, and lapatinib and who had received at least two HER2-directed regimens in the metastatic setting. All had disease progression on the last regimen they received. The median age of the patients was 52.5. Fifty-four (49%) had an Eastern Cooperative Oncology Group performance status of 0, and 53 (48%) had a performance status of 1. Eighty-one patients (74%) had three or more distinct metastatic sites, mainly local-regional, liver, bone, and lung. Participants had received a median of seven and up to 15 agents for metastatic disease, and a median of eight agents in all settings. All but one patient had received five prior agents. The median duration of prior trastuzumab therapy was 19.4 months, and the median duration of prior lapatinib therapy was 6.9 months. The women received an average of 3.6 mg/kg of T-DM1, given as an intravenous infusion every three weeks. A median of seven doses were administered. Eleven patients required a dose reduction to 3.0 mg/kg and six required a dose reduction to 2.4 mg/kg. The reasons for the dose reductions included Grade 2 leukopenia and Grade 4 thrombocytopenia. Study Results The objective response rate as judged by an independent review board—which was the primary endpoint—was 33%, all of which were partial responses. The duration of response ranged from 1.2 to 8.4 months. The clinical benefit rate, defined as stable disease or complete or partial response maintained for at least 28 days, was 44.5% as judged by the review board. The 83.5% of patients confirmed to have HER2-positive disease had even better outcomes: objective response rate of 39.5% and a clinical benefit rate of 53%. There were no new or unusual safety signals with the drug, Dr. Krop said, adding that most toxicities were “acceptable and manageable,” “One patient died of liver disease, but he had renal dysfunction and underlying fatty liver disease, so we don't know if it was due to the study drug,” Dr. Krop added. Overall, 22.7% of patients had a serious adverse event—most frequently fever, cellulitis, or pneumonia. A total of 5.5% of patients discontinued therapy because of an adverse event. Two patients had a drop in left ventricular ejection fraction of 15% to 24% but none developed heart failure. “This is the first study looking at women who have failed so many other treatments. But we think these results are as good as we've ever seen is such a refractory population,” Dr. Krop said. Results Well Received Other attendees uniformly praised the new study. “The response rate in the study is exceptional in a group of patients this ill,” said Edith A. Perez, MD, Director of the Breast Cancer Program and Professor of Medicine in the Division of Hematology/ Oncology at the Mayo Clinic in Jacksonville, FL. She agreed with Dr. Krop that the death due to liver failure is not overly concerning given the women's overall poor health: “These patients are very sick, and right now we have no choices to offer them.” The moderator of the poster discussion session, Jose Baselga, MD, Chairman of the Medical Oncology Service and Director of the Division of Medical Oncology, Hematology, and Radiation Oncology at Vall d'Hebron University Hospital in Barcelona, said, “We didn't think it was possible to see [such a good response] in patients treated with a median of seven other agents. “This is very nice work, and the conclusion is quite solid. This agent clearly has activity in the third-line HER2 setting. One has to be very hopeful and excited about a drug that extends [these patients’ lives] further.” Dr. Krop told OT that “many people feel the data is worth bringing to the FDA, even though it is only Phase II, because these patients have no other options.” Several Phase II Trials in the Works Dr. Baselga told the audience that several Phase II and Phase II trials of T-DM1 in various setting are under way or planned. The current study was funded by Genentech, Inc. and F. Hoffmann-LaRoche, Ltd., and according to the Genentech Web site, T-DM1 is currently being evaluated in Phase II and Phase III clinical trials in patients with locally advanced or metastatic HER2-positive breast cancer who have disease progression on a chemotherapy regimen containing trastuzumab. www.oncology-times.com
Lapatinib
Pertuzumab
Cite
Citations (0)
A bstract : Trastuzumab (Herceptin™) is an excellent model of rationally designed targeted cancer treatment. However, less than 35% of patients with ErbB2‐positive breast tumors respond to trastuzumab as a single agent, and 2‐5% of trastuzumab‐treated patients suffer from severe side effects, including cardiac dysfunction. Recent progress in understanding the mechanisms of trastuzumab antitumor function and cellular defects leading to trastuzumab resistance is summarized. Also explored is the potential of combination therapies for reversing trastuzumab resistance.
Acquired resistance
Cite
Citations (77)
Abstract Trastuzumab is a biologic therapy indicated for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer and metastatic gastric cancer. Trastuzumab was originally approved as an intravenous (IV) formulation but has since been developed for subcutaneous (SC) administration for patients with HER2-positive breast cancer. Both formulations demonstrate generally comparable pharmacological and clinical profiles. Therefore, when deciding between treatment options, factors such as the route of administration, patient preference, value and cost must be considered. Studies comparing IV with SC trastuzumab indicate that each formulation offers unique advantages to patients depending on their individual needs. Concurrent with the development of SC trastuzumab, IV trastuzumab biosimilars comprise another treatment option that, in view of their reduced cost, might improve patient access and increase cost-effectiveness for healthcare providers and payers. In this review, we seek to raise awareness of the current options available for trastuzumab so that healthcare providers can optimally treat patients according to their individual situations and preferences.
Biosimilar
Cite
Citations (31)
Trastuzumab is one of the most important agents that target human epidermal growth factor receptor 2, but its cardiotoxic effect limits to use it. The mechanism of cardiac dysfunction-related trastuzumab is still unclear. In literature, there is no definite information about the cumulative dose of trastuzumab for cardiotoxicity. In presented case, we reported a breast cancer patient who has been receiving long-term trastuzumab. We have not found any cardiac problems for duration of over four years. According to our case and literature review, we may say that trastuzumab is safely used with periodically echocardiographic control in patients with breast cancer.
Cardiotoxicity
Cumulative dose
Cite
Citations (2)
Trastuzumab (Herceptin) is a monoclonal antibody targeting the extracellular domain of the human epidermal growth factor receptor 2 (HER2) (1) utilized for the treatment of adjuvant and metastatic breast cancer (2) in the United States and worldwide. We mined published microarray data (3, 4) to discover in an unbiased manner the most significant transcriptional changes associated with trastuzumab treatment. We identified PTPN9 among the genes most differentially expressed in the primary tumors of patients with breast cancer treated with trastuzumab. The primary tumors of breast cancer patients treated with trastuzumab expressed higher levels of PTPN9 messenger RNA than did patients not treated with trastuzumab, and a single administration of trastuzumab was sufficient to result in differential expression of PTPN9 in primary tumors of the breast, demonstrating decreased expression of a negative regulator of the molecular target of trastuzumab (5) as an apparent transcriptional consequence of trastuzumab administration in patients with breast cancer.
Cite
Citations (0)
Weekly Trastuzumab Therapy Cannot Prevent Severe Trastuzumab-induced Thrombocytopenia: A Case Report
Abstract Background: Trastuzumab can significantly prolong the survival of patients with positive human epidermal growth factor receptor-2 breast cancer. Until now, trastuzumab has been used by millions of people, and trastuzumab-induced thrombocytopenia is rare. There is no report of acute grade 4 thrombocytopenia after weekly trastuzumab therapy. We report a breast cancer patient with severe thrombocytopenia due to trastuzumab (8mg/Kg) who experienced a recurrence of severe thrombocytopenia after attempting weekly trastuzumab therapy (4mg/Kg). Case presentation ：A 52-year-old woman with positive human epidermal growth factor receptor-2 breast cancer developed acicular rash with dense skin all over the body and gingival bleeding within 24 hours of trastuzumab infusion (8mg/Kg) and was confirmed to have severe thrombocytopenia, which was quickly recovered after high-dose corticosteroid pulse therapy. When the platelet count recovered, we tried weekly trastuzumab therapy (4mg/kg), Unfortunately, thrombocytopenia recurred within 24 hours. No third trastuzumab treatment was attempted. Conclusion: We are the first report to try weekly trastuzumab therapy after thrombocytopenia induced by first trastuzumab. The patient showed that reducing the dose of trastuzumab was ineffective in preventing trastuzumab-induced thrombocytopenia.
Cite
Citations (0)