The ENGAGE study: evaluation of a conversational virtual agent that provides tailored pre-test genetic education to cancer patients.

PURPOSE: Novel approaches are needed to ensure all patients with cancer have access to quality genetic education before genetic testing to enable informed treatment decisions. The purpose of this study was to test the use of an artificial intelligence (AI) intervention for the delivery of genetic education by non-genetic providers to patients with cancer undergoing active treatment. METHODS: A conversational AI-based application was developed on the HealthFAX platform to provide tailored genetic education to patients with cancer and tested at Johns Hopkins Hospital between April 2021 and Feb 2022. Patients' responses around the adoption, use, and experience of the AI application were assessed. RESULTS: Out of 64 individuals who consented to the study, 51 accessed the tool. The responding participants had a mean age of 61 years (ranging from 30-90 years) with 39 individuals undergoing active treatment for breast cancer and 12 for advanced prostate cancer. All patients chose to complete the tool at home. The median time between study enrollment and AI application initiation was 1 day, and the median time to complete the application was 24 min. All participants in their survey responses felt that the tool was secure, easy to use, liked the convenience of viewing it at home, and felt it provided valuable information. Eighteen percent of participants viewed the application with a family member. Ninety-eight percent of the participants completed their genetic education prior to receiving their test results. In 16%, a pathogenic variant was identified. CONCLUSIONS: The 51 patients who adopted the AI application were highly satisfied with its usability and convenience. Our results support the continued evaluation of this cost-effective AI application in a large-scale study. IMPLICATIONS FOR CANCER SURVIVORS: Tailored pre-test genetic education can be successfully delivered to patients with cancer undergoing active treatment via an AI application at their convenience.

A randomized intervention involving family to improve communication in breast cancer care.

We examined the effects of a communication intervention to engage family care partners on patient portal (MyChart) use, illness understanding, satisfaction with cancer care, and symptoms of anxiety in a single-blind randomized trial of patients in treatment for breast cancer. Patient-family dyads were recruited and randomly assigned a self-administered checklist to clarify the care partner role, establish a shared visit agenda, and facilitate MyChart access (n = 63) or usual care (n = 55). Interviews administered at baseline, 3, 9 (primary endpoint), and 12 months assessed anxiety (GAD-2), mean FAMCARE satisfaction, and complete illness understanding (4 of 4 items correct). Time-stamped electronic interactions measured MyChart use. By 9 months, more intervention than control care partners registered for MyChart (77.8 % vs 1.8%; p < 0.001) and logged into the patient's account (61.2% vs 0% of those registered; p < 0.001), but few sent messages to clinicians (6.1% vs 0%; p = 0.247). More intervention than control patients viewed clinical notes (60.3% vs 32.7%; p = 0.003). No pre-post group differences in patient or care partner symptoms of anxiety, satisfaction, or complete illness understanding were found. Intervention patients whose care partners logged into MyChart were more likely to have complete illness understanding at 9 months (changed 70.0% to 80.0% vs 69.7% to 54.6%; p = 0.03); symptoms of anxiety were numerically lower (16.7% to 6.7% vs 15.2% to 15.2%; p = 0.24) and satisfaction numerically higher (15.8-16.2 vs 18.0-17.4; p = 0.25). A brief, scalable communication intervention led to greater care partner MyChart use and increased illness understanding among patients with more engaged care partners (NCT03283553).

The effect of 1-day multidisciplinary clinic on breast cancer treatment.

PURPOSE: A delay in breast cancer treatment is associated with inferior survival outcomes; however, no clear guidelines exist defining the appropriate time frame from diagnosis to definitive treatment of breast cancer. A multidisciplinary approach for breast cancer treatment can minimize the time from diagnosis to first treatment. We hypothesized single-day multidisciplinary clinic (MDC) may accelerate the time to first treatment on complex breast cancer cases at our institution. METHODS: We identified patients who were treated at Johns Hopkins for stage II or III breast cancer, who were at least 18 years of age, and were seen in a new single-day MDC with coordination between two or three specialties or by specialists from varying disciplines on different days (IDC). Patients who initiated treatment between May 2015 (initiation of MDC clinic) and December 2017 were included in our study. RESULTS: A total of 296 patient records were reviewed independently. The mean (SD) patient age was 55 (13) years. The median time to first neoadjuvant chemotherapy (NACT) was significantly reduced for patients seen in the MDC (12.7 days), compared to those seen at the IDC (24.4 days, logrank p < 0.001). The median time to definitive surgery was similar between groups (31 and 32 days for the MDC and IDC cohorts, respectively). CONCLUSIONS: A single-day MDC visit is associated with a reduced time from diagnosis to NACT. Further studies are needed to determine if a shorter interval can improve the management and the outcome of complex breast cancer cases.

The State of Cancer Care in the United Arab Emirates in 2020: Challenges and Recommendations, A report by the United Arab Emirates Oncology Task Force.

With cancer being the third leading cause of mortality in the United Arab Emirates (UAE), there has been significant investment from the government and private health care providers to enhance the quality of cancer care in the UAE. The UAE is a developing country with solid economic resources that can be utilized to improve cancer care across the country. There is limited data regarding the incidence, survival, and potential risk factors for cancer in the UAE. The UAE Oncology Task Force was established in 2019 by cancer care providers from across the UAE under the auspices of Emirates Oncology Society. In this paper we summarize the history of cancer care in the UAE, report the national cancer incidence, and outline current challenges and opportunities to enhance and standardize cancer care. We provide recommendations for policymakers and the UAE Oncology community for the delivery of high-quality cancer care. These recommendations are aligned with the UAE government's vision to reduce cancer mortality and provide high quality healthcare for its citizens.

Sharing in care: engaging care partners in the care and communication of breast cancer patients.

PURPOSE: Family is often overlooked in cancer care. We developed a patient-family agenda setting intervention to engage family in cancer care communication. METHODS: We conducted a pilot randomized controlled trial (NCT03283553) of patients on active treatment for breast cancer and their family "care partner." Intervention dyads (n = 69) completed a self-administered checklist to clarify care partner roles, establish a shared visit agenda, and facilitate MyChart patient portal access. Control dyads (n = 63) received usual care. We assessed intervention acceptability and initial effects from post-visit surveys and MyChart utilization at 6 weeks. RESULTS: At baseline, most patients (89.4%) but few care partners (1.5%) were registered for MyChart. Most patients (79.4%) wanted their care partner to have access to their records and 39.4% of care partners reported accessing MyChart. In completing the checklist, patients and care partners endorsed active communication roles for the care partner and identified a similar visit agenda: most (> 90%) reported the checklist was easy, useful, and recommended it to others. At 6 weeks, intervention (vs control) care partners were more likely to be registered for MyChart (75.4% vs 1.6%; p < 0.001), to have logged in (43.5% vs 0%; p < 0.001) and viewed clinical notes (30.4% vs 0%; p < 0.001), but were no more likely to exchange direct messages with clinicians (1.5% vs 0%; p = 0.175). No differences in patients' MyChart use were observed, but intervention patients more often viewed clinical notes (50.7% vs 9.5%; p < 0.001). CONCLUSIONS: A patient-family agenda setting intervention was acceptable and affected online practices of cancer patients and care partners.

Prevalence of chemopreventive agent use among hospitalised women at high risk for breast cancer: a cross-sectional study.

OBJECTIVE: To characterise the current usage of chemoprevention agents among hospitalised women who are at higher risk for breast cancer. STUDY DESIGN: A cross-sectional study. SETTING: Academic hospital at Baltimore. PARTICIPANTS: A bedside survey of 250 women aged 50-75 years was conducted who were cancer-free at the time of study enrolment and hospitalised to a general medicine service. Reproductive history, family history for breast cancer, chemopreventive agents use and medical comorbidities data was collected for all patients. χ2 and t-tests were used to analyse population characteristics. PRIMARY OUTCOME MEASURES: Prevalence of women at high risk for developing breast cancer (5-year Gail risk score ≥1.7) and their chemopreventive agent use. RESULTS: Mean age for the study population was 61.5 years (SD 7.5), and mean 5-year Gail risk score was 1.67 (SD 0.88). A third of study population was at high risk for breast cancer. None of the high-risk women (0%) were taking chemoprevention for breast cancer risk reduction, and 23% were at very high risk with 5-year Gail score ≥3%. These women were not recognised as being high risk by their hospital providers and none were referred to the high-risk breast cancer clinics following discharge. CONCLUSIONS: Many hospitalised women are at high risk for breast cancer and we could not identify even a single woman who was using chemoprevention for risk reduction. Current chemoprevention guidelines may be falling short in their dissemination and implementation. Since women at high risk for breast cancer may only interface with the healthcare system at select points, all healthcare providers must be willing and able to do risk assessment. For those identified to be at high risk, providers must then either engage in chemopreventive counselling or refer patients to providers who are more comfortable working with patients on this critical decision.

Phase 1b safety study of farletuzumab, carboplatin and pegylated liposomal doxorubicin in patients with platinum-sensitive epithelial ovarian cancer.

OBJECTIVE: Farletuzumab is a humanized monoclonal antibody that binds to folate receptor alpha, over-expressed in epithelial ovarian cancer (EOC) but largely absent in normal tissue. Previously, carboplatin plus pegylated liposomal doxorubicin showed superior progression-free survival and an improved therapeutic index compared with carboplatin/paclitaxel in relapsed platinum-sensitive EOC. This study assessed safety of farletuzumab/carboplatin/pegylated liposomal doxorubicin in women with platinum-sensitive recurrent EOC. METHODS: This multicenter, single-arm study enrolled patients with platinum-sensitive EOC in first or second relapse for treatment with weekly farletuzumab 2.5mg/kg plus carboplatin AUC5-6 and pegylated liposomal doxorubicin 30mg/m(2) every 4weeks for 6cycles. Subsequently, maintenance with single-agent farletuzumab 2.5mg/kg once weekly or farletuzumab 7.5mg/kg once every three weeks continued until progression. The primary objective was to assess the safety of farletuzumab/carboplatin/pegylated liposomal doxorubicin. RESULTS: Fifteen patients received a median of 12.0cycles (range, 3-26) of farletuzumab as combination therapy or maintenance, for a median of 45.0weeks (range 9-95). Farletuzumab/carboplatin/pegylated liposomal doxorubicin was generally well tolerated, with no farletuzumab-related grades 3-4 adverse events. The most commonly reported adverse events were associated with combination chemotherapy: fatigue (73.3%), nausea (46.7%), and neutropenia (40%). Ten patients had grade ≥3 adverse events, most frequently neutropenia and fatigue. No cardiac toxicity was seen. Best overall responses (RECIST) were a complete response for one patient, partial responses for 10 patients, and stable disease for four patients. CONCLUSIONS: Farletuzumab plus carboplatin/pegylated liposomal doxorubicin in women with platinum-sensitive EOC demonstrated a safety profile consistent with that of carboplatin plus pegylated liposomal doxorubicin.

Emerging immunotherapies in ovarian cancer.

Despite a global effort to significantly reduce mortality, ovarian cancer remains the fifth leading cause of cancer death among American women, and five-year survival rates remain discouragingly low at 45%. Novel therapies are urgently needed. Notably, higher infiltration of activated immune cells into the tumor microenvironment correlates with improved ovarian cancer survival, suggesting that promoting their activity could favorably impact clinical outcomes. Immunotherapy has recently demonstrated impressive clinical benefit in a variety of solid tumors. Immunotherapy strategies tested in ovarian cancer include vaccines, adoptive T cell therapy, and immune checkpoint blockade. Ultimately, a combination immunotherapy approach that integrates immunotherapy with other cancer treatment modalities in additive or synergistic ways will most effectively improve survival.

Detection of cancer DNA in plasma of patients with early-stage breast cancer.

PURPOSE: Detecting circulating plasma tumor DNA (ptDNA) in patients with early-stage cancer has the potential to change how oncologists recommend systemic therapies for solid tumors after surgery. Droplet digital polymerase chain reaction (ddPCR) is a novel sensitive and specific platform for mutation detection. EXPERIMENTAL DESIGN: In this prospective study, primary breast tumors and matched pre- and postsurgery blood samples were collected from patients with early-stage breast cancer (n = 29). Tumors (n = 30) were analyzed by Sanger sequencing for common PIK3CA mutations, and DNA from these tumors and matched plasma were then analyzed for PIK3CA mutations using ddPCR. RESULTS: Sequencing of tumors identified seven PIK3CA exon 20 mutations (H1047R) and three exon 9 mutations (E545K). Analysis of tumors by ddPCR confirmed these mutations and identified five additional mutations. Presurgery plasma samples (n = 29) were then analyzed for PIK3CA mutations using ddPCR. Of the 15 PIK3CA mutations detected in tumors by ddPCR, 14 of the corresponding mutations were detected in presurgical ptDNA, whereas no mutations were found in plasma from patients with PIK3CA wild-type tumors (sensitivity 93.3%, specificity 100%). Ten patients with mutation-positive ptDNA presurgery had ddPCR analysis of postsurgery plasma, with five patients having detectable ptDNA postsurgery. CONCLUSIONS: This prospective study demonstrates accurate mutation detection in tumor tissues using ddPCR, and that ptDNA can be detected in blood before and after surgery in patients with early-stage breast cancer. Future studies can now address whether ptDNA detected after surgery identifies patients at risk for recurrence, which could guide chemotherapy decisions for individual patients.

A PIK3CA mutation detected in plasma from a patient with synchronous primary breast and lung cancers.

Digital polymerase chain reaction is a new technology that enables detection and quantification of cancer DNA molecules from peripheral blood. Using this technique, we identified mutant PIK3CA DNA in circulating ptDNA (plasma tumor DNA) from a patient with concurrent early stage breast cancer and non-small cell lung cancer. The patient underwent successful resection of both her breast and lung cancers, and using standard Sanger sequencing the breast cancer was shown to harbor the identical PIK3CA mutation identified in peripheral blood. This case report highlights potential applications and concerns that can arise with the use of ptDNA in clinical oncology practice.

Treatment of HER2-positive breast cancer.

The human epidermal growth factor receptor 2 gene (HER2) is overexpressed and/or amplified in ~15% of breast cancer patients and was identified a quarter century ago as a marker of poor prognosis. By 1998, antibody therapy targeting the HER2 pathway was shown to demonstrably improve progression-free and overall survival in metastatic disease, and in 2005 evidence of improvement in disease-free and overall survival from the first generation of trastuzumab adjuvant trials became available. However, not all patients with HER2 overexpression benefit from trastuzumab. Second-generation studies in metastatic disease led to the approval of several new HER2-targeted therapies using small molecule tyrosine kinase inhibitors such as lapatinib, new HER2/HER3 antibodies such as pertuzumab, and the new antibody chemotherapy conjugate ado-trastuzumab emtansine. These successes supported the launch of second-generation adjuvant trials testing single and dual HER2-targeted agents, administered concomitantly or sequentially with chemotherapy that will soon complete accrual. HER2-positive breast cancer in the setting of HER2-targeted therapy is no longer associated with poor prognosis, and recent guidance by the US Food and Drug Administration suggests that pathologic response to HER2-targeted therapy given preoperatively may allow an earlier assessment of their clinical benefit in the adjuvant setting. An adjuvant trial of trastuzumab in patient whose tumors express normal levels of HER2 and trials of single/dual HER2-targeting without chemotherapy are also ongoing. In this article, we review the current data on the therapeutic management of HER2-positive breast cancer.

HER2-directed therapy for metastatic breast cancer.

Human epidermal growth factor receptor 2 (HER2) overexpression drives the biology of 20% of breast cancers, and predicts a poor prognosis for patients. HER2-targeted therapies significantly improve outcomes for HER2-positive patients with both early and metastatic breast cancer. Currently three HER2-targeted agents, trastuzumab (Herceptin), lapatinib (Tykerb), and pertuzumab (Perjeta), are available for the treatment of HER2-positive metastatic breast cancer (MBC). Numerous studies have attempted to optimize their use by combining them with each other, or with endocrine and cytotoxic therapies. Most recently, the FDA approved the combination of trastuzumab, pertuzumab, and docetaxel as first-line treatment for MBC, and in late February 2013 approved a fourth HER2-targeted agent, trastuzumab emtansine (T-DM1, Kadcyla), for accelerated approval. These advances create a number of clinical dilemmas, including identification of the optimal sequence of HER2-targeted agents and the best drug combinations to use, as well as the recognition of primary and acquired drug resistance. In this article, we review clinical data informing the effective management of HER2-positive MBC.

Single copies of mutant KRAS and mutant PIK3CA cooperate in immortalized human epithelial cells to induce tumor formation.

The selective pressures leading to cancers with mutations in both KRAS and PIK3CA are unclear. Here, we show that somatic cell knockin of both KRAS G12V and oncogenic PIK3CA mutations in human breast epithelial cells results in cooperative activation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in vitro, and leads to tumor formation in immunocompromised mice. Xenografts from double-knockin cells retain single copies of mutant KRAS and PIK3CA, suggesting that tumor formation does not require increased copy number of either oncogene, and these results were also observed in human colorectal cancer specimens. Mechanistically, the cooperativity between mutant KRAS and PIK3CA is mediated in part by Ras/p110α binding, as inactivating point mutations within the Ras-binding domain of PIK3CA significantly abates pathway signaling. In addition, Pdk1 activation of the downstream effector p90RSK is also increased by the combined presence of mutant KRAS and PIK3CA. These results provide new insights into mutant KRAS function and its role in carcinogenesis.

Role of farletuzumab in epithelial ovarian carcinoma.

Epithelial ovarian cancer (EOC) is the most lethal of the gynecologic malignancies, largely due to the advanced stage at diagnosis in most patients. Standard treatment for EOC is surgical debulking followed by platinum-based chemotherapy. While the majority of ovarian cancer patients will respond to initial chemotherapy, most will ultimately relapse. The major focus of current clinical trials for treatment of recurrent ovarian cancer is the use of targeted biologic agents. Folate receptor alpha (FRα) is upregulated in majority of EOC and correlated with tumor stage and grade. It is hypothesized that the presence of overexpressed FRα correlates with the propagation rate of the tumors. FRα is largely absent from normal tissue, making it an attractive therapeutic target. Farletuzumab (MORAb-003), a humanized monoclonal antibody against FRα, has shown antitumor activity in preclinical xenograft models. A Phase 1 dose escalation study did not demonstrate dose-limiting toxicities, or severe adverse effects. A phase 2 efficacy and safety study of farletuzumab with carboplatin and taxane in patients with platinum-sensitive EOC in first relapse, have shown an improved response rate and time to progression compared with historical controls. Recently, preliminary safety data from a phase 1 trial reported that the combination of farletuzumab, carboplatin and PLD has an acceptable safety profile in patients with platinum- sensitive EOC following first or second relapse. Two randomized, double-blind, placebo-controlled Phase 3 studies with farletuzumab plus chemotherapy have been done. A trial of: farletuzumab with weekly paclitaxel in platinum-resistant EOC closed in December 2011 with full report pending. A second trial of farletuzumab with carboplatin and taxane in platinum-sensitive EOC in first relapse is slated to complete accrual in early 2012. Results from these trials will help define the role of farletuzumab in EOC.

The adjuvant treatment of HER2-positive breast cancer.

OPINION STATEMENT: About 15-20% of patients with early stage breast cancer present with tumors that have overexpression or amplification of the human epidermal growth factor receptor 2 (HER2) gene. Before 2005, these individuals had an increased risk of recurrence and death, but since then their outcomes have substantially improved with the adoption in most countries of adjuvant trastuzumab as a standard component of therapy for HER2-positive early-stage breast cancer. Consequently, access to high-quality and accurate HER2 testing methods is critical to accurately determine HER2 status, guide treatment decisions, and ultimately improve clinical outcomes. In 2012, the humanized monoclonal anti-HER antibody trastuzumab was the only approved HER2-targeted therapy in the adjuvant setting. Data from the first generation of trials combining it with various chemotherapy regimens showed significant improvements in disease-free and overall survival (DFS/OS). Based on results from five randomized clinical trials, a trastuzumab-containing regimen for up to 1 year is now considered standard for all patients with HER2-positive tumors larger than 1 cm in size who would have fulfilled eligibility to those studies, and this recommendation is sometimes extended to patients with stage I tumors greater than 0.5 cm (T1b). Second generation adjuvant studies with other HER2-targeted agents like lapatinib and pertuzumab are ongoing, and newer drugs like T-DM1 and neratinib are being actively tested in the metastatic setting.

Detection of tumor PIK3CA status in metastatic breast cancer using peripheral blood.

PURPOSE: We sought to evaluate the feasibility of detecting PIK3CA mutations in circulating tumor DNA (ctDNA) from plasma of patients with metastatic breast cancer using a novel technique called BEAMing. EXPERIMENTAL DESIGN: In a retrospective analysis, 49 tumor and temporally matched plasma samples from patients with breast cancer were screened for PIK3CA mutations by BEAMing. We then prospectively screened the ctDNA of 60 patients with metastatic breast cancer for PIK3CA mutations by BEAMing and compared the findings with results obtained by screening corresponding archival tumor tissue DNA using both sequencing and BEAMing. RESULTS: The overall frequency of PIK3CA mutations by BEAMing was similar in both patient cohorts (29% and 28.3%, respectively). In the retrospective cohort, the concordance of PIK3CA mutation status by BEAMing between formalin-fixed, paraffin-embedded (FFPE) samples and ctDNA from temporally matched plasma was 100% (34 of 34). In the prospective cohort, the concordance rate among 51 evaluable cases was 72.5% between BEAMing of ctDNA and sequencing of archival tumor tissue DNA. When the same archival tissue DNA was screened by both sequencing and BEAMing for PIK3CA mutations (n = 41 tissue samples), there was 100% concordance in the obtained results. CONCLUSIONS: Analysis of plasma-derived ctDNA for the detection of PIK3CA mutations in patients with metastatic breast cancer is feasible. Our results suggest that PIK3CA mutational status can change upon disease recurrence, emphasizing the importance of reassessing PIK3CA status on contemporary (not archival) biospecimens. These results have implications for the development of predictive biomarkers of response to targeted therapies.

The growth response to androgen receptor signaling in ERα-negative human breast cells is dependent on p21 and mediated by MAPK activation.

INTRODUCTION: Although a high frequency of androgen receptor (AR) expression in human breast cancers has been described, exploiting this knowledge for therapy has been challenging. This is in part because androgens can either inhibit or stimulate cell proliferation in pre-clinical models of breast cancer. In addition, many breast cancers co-express other steroid hormone receptors that can affect AR signaling, further obfuscating the effects of androgens on breast cancer cells. METHODS: To create better-defined models of AR signaling in human breast epithelial cells, we took estrogen receptor (ER)-α-negative and progesterone receptor (PR)-negative human breast epithelial cell lines, both cancerous and non-cancerous, and engineered them to express AR, thus allowing the unambiguous study of AR signaling. We cloned a full-length cDNA of human AR, and expressed this transgene in MCF-10A non-tumorigenic human breast epithelial cells and MDA-MB-231 human breast-cancer cells. We characterized the responses to AR ligand binding using various assays, and used isogenic MCF-10A p21 knock-out cell lines expressing AR to demonstrate the requirement for p21 in mediating the proliferative responses to AR signaling in human breast epithelial cells. RESULTS: We found that hyperactivation of the mitogen-activated protein kinase (MAPK) pathway from both AR and epidermal growth factor receptor (EGFR) signaling resulted in a growth-inhibitory response, whereas MAPK signaling from either AR or EGFR activation resulted in cellular proliferation. Additionally, p21 gene knock-out studies confirmed that AR signaling/activation of the MAPK pathway is dependent on p21. CONCLUSIONS: These studies present a new model for the analysis of AR signaling in human breast epithelial cells lacking ERα/PR expression, providing an experimental system without the potential confounding effects of ERα/PR crosstalk. Using this system, we provide a mechanistic explanation for previous observations ascribing a dual role for AR signaling in human breast cancer cells. As previous reports have shown that approximately 40% of breast cancers can lack p21 expression, our data also identify potential new caveats for exploiting AR as a target for breast cancer therapy.

Intraperitoneal treatment in ovarian cancer: the gynecologic oncology group perspective in 2012.

The peritoneal cavity is the major site of disease in ovarian cancer. The peritoneal predominance of disease provides a rationale for administration of chemotherapy within the peritoneal cavity. Intraperitoneal (IP) chemotherapy for ovarian cancer has been studied rigorously for more than 30 years and has been reproducibly shown to improve the survival of patients with ovarian cancer. Three large randomized trials of IP compared with intravenous (IV) therapy have demonstrated statistically significant improvement in clinical outcome measures. Despite this, the IP approach has not gained widespread acceptance in the treatment of ovarian cancer. Here, we review reported, recently completed, and ongoing trials of IP therapy in ovarian cancer including attempts to improve the tolerability and acceptance of this proven approach.

Mutation of a single allele of the cancer susceptibility gene BRCA1 leads to genomic instability in human breast epithelial cells.

Biallelic inactivation of cancer susceptibility gene BRCA1 leads to breast and ovarian carcinogenesis. Paradoxically, BRCA1 deficiency in mice results in early embryonic lethality, and similarly, lack of BRCA1 in human cells is thought to result in cellular lethality in view of BRCA1's essential function. To survive homozygous BRCA1 inactivation during tumorigenesis, precancerous cells must accumulate additional genetic alterations, such as p53 mutations, but this requirement for an extra genetic "hit" contradicts the two-hit theory for the accelerated carcinogenesis associated with familial cancer syndromes. Here, we show that heterozygous BRCA1 inactivation results in genomic instability in nontumorigenic human breast epithelial cells in vitro and in vivo. Using somatic cell gene targeting, we demonstrated that a heterozygous BRCA1 185delAG mutation confers impaired homology-mediated DNA repair and hypersensitivity to genotoxic stress. Heterozygous mutant BRCA1 cell clones also showed a higher degree of gene copy number loss and loss of heterozygosity in SNP array analyses. In BRCA1 heterozygous clones and nontumorigenic breast epithelial tissues from BRCA mutation carriers, FISH revealed elevated genomic instability when compared with their respective controls. Thus, BRCA1 haploinsufficiency may accelerate hereditary breast carcinogenesis by facilitating additional genetic alterations.

Recent progress in the diagnosis and treatment of ovarian cancer.

Epithelial ovarian cancer is the most lethal of the gynecologic malignancies, largely due to the advanced stage at diagnosis in most patients. Screening strategies using ultrasound and the cancer antigen (CA) 125 tumor marker are currently under study and may lower stage at diagnosis but have not yet been shown to improve survival. Women who have inherited a deleterious mutation in the BRCA1 or BRCA2 gene and those with the Lynch syndrome (hereditary nonpolyposis colorectal cancer) have the highest risk of developing ovarian cancer but account for only approximately 10% of those with the disease. Other less common and less well-defined genetic syndromes may increase the risk of ovarian cancer, but their contribution to genetic risk is small. A clear etiology for sporadic ovarian cancer has not been identified, but risk is affected by reproductive and hormonal factors. Surgery has a unique role in ovarian cancer, as it is used not only for diagnosis and staging but also therapeutically, even in patients with widely disseminated, advanced disease. Ovarian cancer is highly sensitive to chemotherapy drugs, particularly the platinum agents, and most patients will attain a remission with initial treatment. Recent advances in the delivery of chemotherapy using the intraperitoneal route have further improved survival after initial therapy. Although the majority of ovarian cancer patients will respond to initial chemotherapy, most will ultimately develop disease recurrence. Chemotherapy for recurrent disease includes platinum-based, multiagent regimens for women whose disease recurs more than 6 to 12 months after the completion of initial therapy and sequential single agents for those whose disease recurs earlier. New targeted biologic agents, particularly those involved with the vascular endothelial growth factor pathway and those targeting the poly (ADP-ribose) polymerase (PARP) enzyme, hold great promise for improving the outcome of ovarian cancer.