Open-Label Single-Arm Phase II Trial of Sorafenib Therapy with Drug-eluting Bead Transarterial Chemoembolization in Patients with Unresectable Hepatocellular Carcinoma: Clinical Results.

PURPOSE: To determine the efficacy of combined continuous sorafenib therapy and drug-eluting bead (DEB) transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This study was conducted in accordance with the principles of the Declaration of Helsinki, and all patients provided written informed consent prior to enrollment. Inclusion criteria included unresectable HCC, a treatment naïve status, an Eastern Cooperative Oncology Group score of 0-1, and a Child-Pugh score of A-B7. Continuous sorafenib therapy (400 mg twice daily) was started 1 week before the first round of DEB TACE, which was performed in 6-week cycles. Up to four rounds of DEB TACE therapy were allowed on demand within 6 months. The primary end point was safety. Secondary end points were time to progression (TTP), response rate, and overall survival (OS) and were stratified by the Barcelona Clinic Liver Cancer (BCLC) stage and the duration of sorafenib therapy. OS was assessed with Kaplan-Meier estimates, and the Mantel-Cox log-rank test was used to determine differences in survival. A two-sided P value of less than .05 was considered to indicate a significant difference. The study was approved by the Johns Hopkins institutional review board and remained open from March 2009 to January 2012. RESULTS: Fifty patients--of whom 76% were male, 92% had a Child-Pugh score of A, and 62% had BCLC stage C disease--underwent a median of three cycles of therapy. The 6-month disease control rate (defined as complete response plus partial response plus stable disease) was 94% according to the response evaluation criteria in solid tumors. Median TTP and OS were 13.9 and 20.4 months, respectively, and 81% of toxicities were grades 1-2. There was one death that was possibly treatment related. CONCLUSION: Combined continuous sorafenib therapy and on-demand DEB TACE provided excellent local disease control and did not lead to multiplicative toxicities. Long-term administration of sorafenib therapy in combination with DEB TACE may have a survival benefit in patients with advanced HCC.

The relative net health benefit of liver resection, ablation, and transplantation for early hepatocellular carcinoma.

BACKGROUND: There are no conclusive cost-effectiveness studies measuring the efficacy of salvage LT after liver resection (LR) and radiofrequency ablation (RFA) in patients with early hepatocellular carcinoma (HCC) and compensated cirrhosis. The aim of the present study is to compare liver transplantation (LT) versus locoregional therapy plus salvage LT (to treat tumor recurrence) in patients with early HCC and compensated cirrhosis. METHODS: Reference case: 55-year old male with HCC within Milan criteria and Child-Pugh A cirrhosis. The analysis was performed in two geographical cost settings: USA and Italy. Survival benefit measured in quality-adjusted life years (QALYs), costs (C) in US$, incremental cost-effectiveness, willingness to pay, and net health benefit (NHB). RESULTS: In the base-case analysis, NHB of LT vs. LR and RFA was -1.7 and -1.3 years for single tumor ≤3 cm, -1.2 and -0.7 for single nodules measuring 3.1-5 cm and -0.7 and -0.7 for multi-nodular tumor ≤3 cm in Italy. In USA, NHB of LT versus LR and RFA were -1.2 and -0.8 years for single tumor ≤3 cm, -0.9 and -0.5 for single nodules measuring 3.1-5 cm, and -0.5 and -0.4 for multi-nodular tumor ≤ 3 cm. On the Monte Carlo simulation, only young patients with multi-nodular HCC and short waiting list time had a positive NHB. Salvage LT proved to be an ineffective cost strategy after RFA or LR. CONCLUSION: In patients with HCC within Milan criteria and Child-Pugh A cirrhosis, LR and RFA were more cost-effective than LT. Salvage LT was not cost-effective.

Unresectable hepatocellular carcinoma: MR imaging after intraarterial therapy. Part II. Response stratification using volumetric functional criteria after intraarterial therapy.

PURPOSE: To assess whether volumetric functional magnetic resonance (MR) results 3-4 weeks after initial intraarterial therapy can aid accurate distinction between responders and nonresponders, to determine whether overall survival (OS) is improved, and to compare volumetric functional MR response with anatomic response criteria (Response Evaluation Criteria in Solid Tumors [RECIST], modified RECIST [mRECIST], European Association for the Study of the Liver [EASL]), as well as α1-fetoprotein [AFP] level. MATERIALS AND METHODS: In this single-institution HIPAA-compliant retrospective, institutional review board-approved study, informed consent was waived; 143 patients with hepatocellular carcinoma underwent intraarterial therapy between October 2005 and February 2011. Volumetric functional MR response (25% or more increase in apparent diffusion coefficient, 65% or more decrease in enhancement) was stratified as follows: Dual-parameter responders fulfilled both criteria, single-parameter responders fulfilled one criterion, and those with stable disease (SD) fulfilled neither. RECIST, mRECIST, EASL, and AFP response criteria were determined. Kaplan-Meier technique, log-rank tests, and the Cox proportional hazards model were used to test whether OS was different per response. RESULTS: OS differed significantly between single-parameter responders and dual-parameter responders (P = .01) and between single-parameter responders and those with SD (P = .001). Dual-parameter responders' response improved OS compared with single-parameter responders; risk of death decreased (hazard ratio [HR] = 0.28, P = .01). In those with SD compared with single-parameter responders, risk of death increased (HR = 2.09, P = .001). RECIST, mRECIST, and EASL stratification was short of significant; most lesions were classified as SD. Baseline AFP level increased in 55 patients; AFP responders versus AFP nonresponders had decreased risk of death (HR = 0.36, P = .002). Agreement between anatomic response criteria and volumetric functional MR findings (κ = 0.06-0.12) and between AFP response and imaging criteria (κ = -0.04 to 0.14) was low. CONCLUSION: Volumetric functional MR response 3-4 weeks after initial intraarterial therapy showed improved OS. Volumetric functional MR was superior to current imaging (RECIST, mRECIST, and EASL) and biochemical (AFP level) response criteria.

Chromophobe hepatocellular carcinoma with abrupt anaplasia: a proposal for a new subtype of hepatocellular carcinoma with unique morphological and molecular features.

Hepatocellular carcinomas exhibit heterogeneous morphologies by routine light microscopy. Although some morphologies represent insignificant variations in growth patterns, others may represent unrecognized subtypes of hepatocellular carcinoma. Identification of these subtypes could lead to separation of hepatocellular carcinomas into discrete groups with unique underlying genetic changes, prognosis, or therapeutic responses. In order to identify potential subtypes, two pathologists independently screened a cohort of 219 unselected hepatocellular carcinoma resection specimens and divided cases into potential subtypes. One of these promising candidate subtypes was further evaluated using histological and molecular techniques. This subtype was characterized by a unique and consistent set of histological features: smooth chromophobic cytoplasm, abrupt focal nuclear anaplasia (small clusters of tumor cells with marked nuclear anaplasia in a background of tumor cells with bland nuclear cytology), and scattered microscopic pseudocysts--we designate this variant as 'chromophobe hepatocellular carcinoma with abrupt anaplasia'. Thirteen cases were identified (6% of all hepatocellular carcinomas), including 6 men and 7 women with an average age of 61 years. Six cases occurred in cirrhotic livers. Serum AFP was elevated in 6 out of 10 cases. There were a variety of underlying liver diseases, but cases were enrichment for chronic hepatitis B, P=0.006. Interestingly, at the molecular level, this variant was strongly associated with the alternative lengthening of telomere (ALT) phenotype by telomere FISH. ALT is a telomerase-independent mechanism of telomere maintenance and is found in approximately 8% of unselected hepatocellular carcinomas. In contrast, 11/12 (92%) of the cases of chromophobe hepatocellular carcinoma with abrupt anaplasia were ALT-positive. In summary, we propose that chromophobe hepatocellular carcinoma with abrupt anaplasia represents a new subtype of hepatocellular carcinoma with unique morphological and molecular features.

Real-world outcomes among patients with advanced or metastatic biliary tract cancers initiating second-line treatment.

BACKGROUND: Limited data are available regarding second-line (2 L) treatment for advanced or metastatic biliary tract cancers (BTC) in the US real-world setting. This study explores the rapidly evolving and growing treatment landscape in the 2 L setting for advanced or metastatic BTC with a large cohort of patients treated in a community oncology setting. METHODS: Adult patients with BTC initiating 2 L treatment after a platinum-containing first-line between 1/1/10- and 6/30/19 were identified from the US Oncology Network electronic healthcare record database and followed through 12/31/19. Baseline patient and treatment characteristics were analyzed descriptively, including overall response rate (ORR) in the real-world clinical setting. Kaplan-Meier methods were used to measure duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS: The overall population (N = 160) included 74 patients (46.3%) with intrahepatic cholangiocarcinoma, 41 (25.6%) with extrahepatic cholangiocarcinoma, and 45 (28.1%) with gallbladder cancer. Thirty unique 2 L regimens were recorded for the study population, with folinic acid, fluorouracil and oxaliplatin (FOLFOX, 34.4%) and capecitabine monotherapy (20.0%) being the most common. ORR was 7.5% (95% CI, 3.9%-12.7%). From 2 L initiation, median PFS was 2.8 months (95% CI, 2.4-3.3 months), and median OS was 5.2 months (95% CI, 4.2-6.7 months). CONCLUSION: Results from this study provide real-world evidence that although patients treated in the community oncology setting receive a wide variety of 2 L treatments, the regimens are consistent with those recommended by guidelines. Although responses are observed with 2 L treatment, duration is brief and associated with poor OS in patients with advanced or metastatic disease.

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.

Treating patients with colon cancer liver metastasis: a nationwide analysis of therapeutic decision making.

BACKGROUND: Criteria for resectability of colon cancer liver metastases (CLM) are evolving, yet little is known about how physicians choose a therapeutic strategy for potentially resectable CLM. METHODS: Physicians completed a national Web-based survey that consisted of varied CLM conjoint tasks. Respondents chose among three treatment strategies: immediate liver resection (LR), preoperative chemotherapy followed by surgery (C â†’ LR), or palliative chemotherapy (PC). Data were analyzed by multinomial logistic regression, yielding odds ratios (OR). RESULTS: Of 219 respondents, 79 % practiced at academic centers and 63 % were in practice ≥10 years. Median number of cases evaluated was four per month. Surgical training varied: 51 % surgical oncology, 44 % hepato-pancreato-biliary/transplantation, 5 % no fellowship. Although each factor affected the choice of CLM therapy, the relative effect differed. Hilar lymph node disease predicted a strong aversion to LR with surgeons more likely to choose C â†’ LR (OR 8.92) or PC (OR 49.9). Solitary lung metastasis also deterred choice of LR, with respondents favoring C â†’ LR (OR 4.43) or PC (OR 6.97). After controlling for clinical factors, surgeons with more years in practice were more likely to choose PC over C → LR (OR 1.94) (P = 0.005). Surgical oncology-trained surgeons were more likely than hepatobiliary/transplant-trained surgeons to choose C â†’ LR (OR 2.53) or PC (OR 4.15) (P < 0.001). CONCLUSIONS: This is the first nationwide study to define the relative impact of key clinical factors on choice of therapy for CLM. Although clinical factors influence choice of therapy, surgical subspeciality and physician experience are also important determinants of care.

Neuroendocrine tumor liver metastases treated with yttrium-90 radioembolization.

OBJECTIVE: Yttrium-90 (Y-90) radioembolization is an emerging treatment option for unresectable neuroendocrine liver metastases (NELM). However, the data regarding this treatment are currently limited. This study evaluates the efficacy and tolerability of Y-90 radioembolization and identifies prognostic factors for radiographic response and survival. METHODS AND MATERIALS: Thirty-eight patients underwent Y-90 radioembolization for NELM at our institution between April 2004 and February 2012. Patients were assessed radiographically (RECIST criteria, enhancement), serologically, and clinically at 1month, and then at every 3months after treatment for tumor response, toxicity, and survival outcomes. RESULTS: Median length of follow-up was 17.0months (IQR, 9.0-37.0). Median survival was 29.2months. Three patients (9%) had a radiographic complete response to treatment, 6 (17%) had a partial response, 21 (60%) had stable disease, and 5 (14%) developed progressive disease. Two factors were significantly associated with a good radiographic response (complete/partial response): islet cell histological subtype (p=0.043) and hepatic tumor burden ≥33% (p=0.031). Multivariate analysis revealed that patients requiring multiple Y-90 treatments (HR 2.9, p=0.035) and patients who had previously failed systemic therapy with octreotide/chemotherapy (HR 4.4, p=0.012) had worse survival. Grade 3 serologic toxicity was observed in 2 patients (5%; hyperbilirubinemia, elevated alkaline phosphatase) after treatment. Grade 3 non-serologic toxicities included abdominal pain (11%), fatigue (11%), nausea/vomiting (5%), ascites (5%), dyspnea (3%), diarrhea (3%), and peripheral edema (3%). No grade 4 or 5 toxicity was reported. CONCLUSIONS: Y-90 radioembolization is a promising treatment option for inoperable NELM and is associated with low rates of grade≥3 toxicity.

Hilar cholangiocarcinoma: diagnosis, treatment options, and management.

Hilar cholangiocarcinoma (HC) is a rare disease with a poor prognosis which typically presents in the 6(th) decade of life. Of the 3,000 cases seen annually in the United States, less than one half of these tumors are resectable. A variety of risk factors have been associated with HC, most notably primary sclerosing cholangitis (PSC), biliary stone disease and parasitic liver disease. Patients typically present with abdominal pain, pruritis, weight loss, and jaundice. Computed topography (CT), magnetic resonance imaging (MRI), and ultrasound (US) are used to characterize biliary lesions. Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) assess local ductal extent of the tumor while allowing for therapeutic biliary drainage. MRCP has demonstrated similar efficacies to PTC and ERCP in identifying anatomic extension of tumors with less complications. Treatment consists of surgery, radiation, chemotherapy and photodynamic therapy. Biliary drainage of the future liver remnant should be performed to decrease bilirubin levels thereby facilitating future liver hypertrophy. Standard therapy consists of surgical margin-negative (R0) resection with extrahepatic bile duct resection, hepatectomy and en bloc lymphadenectomy. Local resection should not be undertaken. Lymph node invasion, tumor grade and negative margins are important prognostic indicators. In instances where curative resection is not possible, liver transplantation has demonstrated acceptable outcomes in highly selected patients. Despite the limited data, chemotherapy is indicated for patients with unresectable tumors and adequate functional status. Five-year survival after surgical resection of HC ranges from 10% to 40% however, recurrence can be as high as 50-70% even after R0 resection. Due to the complexity of this disease, a multi-disciplinary approach with multimodal treatment is recommended for this complex disease.

Trends and patterns of utilization in post-treatment surveillance imaging among patients treated for hepatocellular carcinoma.

BACKGROUND: Little is known about the patterns of utilization of surveillance imaging after treatment of hepatocellular carcinoma (HCC). We sought to define population-based patterns of surveillance and investigate if intensity of surveillance impacted outcome following HCC treatment. METHODS: The Surveillance, Epidemiology, and End Results-Medicare database was used to identify patients with HCC diagnosed between 1998 and 2007 who underwent resection, ablation, or intra-arterial therapy (IAT). The association between imaging frequency and long-term survival was analyzed. RESULTS: Of the 1,467 patients, most underwent ablation only (41.5%), while fewer underwent liver resection only (29.6 %) or IAT only (18.3%). Most patients had at least one CT scan (92.7%) during follow-up, while fewer had an MRI (34.1%). A temporal trend was noted with more frequent surveillance imaging obtained in post-treatment year 1 (2.5 scans/year) vs. year 5 (0.9 scans/year; P = 0.01); 34.5% of alive patients had no imaging after 2 years. Frequency of surveillance imaging correlated with procedure type (total number of scans/5 years, resection, 4.7; ablation, 4.9; IAT, 3.7; P < 0.001). Frequency of surveillance imaging was not associated with a survival benefit (three to four scans/year, 49.5 months vs. two scans/year, 71.7 months vs. one scan/year, 67.6 months; P = 0.01) CONCLUSION: Marked heterogeneity exists in how often surveillance imaging is obtained following treatment of HCC. Higher intensity imaging does not confer a survival benefit.

Impact of sarcopenia on outcomes following intra-arterial therapy of hepatic malignancies.

BACKGROUND: Assessment of patient performance status is often subjective. Sarcopenia--measurement of muscle wasting--may be a more objective means to assess performance status and therefore mortality risk following intra-arterial therapy (IAT). METHODS: Total psoas area (TPA) was measured on cross-sectional imaging in 216 patients undergoing IAT of hepatic malignancies between 2002 and 2012. Sarcopenia was defined as TPA in the lowest sex-specific quartile. Impact of sarcopenia was assessed relative to other clinicopathological factors. RESULTS: Indications for IAT included hepatocellular carcinoma (51 %), intrahepatic cholangiocarcinoma (13 %), colorectal liver metastasis (7 %), or other metastatic disease (30 %). Median TPA among men (568 mm(2)/m(2)) was greater than women (413 mm(2)/m(2)). IAT involved conventional chemoembolization (54 %), drug-eluting beads (40 %), or yttrium-90 (6 %). Median tumor size was 5.8 cm; most patients had multiple lesions (74 %). Ninety-day mortality was 9.3 %; 3-year survival was 39 %. Factors associated with risk of death were tumor size (HR = 1.84) and Child's score (HR = 2.15) (all P < 0.05). On multivariate analysis, sarcopenia remained independently associated with increased risk of death (lowest vs. highest TPA quartile, HR = 1.84; P = 0.04). Sarcopenic patients had a 3-year survival of 28 vs. 44 % for non-sarcopenic patients. CONCLUSIONS: Sarcopenia was an independent predictor of mortality following IAT with sarcopenic patients having a twofold increased risk of death. Sarcopenia is an objective measure of frailty that can help clinical decision-making regarding IAT for hepatic malignancies.

Clinicopathologic characteristics and survival outcomes of patients with fibrolamellar carcinoma: data from the fibrolamellar carcinoma consortium.

BACKGROUND: Fibrolamellar carcinoma is a rare and poorly understood malignancy that affects the young in the absence of underlying liver disease. Despite reported small review series, the literature lacks large retrospective studies that may help in understanding this disease. METHODS: Medical record review was undertaken for all patients histopathologically diagnosed with fibrolamellar carcinoma, seen at Memorial Sloan-Kettering Cancer Center, the University of California San Francisco, and Johns Hopkins Hospital from 1986 to 2011. Demographic, clinical, pathologic, and treatment data were recorded. Overall survival was estimated by using Kaplan-Meier methods. The impact of different clinicopathologic variables on survival was assessed with Cox regression models. RESULTS: Ninety-five patients were identified. Median age was 22 years, 86% were Caucasian, and 50% presented with stage IV disease. There were more females than males (58% vs. 42%). Seventy-seven percent of the patients underwent surgical resection and/or liver transplantation; of these 31.5% received perioperative therapy. Patients with unresectable disease, including 8 patients treated in clinical trials, were treated with chemotherapy, occasionally given with interferon or biologic agents. Ten patients received sorafenib, and 7 received best supportive care. Median survival was 6.7 years. Factors significantly associated with poor survival were female sex, advanced stage, lymph node metastases, macrovascular invasion, and unresectable disease. CONCLUSIONS: The clinicopathologic characteristics and survival outcomes from this dataset are consistent with those reported in the literature. Surgical resection and disease extent were confirmed as important predictors of survival. The possibility of a negative association between female sex and prognosis could represent a clue as to future therapeutic strategies.

Multidisciplinary management of recurrent hepatocellular carcinoma following liver transplantation.

INTRODUCTION: Tumor recurrence remains a main limitation to the long-term survival of patients following liver transplantation for hepatocellular carcinoma (HCC). While the majority of patients recur in the first two years after transplantation, late recurrence is not infrequent. DISCUSSION: Most common sites of recurrence in order of decreasing frequency are liver graft, lung, bone, abdominal lymph nodes, adrenal glands and peritoneum. Reported five-year survival after surgical resection ranges from 27-88%. Few patients, however, are candidates for surgical resection. Other therapeutic options for recurrent HCC include systemic therapy, intra-arterial therapy, or radiation therapy. Although systemic molecular targeted therapy is generally tolerated with very few interactions with immunosuppressive medications, there is only modest success regarding prolongation of survival. Utilization of radiation therapy for extrahepatic recurrences similarly has minimal impact on overall survival, but may effectively in palliate symptoms. While late recurrence is associated with a more favorable prognosis than early recurrences, prognosis is still poor. CONCLUSION: Late recurrence of HCC following transplantation should be borne in mind even after many years from transplant. Surgical salvage, when feasible, remains a viable treatment option in select patients with a chance for long-term survival. A multi-disciplinary approach is critical as different therapeutic modalities have a role in treating recurrent HCC following transplant.

PIK3CA mutations and EGFR overexpression predict for lithium sensitivity in human breast epithelial cells.

A high frequency of somatic mutations has been found in breast cancers within the gene encoding the catalytic p110α subunit of PI3K, PIK3CA. Using isogenic human breast epithelial cells, we have previously demonstrated that oncogenic PIK3CA "hotspot" mutations predict for response to the toxic effects of lithium. However, other somatic genetic alterations occur within this pathway in breast cancers, and it is possible that these changes may also predict for lithium sensitivity. We overexpressed the epidermal growth factor receptor (EGFR) into the non-tumorigenic human breast epithelial cell line MCF-10A, and compared these cells to isogenic cell lines previously created via somatic cell gene targeting to model Pten loss, PIK3CA mutations, and the invariant AKT1 mutation, E17K. EGFR overexpressing clones were capable of cellular proliferation in the absence of EGF and were sensitive to lithium similar to the results previously seen with cells harboring PIK3CA mutations. In contrast, AKT1 E17K cells and PTEN -/- cells displayed resistance or partial sensitivity to lithium, respectively. Western blot analysis demonstrated that lithium sensitivity correlated with significant decreases in both PI3K and MAPK signaling that were observed only in EGFR overexpressing and mutant PIK3CA cell lines. These studies demonstrate that EGFR overexpression and PIK3CA mutations are predictors of response to lithium, whereas Pten loss and AKT1 E17K mutations do not predict for lithium sensitivity. Our findings may have important implications for the use of these genetic lesions in breast cancer patients as predictive markers of response to emerging PI3K pathway inhibitors.

The PIK3CA gene as a mutated target for cancer therapy.

The development of targeted therapies with true specificity for cancer relies upon exploiting differences between cancerous and normal cells. Genetic and genomic alterations including somatic mutations, translocations, and amplifications have served as recent examples of how such differences can be exploited as effective drug targets. Small molecule inhibitors and monoclonal antibodies directed against the protein products of these genetic anomalies have led to cancer therapies with high specificity and relatively low toxicity. Recently, our group and others have demonstrated that somatic mutations in the PIK3CA gene occur at high frequency in breast and other cancers. Moreover, the majority of mutations occur at three hotspots, making these ideal targets for therapeutic development. Here we review the literature on PIK3CA mutations in cancer, as well as existing data on PIK3CA inhibitors and inhibitors of downstream effectors for potential use as targeted cancer therapeutics.