Gerald M. Higa

Lapatinib in the treatment of breast cancer

Within the past 2 years, four separate groups have reported marked improvement in relapse-free survival when trastuzumab was added to adjuvant chemotherapy in patients with HER2-overexpressing breast cancer. These results add further credence to the relevance of this receptor as a tumor target. Despite the significant benefits observed in early and advanced HER2-positive breast cancer, overexpression of the receptor is still associated with a poorer prognosis and an increased risk of disease relapse, even in patients with primary operable disease. Besides cytotoxic chemotherapy, and possibly hormonal therapy, patients whose tumors exhibit resistance to trastuzumab have few molecular-targeted options available. Recently, lapatinib, a small molecule dual inhibitor of both HER2 and EGF receptors, has been developed to expand the options for treating HER-positive breast cancer.

Biological mechanisms of bevacizumab-associated adverse events

The perception that inhibition of cancer-associated angiogenesis would be an effective treatment strategy was based on the fundamental difference in cell cycle activity between neoplastic and normal endothelial cells. Selective targeting of tumor vessels could have additional benefits, such as circumventing development of acquired resistance to these types of agents, overcoming intrinsic tumor resistance, exhibiting broad anti-tumor activity and decreasing normal tissue toxicity. Successful translation of anti-angiogenic therapy into the clinical setting was achieved only 5 years ago with the approval of bevacizumab for metastatic colorectal cancer. Although the benefits demonstrated in clinical trials led to the approval of bevacizumab for treatment of colorectal, lung and breast cancers, and most recently glioblastoma, a number of serious soft-tissue and vascular toxicities have also been observed in patients receiving this anti-angiogenic agent. This review assesses the relationship between inhibition of VEGF and toxicity, and proposes the pathogenic mechanisms that lead to the adverse events.

5-Hydroxyindoleacetic acid and substance P profiles in patients receiving emetogenic chemotherapy.

Background. Even though direct cause and effect has not been proved, clinical evidence suggests serotonin and substance P (SP) are involved in the emetic response following chemotherapy. Because of several parallels, we hypothesized that SP release, like serotonin, may be propagated by chemotherapy and both substances can be measured in biological fluids, and correlated with a particular phase of emesis. Methods. Urinary 5-hydroxyindoleacetic acid (5-HIAA) was assessed by HPLC; serum and urine SP were measured by immunoassay. In addition to construction of neurotransmitter profiles, all SP data were grouped according to cisplatin dosages, = or>75 mg/m 2 versus <75 mg/m2, and phase of emesis, acute versus delayed. Analyses of these data were performed by repeated measures analysis of variance. Results. Samples were collected over a 72-hour period from 26 adult patients who received cisplatin-(n=13) or non-cisplatin-containing (n=13) chemotherapy. Mean baseline 5-HIAA: creatinine ratios were 5.23 and 5.16 in females and males, respectively; mean baseline SP levels were 392 and 181 pg/mL in females and males, respectively. Comparisons between SP data stratified by cisplatin dosage and emetic phase were significantly different, P <0.0001. Conclusions. Laboratory studies provide additional evidence that serotonin and SP are involved primarily, though not exclusively, in acute and delayed vomiting, respectively.

Sex Hormone Receptor Repertoire in Breast Cancer

Classification of breast cancer as endocrine sensitive, hormone dependent, or estrogen receptor (ER) positive refers singularly to ERα. One of the oldest recognized tumor targets, disruption of ERα-mediated signaling, is believed to be the mechanistic mode of action for all hormonal interventions used in treating this disease. Whereas ERα is widely accepted as the single most important predictive factor (for response to endocrine therapy), the presence of the receptor in tumor cells is also of prognostic value. Even though the clinical relevance of the two other sex hormone receptors, namely, ERβ and the androgen receptor remains unclear, two discordant phenomena observed in hormone-dependent breast cancers could be causally related to ERβ-mediated effects and androgenic actions. Nonetheless, our understanding of regulatory molecules and resistance mechanisms remains incomplete, further compromising our ability to develop novel therapeutic strategies that could improve disease outcomes. This review focuses on the receptor-mediated actions of the sex hormones in breast cancer.

Priorities and uncertainties of administering chemotherapy in a pregnant woman with newly diagnosed colorectal cancer

Background. The absence of treatment standards for the use of chemotherapy in pregnancy is due, in part, to the fact that cancer in the gravid female is relatively uncommon. Method. A case (of a pregnant woman with newly diagnosed colorectal cancer) is presented to explore this area of medical uncertainty. Result. Managed by a multi-disciplinary team, successful prolongation of gestation was achieved with an oxaliplatin-based chemotherapy regimen. Conclusion. A perspective of the ongoing conflict between prolonging the mothers life and preserving fetal development is highlighted. Although not life-saving, administration of chemotherapy in this woman was life-sparing. J Oncol Pharm Practice (2009) 15: 5—8.

Chemotherapy-induced nausea and vomiting: antiemetic trials that impacted clinical practice

Objective. To review the scientific evidence related to serotonin and substance P and the clinical impact targeting these two neurotransmitters have had managing chemotherapy-induced nausea and vomiting (CINV). Data Source. A PubMed search (January 1968 to December 2008), restricted to English-language publications, was conducted using the key words antiemetics, cancer chemotherapy, cisplatin, serotonin, substance P, NK1, and 5-HT3. Abstracts emanating from the meetings of the American Society of Clinical Oncology and Multinational Association of Supportive Care in Cancer during the period May 2000 to June 2008 were also reviewed. Data Synthesis. Two important outcomes emanated from well-conducted antiemetic clinical trials (Table 1): first, evidence that serotonin and substance P are major mediators of acute and delayed symptoms and second, improved, though not complete, control of CINV. Conclusion. Serotonin-type 3 and neurokinin-1 receptor antagonists are the most effective agents currently available. In most cases, these agents are used in conjunction with glucocorticoids. The use of these three types of agents is incorporated into current clinical practice guidelines. Further understanding of the biological and biochemical basis of nausea and vomiting may enhance management of this potentially debilitating adverse effect.

Risk of brain metastases in HER2/neu-positive breast cancer

682 Background: Preliminary data indicate HER2/neu over-expression correlates with more aggressive disease, increased metastatic potential, and a poorer prognosis in patients with breast cancer. We conducted a retrospective study to evaluate whether patients with HER2/neu-positive breast cancer have an increased risk of developing brain metastases. MATERIAL AND METHODS The pathology reports of 405 breast cancer patients diagnosed between April 1998 and January 2003 were reviewed. Based upon immunohistochemistry (IHC 3+) or FISH positivity, all HER2/neu-positive cases were identified and their medical charts reviewed for disease course and sites of metastases. RESULTS One hundred ten of the 405 patients (27%) were HER2/neu positive; sufficient oncologic history was available for 67 patients (24 premenopausal; 43 postmenopausal). Eighteen patients (27%) developed distant metastases (CI 95%: 0.177, 0.385) during follow-up lasting a median of 57 months. Brain metastases developed in 33.3% (6 out of 18)(CI 95%: 0.163, 0.562) of patients, five of who were <50 years of age; the sixth was 53 years old. The median time from diagnosis of breast cancer to development of brain metastases was 24 months (range 8 months -30 months) among the five patients <50 years old. The sixth patient found to have innumerable brain metastases in hemispheres, cerebellum and brain stem, 48 months after breast cancer diagnosis. There was a significant association (p=0.0485) between age of the patients and development of brain metastases in HER2/neu-positive breast cancer. DISCUSSION This small retrospective study shows that younger women with HER/2-neu-positive breast cancer may have a higher risk than reported for general metastatic breast cancer population, of developing brain metastases. This finding, if validated in larger studies, may alter treatment strategies for premenopausal patients with HER/2-neu-positive disease. No significant financial relationships to disclose.

Severe, Disabling Neurologic Toxicity Following Cisplatin Retreatment

Objective: To describe a severe neurotoxic reaction following the second cycle of cisplatin-based chemotherapy. Case Summary: A patient with unresectable non–small-cell lung cancer was treated with combined chemotherapy and radiotherapy. Thirty-six hours after the second course of chemotherapy, the patient developed severe mental status changes consisting of aphasia, confusion, and agitation. Complete neurologic workup was most consistent with an acute vascular event. Discussion: Reports of acute cisplatin-induced neurologic toxicity involving the central nervous system are rare. Potential risk factors are described. Mechanisms of chemotherapy-induced vascular damage are discussed. Conclusions: Total dosage and administration schedule of cisplatin are associated with an increased incidence of neuropathy. However, factors predicting the development of early, acute neurotoxicity are limited by the rarity of these events. It is probable that acute neurotoxic reactions in cancer patients are caused by an unknown complex of interactions involving drugs, tumor, and host factors.

Treatment of Multiple Myeloma in the Targeted Therapy Era

Objective: To review the clinical trials that have impacted treatment standards of multiple myeloma (MM). Data Source: A PubMed search (1980–June 2008) restricted to English-language publications was conducted using the key words multiple myeloma, clinical trials, targeted therapy, thalidomide, lenalidomide, bortezomib, dexamethasone, melphalan, autologous stem-cell transplantation, and tumor biology. Abstracts emanating from the meetings of the American Society of Clinical Oncology and American Society of Hematology from June 2002 to June 2008 were also reviewed. Data Synthesis: Although hematopoietic stem-cell transplantation has improved the response rate and duration of overall survival, MM remains an incurable disease. However, focused research aimed at the molecular basis of the disease has led to a number of new treatment strategies. Evidence from clinical trials indicates that each of the 3 novel agents, thalidomide, lenalidomide, and bortezomib, is remarkably effective as first-line therapy. The data also suggest that clinicians may need to reevaluate the role of stem-cell transplantation in the disease. Conclusions: Thalidomide, lenalidomide, or bortezomib in combination with dexamethasone have replaced traditional chemotherapy such as melphalan, doxorubicin, and vincristine as initial therapy of patients with MM who are eligible for stem-cell transplantation. Furthermore, these novel drugs can be incorporated into regimens used to treat transplant-ineligible patients or those with relapsing disease.

Biological considerations and clinical applications of new HER2-targeted agents

Over the past two decades, since the discovery of the human EGF receptor 2 (HER2) oncogene, the oncoprotein has become one of the best known and intensively studied tumor targets in oncology. In fact, laboratory findings were the basis for clinical proof-of-principle studies, whose results not only confirmed the relationship between gene amplification and an aggressive tumor phenotype but also demonstrated that the poor prognosis associated with receptor overexpression could be improved. Indeed, the success in treating patients with HER2-positive breast cancer extends to those with early as well as advanced disease. Nonetheless, not all tumors respond to treatment targeting the receptor; disease progression also occurs after initially responding to anti-HER2 therapy. This article focuses on the biology of HER2 and three novel agents currently in clinical trials that target HER2 beyond disease progression.