Thursday, January 17, 2013

REVIEW ARTICLE

mTOR Inhibitors in the Treatment of Breast Cancer

By Shaveta Vinayak, MD, MS¹, Robert W. Carlson, MD¹ | January 15, 2013

¹Department of Medicine, Stanford University School of Medicine, Stanford, California

ABSTRACT: The phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway is commonly dysregulated in breast cancer. In preclinical studies, hyperactivation of the PI3K pathway has been linked to resistance to both endocrine therapy and trastuzumab(Drug information on trastuzumab) (Herceptin). Rapalogs, agents that primarily inhibit mTOR-raptor complex 1, have been studied in combination with endocrine therapy to overcome endocrine resistance. Trials of combination endocrine therapy and rapalogs in metastatic hormone receptor–positive breast cancer have demonstrated variable results. However, two independent trials have recently shown that combination everolimus (Afinitor) and tamoxifen(Drug information on tamoxifen) or combination everolimus and exemestane(Drug information on exemestane) (Aromasin) is more effective than either endocrine agent alone. These trials selected patients with cancer refractory to endocrine therapy, which may be important in sensitizing tumors to inhibition of this pathway. In human epidermal growth factor receptor 2 (HER2)-positive breast cancer, the early clinical data with combinations of PI3K/mTOR inhibitors and anti-HER2 therapies are encouraging. Efforts to identify clinical biomarkers of response or resistance to mTOR inhibitors are ongoing. This review will summarize results of preclinical and clinical studies as well as ongoing clinical trials with mTOR or dual PI3K/mTOR inhibitors.

Introduction

The mTOR pathway

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway, of which mammalian target of rapamycin (mTOR) protein is an important component, is commonly dysregulated in cancer. TOR protein, a highly conserved serine/ threonine protein kinase, was first identified in 1991 through yeast studies examining the mechanism of rapamycin.[1] Complex regulatory mechanisms of the mTOR signaling pathway have been elucidated. These mechanisms have been important in the development of mTOR inhibitors for treatment of cancer and also in identifying predictors of response or resistance.

mTOR controls various cellular processes, including growth, survival, and autophagy. It receives input from upstream growth factor receptors, such as the PI3K pathway, and senses nutrient availability; its central role is in integrating these signals and altering cellular processes. Based on nutrient availability, the mTOR pathway can either promote cell growth or it can inhibit growth during the nutrient deprivation state.[2] Autophagy, a catabolic process involved in eradicating damaged cellular material, is under the delicate control of the mTOR pathway. It is utilized as an adaptive rescue mechanism for starving cells to conserve energy and is highly dependent on nutrient availability.[3]
The mTOR pathway also receives input from the adenosine(Drug information on adenosine) monophosphate–activated protein kinase (AMPK) pathway. The AMPK pathway senses cellular energy and negatively regulates the mTOR pathway through the tuberin (TSC1)/hamartin (TSC2) complex. When energy stores are low, AMPK and TSC2 are activated, thereby inhibiting the mTOR pathway. An additional negative regulator of mTOR is phosphatase and tensin homolog (PTEN), which also tightly regulates the PI3K pathway.[4] There are two distinct complexes of mTOR—mTORC1 and mTORC2—which have independent regulatory mechanisms and exert their cellular growth effects through different downstream targets. Activated mTOR-raptor complex 1 (mTORC1) results in enhanced protein synthesis and also inhibits PI3K signaling. Activated mTOR-rictor complex 2 (mTORC2) promotes cell survival.[4]

PI3K/mTOR signaling in breast cancer

Activating PI3K mutations are frequent in human cancers and have been identified as oncogenic, making this pathway an attractive therapeutic target in cancer.[5] These mutations can occur in any component of the PI3K pathway, resulting in its dysregulation; a number of mechanisms, including mutations, methylation, and loss of heterozygosity, may be involved. PIK3CA (p110 catalytic subunit alpha) mutations have been identified as a common occurrence in breast cancer,[6] with a higher frequency in the estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-positive subtypes than in triple-negative breast cancer (TNBC).[7] Studies have confirmed that the PIK3CA gene is among the most highly mutated genes in breast cancer: mutations occur at a frequency of 27% to 36%.[8,9] One such study evaluated the mutational spectrum of PIK3CA by breast cancer subtype,[8] determined by gene expression profiling.[10,11] The PIK3CA somatic mutation spectrum differed both by the frequency of mutation and by the type of PIK3CA mutation seen in each subtype. The luminal A subtype of breast cancer had the highest frequency of PIK3CA mutation (45%), and the basal subtype had the lowest (9%). These data are consistent with the results of prior studies, as luminal A and basal-like subtypes roughly correspond to ER-positive and triple-negative breast cancer by immunohistochemistry (IHC), respectively. Even though PIK3CA mutations are oncogenic, they are a good prognostic factor and are associated with improved survival.[12] This is important to consider when assessing patient survival in trials in patients with PIK3CA mutations.
Additional PI3K pathway alterations in breast cancer include Akt and PTEN mutations, or loss of PTEN protein.[7,13] Activation of the PI3K pathway in breast cancer can occur via a PI3K pathway component aberration or through activation of another crosstalk pathway. Beyond identifying PI3K pathway mutations for understanding breast cancer biology, there are important considerations when this information is used for patient selection for treatment. The specific PI3K mutations and the altered components of the PI3K pathway may both impact treatment response.

Development of mTOR inhibitors in cancer

Rapamycin, a macrolide, was first isolated from a soil sample on Easter Island (Rapa Nui) in 1975, and was shown to have antifungal properties.[14] It was initially used clinically as an immune suppressant to prevent allograft rejection in renal transplant patients. Sirolimus(Drug information on sirolimus) (Rapamune), a rapamycin analog (rapalog), has been shown to inhibit the growth of cancer cell lines and xenografts from different tumor subtypes.[15,16] The first generation of mTOR inhibitors target mTORC1, but they do not bind to mTORC2, which is mostly considered to be rapamycin-insensitive.[2] However, there are limited data that rapamycin reduces mTORC2 levels and inhibits Akt activation.[17] Targeting only mTORC1 with rapalogs leads to increased signaling through upstream receptor tyrosine kinases and increased Akt activation, which promotes cell survival. It has been speculated that rapalogs have had limited clinical activity in cancer due to this mechanism, as well as activation of parallel signaling pathways. This limitation of rapalogs has fueled development of alternate methods of targeting the PI3K signaling pathway, with either adenosine triphosphate (ATP)-competitive mTOR inhibitors that target both mTORC1 and mTORC2, or by using dual PI3K/mTOR inhibitors. Several mTORC1 inhibitors are in clinical trials for various tumor subtypes, including everolimus (Afinitor), temsirolimus (Torisel), and ridaforolimus (AP23573). Temsirolimus was the first rapalog approved by the US Food and Drug Administration (FDA); it was approved in 2007 for the treatment of advanced renal cell cancer.
In breast cancer, the majority of studies have exploited the use of mTORC1 inhibitors in ER-positive or HER2-positive breast cancers, primarily to reverse treatment resistance. The focus of this review will be these preclinical and clinical studies by breast cancer subtype. We will also discuss ongoing breast cancer clinical studies using ATP-competitive mTOR inhibitors, which target mTORC1/mTORC2, and dual PI3K/mTOR inhibitors.

Hormone Receptor–Positive Breast Cancer

Preclinical studies

Preclinical studies, using hormone receptor (HR)-positive cell lines, have demonstrated activation of the PI3K/mTOR pathway after long-term estrogen deprivation.[18,19] Based on these studies, it appeared that estrogen-deprived cells relied heavily on the PI3K signaling pathway, making this an important mechanism of acquired endocrine resistance. This suggested that priming of the PI3K pathway with anti-hormonal treatment might be important in sensitizing these cells to PI3K/mTOR inhibitors. A natural next step was to use combination therapy, simultaneously targeting both the ER and PI3K pathways. Early combination studies showed that rapalogs were synergistic with anti-estrogens, including tamoxifen and letrozole(Drug information on letrozole) (Femara); blocking both pathways not only enhanced antitumor activity but also reversed endocrine therapy resistance related to PI3K signaling.[20-22] Moreover, high Akt activity has also been shown to contribute to resistance to endocrine therapy,[23] and this also can be reversed by rapalogs.[20,22]

Clinical studies

Metastatic setting. Almost all patients with HR-positive breast cancer treated with endocrine therapy develop tumor resistance to treatment. Preclinical data, as described earlier, implicate the PI3K/mTOR pathway in acquired resistance to endocrine therapy, and synergistic preclinical anti-tumor activity has been seen with the combination of rapalogs and anti-estrogens. Based on this biological rationale, clinical trials have combined mTORC1 inhibitors and endocrine therapy in HR-positive breast cancer. Initial studies with temsirolimus and everolimus as single agents in the metastatic setting demonstrated response rates of 9% to 12%.[24,25] Another study with temsirolimus alone was limited to HR-positive or HER2-positive metastatic breast cancer, to enrich it for PIK3CA mutations.[26] Clinical activity was again limited. Primary tumors from this study were analyzed for PIK3CA mutations and PTEN expression by IHC, but no association was seen with clinical response.[26] A limitation of this study is that the PIK3CA mutation status of primary tumors was analyzed, as opposed to the metastatic site, which can be discordant.[27]
The next approach was to combine anti-estrogens and mTORC1 inhibitors in clinical trials. A randomized phase II study of HR-positive metastatic breast cancer tested combination letrozole and temsirolimus vs letrozole alone and found that patients who received combination therapy had superior median progression-free survival (PFS) (13.2 vs 11.6 months). However, the clinical benefit rate (CBR) and the objective response rate (ORR) for patients in the combination arm were not significantly different from the rates in patients who received letrozole alone.[28] Given these somewhat encouraging results, a large randomized phase III trial (N = 1112) was conducted in postmenopausal women with metastatic disease, with letrozole either alone or in combination with temsirolimus as first-line endocrine therapy. The trial was terminated early due to lack of benefit.[29] It has been speculated that this trial failed since it limited the use of mTOR inhibition in combination with endocrine therapy to the first-line metastatic setting. Given lack of prior hormonal therapy exposure, the tumors might not have been dependent on the PI3K/mTOR pathway, thereby remaining insensitive to mTOR pathway inhibition. This highlights the need for identification and selection of patients, whose tumors are dependent on PI3K pathway activation.
The Tamoxifen Plus Everolimus (TAMRAD) study (N = 111) randomized patients with prior exposure to an aromatase inhibitor (AI) in the metastatic setting, to tamoxifen alone versus combination tamoxifen and everolimus.[30] This study demonstrated improvement in CBR (42% vs 61%; P = .045), the primary endpoint, and in time to progression (TTP) (4.5 vs 8.6 months; hazard ratio [HR] = 0.54; 95% confidence interval [CI], 0.36–0.81; P = .002) favoring the combination treatment. This supports that prior endocrine therapy resulting in priming of the PI3K/mTOR pathway may allow for meaningful synergy through attempts to overcome acquired endocrine resistance. In an exploratory analysis, patients were stratified based on primary hormone resistance, defined as relapse during adjuvant AI therapy or progression within 6 months of AI treatment in the metastatic setting, or secondary hormone resistance, defined as late relapse or progression on an AI in the metastatic setting more than 6 months after treatment. A higher CBR (48% vs 74% [secondary]; 36% vs 46% [primary]) and increased TTP (5.5 vs 14.8 months; HR = 0.46; 95% CI, 0.26–0.83; P = .009 [secondary]; 3.8 vs 5.4 months; HR = 0.70; 95% CI, 0.40–1.21; P = nonsignificant [primary]) was predominantly observed in patients with secondary hormone resistance in the everolimus arm.[30]
A phase III trial, Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2), enrolled 724 patients with HR-positive advanced breast cancer to assess the efficacy of everolimus (at a dose of 10 mg per day) and exemestane (Aromasin), in patients with disease refractory to nonsteroidal AIs, including letrozole or anastrozole(Drug information on anastrozole) (Arimidex).[31] An improved median PFS was observed by both local and central assessment with the combination of exemestane and everolimus (2.8 vs 6.9 months; HR = 0.43; 95% CI, 0.35–0.54; P < .001 [local]; 4.1 vs 10.6 months; HR = 0.36; 95% CI, 0.27–0.47; P < .001 [central]). Overall survival results have not been reported. A total of 23% of patients receiving everolimus had serious adverse events compared with 12% receiving placebo, resulting in everolimus discontinuation in 19% of the combination group vs 4% in the placebo group. The most common grade 3 or 4 events with combination therapy were stomatitis, anemia, hyperglycemia, dyspnea, fatigue, and pneumonitis. Notably, there were seven deaths attributed to adverse events (1%) in the everolimus arm; these were due to sepsis, pneumonia, tumor hemorrhage, cerebrovascular incident, renal failure, and suicide.[31]

TABLE

Ongoing Clinical Trials of mTOR Inhibitors for Breast Cancer Treatment

Forthcoming trials are assessing the role of mTORC1 and dual PI3K/mTOR inhibitors in combination with other anti-hormonal therapies and even chemotherapies, in various lines of metastatic disease (Table).
In summary, trials of combination endocrine therapy and mTORC1 inhibitors in metastatic HR-positive breast cancer have demonstrated variable results. Single-agent temsirolimus or everolimus has limited clinical activity in metastastic breast cancer. A large study that combined temsirolimus with letrozole vs letrozole alone in first-line hormonal therapy for metastatic disease found no benefit from the combination. Two trials have found that combination everolimus and tamoxifen (TAMRAD study) or combination everolimus and exemestane (BOLERO-2) is more effective than either endocrine agent alone. The variability among the reported studies may be related to patient selection, prior endocrine therapy exposure, and the specific drug combination being tested. It is noteworthy that both of the positive studies selected patients who were previously exposed to endocrine therapy in the metastatic setting. Thus, prior endocrine therapy exposure may be an important factor in priming the PI3K/mTOR pathway and thereby sensitizing the tumors to inhibition of this pathway.
Adjuvant/neoadjuvant setting. Everolimus was studied as a single agent in a neoadjuvant trial and was associated with a significant reduction in Ki67 after 14 days of therapy.[32] A neoadjuvant, randomized study in postmenopausal women (N = 270) with ER-positive breast cancer compared letrozole and everolimus vs letrozole and placebo.[33] There was an improved clinical response rate and decreased proliferation in the everolimus-plus-letrozole arm compared with letrozole alone. Response was seen in both wild-type and mutant PI3K tumors. In addition, a reduction in phospho-S6, a pharmacodynamic marker, was noted in post-treatment biopsies in the everolimus-containing arm, signifying that mTOR was being inhibited at the dose used.[33]
In the adjuvant setting, a phase III randomized trial is evaluating the role of combining everolimus with standard adjuvant endocrine therapy, for women with high-risk breast cancer (Table).
Based upon the available data, there is no standard role for adjuvant or neoadjuvant use of mTOR or dual PI3K/mTOR inhibitors in combination with endocrine therapy or chemotherapy.

The future is on the move!

UTEP - The University of Texas at El Paso

The UTEP School of Nursing welcomed its largest class ever in the Master of Science in Nursing (MSN) program this week. Ninety-three students from across the United States and five countries enrolled in the online master’s degree program this spring semester. More than 70 MSN students attended orientation in the Health Sciences and Nursing Building on Wednesday and Thursday.
Photo by Laura Trejo, UTEP News Service.

Learning to Swim in the Pool of Genetic Data

Mark G. Kris, MD

Drug & Reference Information

I am Dr. Mark Kris from Memorial Sloan-Kettering Cancer Center, recapping discussions from a regional meeting of oncologists here in the Greater New York area.
I talked earlier about the importance of collaborating and working closely with your pathology department. The next important issue, and a change in practice over the last few years, is the use of molecular testing. If you go to the National Comprehensive Cancer Network (NCCN) guidelines, immediately after you make that accurate histologic diagnosis, there are specifications for molecular diagnostic testing.
Today we routinely test for epidermal growth factor receptor (EGFR) and rearrangements in the anaplastic lymphoma kinase (ALK) chain, but each passing month finds more and more targets. We are going to be testing for more targets. Technology has really helped us. It has allowed so-called "multiplex testing." Think of obtaining the complete blood count. The truth is, I don't think it's possible to order a white blood cell count or a platelet count. In ordering one of those tests, you get all the other ones with it. It is very efficient and has increased accuracy in doing these tests together in a multiplex fashion, and it's the same with these molecular tests as well.
I think that testing will increasingly become multiplexed. I also have to urge that the testing be done at the time of diagnosis. We know from our oncology training that the most critical regimen that we prescribe is the first one. Making the best recommendation and giving the most precise regimen makes the most sense. We need to do it at diagnosis, and we need to do it for all the different targets that we have.
Multiplex testing is definitely the way to go. I think that, more and more, pathology departments are doing these tests in parallel. It saves tissue resources. All the molecular tests can basically be done on one DNA specimen. Also, our patients cannot wait for us to do one test after another. We need to be very, very efficient.
This explosion in the ability to test and the number of test results that we receive is also another great change in our practice. I think it is fair to say that our testing capabilities now and in the years to come will clearly exceed our comfort level, and it will also exceed the clinical trial data we need to process the results. I think that individual oncologists are going to be given information that is not put in any sort of context, and we have to make the best decisions that we can.
When one of these multiplex test results comes to you -- 200 genes -- you can easily start with the critical genes; for example, EGFR and ALK. But then, as you find other ones, it is important to speak to your colleagues, look at the literature, and try to use that material as best as you can.
Frankly, I think we all have to be comfortable with being uncomfortable. We are going to have more data than we have ever had before. The data arriving on our desk are going to exceed our literature base to analyze them, and we are going to have to seek all the information we can to make the best decisions for our patients.
Where it is clear how to use the data -- ALK rearrangement, for example -- that's easy. But as other pieces of information come through, we are going to have to work hard together to make the best decisions and to try to marshal our resources as best as we can.

POLYUBIQUITINATION

The rise of the role of antiproteasome in the treatment of hematologic malignancies such Multiple Myeloma
requires us to stop a bit and reflect on the basic role of proteasomes which is to destroy used proteins. To be recognized as old proteins ready for destruction, the protein is Ubiquitinated and ready for disposal. The anti-proteasomes in effect block this plan. And sure enough, Ubiquitinated proteins stay alive longer and guess what, it is an ubiquitinated proteins that seems to contribute to the negative effect on Modulators of pathways. Ubiquitinated proteins forms stops transcriptions factors at check points, block the NF-kB, and drives the effects of Antiproteasomes.
Can a simple infusion of ubiquitinated TNF blocks its effects, can we start just ubiquitinating growth factors and infuse them to stop infectious process or cancer growth? Remember, DRIVER Pathways are driven most of the time by regulators who seems to have a negative feedback from UBIQUITINATED specific pathway proteins in general terms (rare exception will exist)! What do you think? Can a polyubiquitinated growth factor still stimulate effectively its receptor or will it dampen the stimulation and slow the devastating effect of say, TNF?

New Meta-Analysis on Sugar Sparks Old Debate

Lisa Nainggolan

Jan 16, 2013

DUNEDIN, New Zealand — Cutting consumption of sugar produces a small but significant reduction in body weight for adults, a new meta-analysis concludes [1]. The study found less consistent evidence for this effect in children, but this is likely because the kids in the included trials did not tend to comply with advice to reduce intake of sugar-sweetened foods and drinks, say Dr Lisa Te Morenga (University of Otago, Dunedin, New Zealand) and colleagues in their paper published online January 15, 2013 in BMJ.
The review is accompanied by an editorial [2] by Dr Walter C Willett (Harvard School of Public Health, Boston, MA) and Dr David S Ludwig (New Balance Foundation Obesity Prevention Center, Boston Children's Hospital, MA), which concludes that the tide is beginning to turn against sugar, with evidence continuing to accumulate that it is indeed deleterious to health.

Sugar is not the only issue; there is the bigger problem of carbohydrate quality. Large amounts of refined carbohydrates are also a problem.

"It's clear that sugar does have adverse effects, particularly in liquid form as sugar-sweetened drinks," Willett told heartwire . "This study addresses a piece of the picture, the effect on weight gain. There is also a strong body of evidence showing that sugar-sweetened beverages are related to type 2 diabetes. And sugar is not the only issue; there is the bigger problem of carbohydrate quality. Large amounts of refined carbohydrates are also a problem," he added.
This meta-analysis "and other evidence in the broader literature suggest that sugar intake should be limited," say Willett and Ludwig. But the question remains as to what is a desirable limit, they note. Current intake of added sugar in the US and UK is about 15% of total energy, so the 2003 World Health Organization (WHO) aim of limiting intake to 10% "could be viewed as a realistic and practical goal." However, the American Heart Association (AHA) suggests a limit of 5% of energy, "which would be more consistent with a goal for optimal health," they point out.
Refined Carbohydrates Just as Detrimental, Say Editorialists
Willett and Ludwig note that the meta-analysis by Te Morenga et al was commissioned by the WHO, which is in the process of updating its recommendations on intake of dietary sugars. The meta-analysis shows that exchanging dietary sugars with other carbohydrates made no difference to the changes in body weight that they saw, indicating that highly processed carbohydrates are just as detrimental as sugar, say the editorialists.
"Unfortunately, the 2003 WHO report disregarded evidence suggesting that refined grain and potato products have metabolic effects comparable to those of sugar," they note.
Actions are needed at many levels, Willett and Ludwig state. Efforts to reduce sugar intake "are appropriate" but "should form part of a broader effort to improve the quality of carbohydrates." This should include educational programs, improvements in foods and drinks provided in schools and work sites, and supplemental nutrition programs for people with low incomes.
"This is analogous to what we see for fats in that the type of fat you consume is really important. A similar picture is emerging for carbohydrates; quality turns out to be really important," Willett commented. "Another nuance," he says, "is the way we consume things, because that affects the physiologic response." For example, eating a whole fruit is much preferable to drinking fruit juice, he notes. "The sugar in fruits is balanced out by the fiber and other nutrients, and it takes time to be released. When we eat a whole apple or orange, we limit our intake. If you are drinking fruit juice, you might have three or four servings, but you would almost never eat three apples or oranges in a row."
Reducing the amount of sugar consumed in drinks "deserves special attention because of the strength of evidence and the ease with which excessive sugar is consumed in this form," he and Ludwig state. Policy approaches--such as imposing tax on sodas--are "useful," as are restrictions on advertising to children and limits on serving sizes, as have been tried in New York.

This is a global issue, with Coke and Pepsi pushing very hard, and the implications are horrendous.

"Sugar-sweetened beverages are such a big part of the picture," Willett commented to heartwire . "The average consumption among low-income groups in the US is about three servings a day; it's huge. And this is a global issue, with Coke and Pepsi pushing very hard, and the implications are horrendous."
The AHA agrees, showcasing in its top 10 advances of 2012 studies that illustrated the effect of sugar-sweetened beverages on body weight in children.
Willett says physicians and other healthcare providers have an important role to play "by routinely asking about consumption of sugar-sweetened drinks as well as tobacco and alcohol use" and by assuming leadership in public-health efforts to limit sugar as a source of harm.
Advice to Cut Sugar Intake Important for Obesity Reduction Strategies
In their meta-analysis, Te Morenga and colleagues included the results of 30 randomized controlled trials and 38 cohort studies of dietary sugar intake and adiposity. Free sugars were defined as sugars that are added to foods by the manufacturer, cook, or consumer, plus those naturally present in honey, syrups, and fruit juices.

Healthcare providers could play an important role by routinely asking about consumption of sugar-sweetened drinks as well as tobacco and alcohol use.

In trials of adults with at-will--no strict control of food intake--diets, reduced intake of dietary sugars was associated with a small decrease in body weight (0.80 kg; p<0.001). Conversely, increased sugar intake was associated with a comparable weight increase (0.75 kg; p=0.001). Isoenergetic exchange of dietary sugars with other carbohydrates showed no change in body weight.
Trials in children showed no overall change in body weight. But in relation to intake of sodas, after one-year follow-up in prospective studies, the odds ratio for being overweight or obese was 1.55 among the groups with the highest intake compared with those with the lowest intake, they note.
"It seems reasonable to conclude that advice relating to sugars is a relevant component of a strategy to reduce the high risk of overweight and obesity in most countries," the New Zealand group concludes.
Te Morenga et al have no conflicts of interest, nor do Willett and Ludwid.

References

.FROM MEDSCAPE

Wednesday, January 16, 2013

FDA Approval for Ixabepilone

Brand name: Ixempra™ (this is old news)

Approved for breast cancer

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions, and contraindications.
On October 16, 2007, the U.S. Food and Drug Administration (FDA) approved ixabepilone for injection (Ixempra™, made by Bristol-Myers Squibb) for the following two indications:

Ixabepilone is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated.
Ixabepilone is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.

A randomized, multinational, open-label trial of 752 patients with locally advanced or metastatic breast cancer evaluated the efficacy and safety of ixabepilone (40 mg/m2 IV once every three weeks) plus capecitabine compared to therapy with capecitabine alone. Patients had previously received an anthracycline and a taxane, had evidence of disease progression or resistance, or, in the case of the anthracycline, received a minimum required cumulative dose.
Treatment arms were balanced with regards to prior therapies, disease sites, hormone receptor status and HER2 expression. Patients receiving combination therapy had a statistically significant improvement in progression-free survival (PFS), defined as radiologic progression or death from any cause (hazard ratio 0.69, p<0.0001). The median PFS was 5.7 months in the combination arm and 4.1 months in the capecitabine alone arm. Patients in the combination arm also had an increased objective tumor response rate. Survival data for this trial are not yet mature.
Ixabepilone monotherapy was evaluated in a single arm trial of 126 patients with metastatic or locally advanced breast cancer who had previously received an anthracycline, a taxane and capecitabine, and who had disease progression or, in the case of the anthracycline, received a minimum required cumulative dose. Ixabepilone was administered at the same dose and schedule as in the combination trial. The objective response rate based on independent radiologic review was 12.4 percent (95 percent CI: 6.9, 19.9). The objective response rate based on investigator assessments was 18.3 percent (95 percent CI: 11.9, 26.1). The median response duration was 6.0 months (95 percent CI: 5.0, 7.6).
Treatment with ixabepilone caused new or worsening peripheral neuropathy in approximately 65 percent of patients treated. Grade 3 or 4 peripheral neuropathy occurred in 23 percent of patients treated with ixabepilone and capecitabine, with no grade 3 or 4 peripheral neuropathy reported in the capecitabine arm. In the ixabepilone monotherapy trial, 14 percent experienced grade 3 or 4 peripheral neuropathy. Neuropathy was generally reversible to grade 1 or better with cessation of therapy.
Ixabepilone in combination with capecitabine resulted in a 68 percent incidence of grade 3 or 4 neutropenia compared to 11 percent with capecitabine alone. Twelve patients receiving ixabepilone in combination with capecitabine died from complications arising from neutropenia.
The incidence of neutropenia related deaths was higher in patients with baseline moderate or severe hepatic impairment when treated with both ixabepilone and capecitabine. This combination should not be used in patients with moderate or severe hepatic impairment. When used as monotherapy, 54 percent of patients treated with ixabepilone experienced grade 3 or 4 neutropenia.
Other commonly observed toxicities (>20 percent) included anemia, leukopenia, thrombocytopenia, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The following additional reactions occurred in ≥20 percent in the combination treatment arm: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation.

This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Understanding the Approval Process for New Cancer Treatments.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.
=====================================================from FDA pages.
Ixabepilone,
from Sorangium cellulosum
promote tumor cell death by causing cell arrest in G2/Mphase.
has unique Beta -tubulin binding site
given 16mg/m2 (Vs 40mg Q21D )weekly for 3 weeks every 4weeks. (with Bevacizumab) or in combination with Xeloda as recommended appears to have been used in clinical trial.

BRCA 1,2
BR=Breast CA=cancer
Tumor suppressor gene which encodes a protein regulator of transcription gene involved with cell proliferation (once again it is a regulator that is involved!)

1. Prophylactic Bilateral mastectomy reduces the short term risk of Breast cancer, and overall risk by 90%
2.Adding Bilateral Salpingo-Oophorectomy decreases risk of Breast and Ovarian cancer.
3.BRCA1 high grade and Hormone Receptor Negative, majority are basal like subtype (but also more Atypia and Medullary histology found here!
4.whereas BRCA2 are more likely receptor positive and of luminal subtype
5. Risk of contralateral breast cancer in those with the disease 50-60%
6.BRCA 2 increases risk of Gastric,bilary,gallbladderand pancreatic cancer also.
7. The 2 HITS Theory assumes that the first hit is to have the abnormality but with the protecting presence of the normal BRCA gene. The second (environment factor) Hit knock out the normal BRCA to unleash the effect of the abormal BRCA1-100
IF YOU HAVE IT
1-Abide by strict surveillance protocol
2-Bilateral protective Mastectomy
3. Bilateral protective Oophorectomy
4. participation in preventive research drug (Tamoxifen,Raloxifen)

and know about possibility of insurance issues that may arise
SEE A GENETIC COUNSELOR PRIOR TO TESTING!

Tuesday, January 15, 2013

Study: Beta-Blockers May Help Lung Cancer Patients Live Longer

By Anna Azvolinsky, PhD¹ | January 11, 2013

¹Freelance Science Writer and Cancer Network Contributor. Follow Her on Twitter

Lung cancer patients who take beta-adrenergic receptor antagonists (beta-blockers) may survive longer and have a lower rate of tumor spread.
This is the result of a retrospective study of 722 non–small-cell lung cancer (NSCLC) patients published in Annals of Oncology.

Ball-and-stick model of the beta-blocker propranolol(Drug information on propranolol

NSCLC patients who were taking beta-blockers for an independent condition during their radiotherapy cancer treatment had a 22% improved survival compared to patients not taking beta-blockers after adjustment for factors such as age, disease stage, and concurrent chemotherapy. Patients on beta-blockers survived 23.7 months compared to 18.6 months for patients who were not taking the drugs.
Beta-blockers target the beta receptors on heart muscles and smooth muscles and are commonly prescribed for hypertension, cardiac arrhythmias, and as secondary prevention after a heart attack.
Zhongxing Liao, MD, and Daniel Gomez, MD, both from the department of radiation oncology at the MD Anderson Cancer Center in Houston, and colleagues compared outcomes of those NSCLC patients being treated with radiotherapy as their main line of treatment who were either not taking or regularly taking beta-blockers to treat another unrelated condition.
While beta-blockers didn’t influence the locoregional progression-free survival, the 155 patients on beta-blockers at the time of their radiotherapy lung cancer treatment had better distant metastasis-free survival (P < .01) and disease-free survival (P < .01) compared to the 567 patients not taking beta-blockers.
When adjusting for other factors including age, performance status, histology, concurrent chemotherapy, total tumor volume, stage of disease, those on beta-blockers did better in terms of distant metastasis-free survival (hazard ratio [HR], 0.67; P = .01), disease-free survival (HR, 0.74; P = .02), and overall survival (HR, 0.78; P = .02). There was no correlation, however, with locoregional progression-free survival (HR, 0.91, P = .63).
There is nothing unique about the combination of radiation therapy as a modality and beta-blocker usage, according to Gomez. “It would not be unreasonable to propose that these results may be extrapolated to other modalities, such as chemotherapy or surgery.”
This study is the first to show a link between improved survival and beta-blocker usage in lung cancer patients. Similar retrospective results have been shown for breast cancer, including triple-negative breast cancer and melanoma. Previous studies have also shown that beta-blockers may have antitumor activity, including in lung cancer models.
One previous retrospective lung cancer study did not show any benefit of beta-blockers on patient outcomes. The authors note that the study did not take into account any other clinical factors other than beta-blocker usage and excluded patients with chronic obstructive pulmonary disease or coronary heart disease, both of which are common among cancer patients.
Further studies, including prospective trials are needed to follow up and confirm these results. Weakness of the current study include missing data of other medications the patients may have taken during their cancer, data from only a single institution, and lack of data on beta-blocker usage prior to and post-radiation therapy.
How beta-blockers may affect metastasis is not clear but may help to suppress chronic stress conditions that result from stress hormones, which have been shown to facilitate the spread of tumor cells from their primary site of origin.
“We hypothesize that the mechanism of this benefit is by blocking the beta-adrenergic signaling pathway,” said Gomez. It has been demonstrated in both tissue culture and animal model experiments that blocking this pathway can affect the spread and growth of tumors.
“Future molecular studies will help us to understand if the mechanism that we propose is correct, and thus if beta-blockers are indeed directly affecting the aggressiveness of this malignancy, or if these findings are due to the activation or inhibition of another pathway,” said Gomez.

CPRIT Foundation releases donor list

Enlarge Image

The Cancer Prevention and Research Institute of Texas Foundation — the nonprofit that adds to the salaries of CPRIT executives — on Thursday released a copy of its donor list.

	Sponsored Links
	Florida Tech Degrees Now 100% Online!Give your career a boost with an associate’s, bachelor’s or master’s degree.www.FloridaTechOnline.com
	The Largest Supplier of HP Printer Parts HP Parts Store Has the Printer Parts You Need. Visit Us & Order Your Part Today!www.HPParts.com/Printer
Get Listed Here

Bayan Raji: Reporter- Houston Business Journal; Email | Twitter

The Cancer Prevention and Research Institute of Texas Foundation — the nonprofit that adds to the salaries of CPRIT executives — on Thursday released a copy of its donor list, which shows big-name companies like Pfizer (NYSE: PFE) have donated hundreds of thousands of dollars over the past three years.
To view the full list in PDF form, click here.
Lawmakers, in a December Texas House Committee Meeting, voiced concern over opaqueness at the CPRIT Foundation. More hearings are supposed to take place, and an auditor report is due this month.
Meanwhile, the future of the $3 billion institute seems uncertain. Gov. Rick Perry, Lt. Gov. David Dewhurst and Speaker Joe Straus sent a letter last month to CPRIT's Oversight Committee calling on the agency to fully address concerns that have been raised about the organization.
Jimmy Mansour, the committee's chairman, and Dr. Joseph Bailes, the vice chairman, issued a joint statement Dec. 19 endorsing the call for a moratorium on CPRIT grants until public confidence has been restored.

Bayan Raji covers health care.

CPRIT Foundation: Names are coming out of the hiding...

http://www.dallasnews.com/news/state/headlines/20130111-dallas-nonprofit-among-donors-to-embattled-texas-cancer-fighting-agency-s-foundation.ece

The CPRIT Foundation released the donor list to state legislators and other officials who have raised questions whether the foundation was used as a “pay-to-play” vehicle for the state agency. CPRIT and officials of the foundation have rejected that charge.
A rider inserted into the state appropriations bill in 2009 says “an individual, an organization, or an employee, officer or director of an organization that makes a contribution to the CPRIT Foundation” is not eligible to receive grants from the agency. Ellen Read, a CPRIT spokesman, said that provision would prohibit any grants to the Crowley Cancer Foundation itself.
The CPRIT Foundation also disclosed that Shanahan is among several individuals and companies to which it issued refunds “in order to avoid any appearance of impropriety.” A $1,000 donation from Shanahan was refunded because he is “affiliated with Gradalis,” said Marc Palazzo, a CPRIT Foundation spokesman.
Glenn Smith, director of the liberal advocacy group Progress Texas Political Action Committee, said the problem with the CPRIT Foundation, which had not released its donor list until Thursday, is that “it’s a way to buy the favor that you want from the state.”
The donor list shows, as The News reported in November, that Dallas philanthropist Peter O’Donnell contributed $1.5 million to the CPRIT Foundation.
CPRIT confirmed in November that it awarded $11 million in June 2010 to a Dallas biotechnology firm, Peloton Therapeutics, without the required review of business or science experts.
O’Donnell has said he invested in Peloton in July 2011, more than a year after the CPRIT Oversight Committee ratified the award. He said he purchased 900,000 shares of Peloton stock and donated all of his shares, as well as his right to future shares, to UT Southwestern Medical Center in December 2011.
O’Donnell and his wife have contributed more than $240,000 to Perry’s state campaigns since 2000 and about $200,000 to Dewhurst’s, according to the Texas Ethics Commission.

MICROSATELLITE INSTABILITY IN TRIPLE NEGATIVE BREAST CANCER?.

One will not think of this normally, but because of its good prognosis a biomarker, and because of its positive predictive value in terms of response to therapy, One may want to know its participation if any or share in triple negative breast cancer.
Microsatellite instability is almost standard of care a request in Colorectal cancer as it has entered the ASCO and NCCN guidelines. But is it exclusive to COLORECTAL cancers.

' Lynch syndrome (HNPCC or Hereditary nonpolyposis colorectal cancer ) is an autosomal dominant genetic condition which has a high risk of colon cancer^[1] as well as other cancers including endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited mutations that impair DNA mismatch repair.'

This definition clearly exclude Breast Cancer however it would be of clinic interest to test triple negative breast cancer for these features in trying to further define the various group of this condition. Likelihood of finding anything is low. But may be we can find a cohort, a subtype that we can declare of good prognosis?

WHAT IS A DRIVER MUTATION ANYWAY?

In a cell, there are aberrancies which are bound to happen during cell division that are not critical cell functions and get by like any heterogeneity in our genes. These aberrancies with no impact in cell survivors are some time called or includes the "passenger" Mutations. life follows a flow of forces which, when unhindered, keeps living cells going strong. Until an alteration occurs affecting one pathways that belong to this main flow of force without clearly stopping it but causing enough distorsion to detour its normal evolution.
Such an alteration is driver mutation.
The effect of a driver mutation can be a stoppage in Maturity or acquisition of new capability while maintaining survival. It could be a loss of restrain or an unwelcome augmentation of autocrine function, A stimulation of enzymatic processes release at a promoter gene. All these scenarios depict a driver Mutation.
Our current standard of defining a Driver Mutation is not only linked to finding a Mutation (testing for EGFR, KRAS, BRAF and HER-2 in lung cancer) but also by weighing therapeutic response to selected target therapy. So if you find EGFR and gave related medication, you get a response. You conclude that EGFR was a driver. This kind of conclusion however leaves room to the fact that an overwhelming action can move things along without it being a driver.
We have to have more information. Finding a mutation could imply it is active or it may not. We need to dig deeper. Does it overwhelmingly stimulate other pathways? Does it induces more transcription factors more enzymes, more regulator proteins etc...

Gene sequencing of certain Axons has so far been great at finding Mutation, let's find better ways to gauge intensity of pathways and gene transcription to further define our "Drivers".

Monday, January 14, 2013

NF-kB PATHWAY AND CANCER SURVIVAL, (Inhibitor: Parthenolide)
All refractory cancers seem to have one strong characteristic. They survive even when the kitchen sink is thrown at them. By kitchen sink, I mean all kinds of combination chemotherapy. In fact, times and again we have seen that only one medication turns out to be working as comparative studies end up showing equivalency between a combination therapy Vs a monotherapy. The story of DTIC in Melanoma is an example that combination therapy Vs DTIC alone, there was no difference in survival. The reasons for this drug resistance is multiple. The cell may have an MDR (Multiple drug Resistance) protein that effectively shut down cellular processes to the various drugs, but can't mount an elective resistance to DTIC. Or the cell may activate its NF-kB pathways to survive.

As cells live their lives in our body they come in contact with all kinds of neighbors and enemies, including drugs constantly thrown around in our body. The cells register the invasion, exposure or attack and send the message through a pathway of survival called NF-kB. Signals from this pathways are interpreted quickly and our body modulate the attack in the general sense of survival. To achieve this, some transcription genes are amplified to make more blockers to the invasion (ie. Bcl-2), some transcription genes are shut down to reduce susceptibility to the attack. The NF-kB pathway is in this a critical pathway of adaptation to life. It is central to all immune diseases, it is critical to resistance to diseases, it is the force to reckon with when you give a drug to treat anything including cancer. You got to stop NF-kB from working effectively to achieve your goal. Because, unlike the MDR and Flippase which are determined in their place of action and mechanism, this pathway is constantly searching for an answer against therapy by modulating various transcription factors! You see here now why attempts to target this pathway are so important.

To assure versatility in its action, NF-kB knows it cannot do it on its own, it "cross-talks" to many other pathways and important molecules. One of which is the STAT3 for rapid transcription of whatever protein is needed to decrease Apoptosis and protect the cell. NF-kB a constant, moving and changing fighter which will do anything to decrease activities that can lead to death of the cell. So far Phosphorylating it has been with limited success. May be its inhibitors need to be given with Velcade or Cabozantinib.

Allez Hop! another mighty combination to try in a difficult disease has been created!
Taxol/cisplatin/Velcade and Parthenolide for triple negative Breast cancer!
(Instead of Parthenolide, may be IL-2 could work)

Lack of Clear Evidence for Sentinel Node Biopsy in Melanoma?

Roxanne Nelson

Jan 11, 2013

Editors' Recommendations

Sentinel lymph node (SLN) biopsy has become a common procedure in melanoma and has been endorsed by professional guidelines. It is considered to be a minimally invasive and highly accurate procedure that allows for appropriate regional nodal staging and identification of patients without nodal metastases.
However, in a feature published online January 8 in BMJ, freelance journalist Ingrid Torjesen, from London, United Kingdom, describes SLN biopsy as an "expensive and invasive procedure" and reports that thousands of melanoma patients around the world are having it done despite a lack of clear evidence that it will improve outcomes.
She focuses on the Multicenter Selective Lymphadenectomy Trial (MSLT-I), which was designed to determine the ability of SLN biopsy to identify patients with clinically occult nodal metastases and to evaluate the effectiveness of immediate completion lymph node dissection (CLND) in patients with positive SLNs.
The 5-year follow-up of the MSLT-I, published in 2006 ( N Engl J Med. 2006;355:1307-1317), failed to show a survival advantage from SLN biopsy. However, it did confirm that SLN biopsy was highly accurate in identifying positive nodes in patients with melanomas 1.2 to 3.5 mm thick, and that SLN biopsy followed by CLND was associated with prolonged disease-free survival.
In addition, clinically node-negative patients with SLN metastases who underwent CLND had significantly better melanoma-specific 5-year survival rates than those who had delayed CLND for clinically detected nodal relapse.
SLN biopsy is now commonly used in Australia, Canada, the United States, and Western Europe, but is not routinely used in the United Kingdom.
A guideline issued jointly by the American Society of Clinical Oncology (ASCO) and the Society of Surgical Oncology (SOS) recommends SLN biopsy for patients with melanomas of intermediate thickness. The procedure has also been endorsed by the American Joint Committee on Cancer as a valuable staging procedure for those at risk of developing clinically occult nodal metastases.
Why No Interim Results?
In her report, Torjesen states that the results of the MSLT-I were controversial, and that critics said it was not surprising "to see an improved disease-free survival in the biopsy arm [because] patients whose disease was most likely to progress had had their regional nodes removed."
She notes that the fourth interim analysis of the MSLT-I data (showing 7-year follow-up data), which was expected in 2008, and the fifth and final analysis (with 10-year data), expected in 2011, will settle the question once and for all.
So why haven't they been published, Torjesen asks.
"A minimum of 10 years of follow-up is required to see the full benefit of the technique," said Alistair Cochran, MD, MB ChB, distinguished professor of pathology, laboratory medicine, and surgery at the University of California Los Angeles School of Medicine.
"The 10-year data have been analyzed and are being prepared for submission, hopefully within the next month or so," Dr. Cochran told Medscape Medical News.
Dr. Cochran was involved in developing the technique, is a coauthor of the ASCO/SOS guidelines, and has worked with Donald Morton, MD, lead author of the MSLT-I.
Sandra Wong, MD, associate professor of surgery at the University of Michigan Health Systems in Ann Arbor, and lead author of the ASCO/SOS guidelines, agrees. "In a lot of studies, the follow-up time just isn't long enough," she told Medscape Medical News. "Melanoma is not like a lot of other cancers, where you start seeing recurrences within the first 2 years. I have patients who are a decade out and they are having a recurrence. It's just a very different disease process," she explained.
Lacking Balance
Dr. Cochran pointed out that Torjesen relies heavily on comments from J. Meiron Thomas, MS, FRCP, FRCS, who is a consultant surgeon at the Royal Marsden Hospital London and chair of surgical oncology at Imperial College, London, United Kingdom.
Dr. Thomas has been very vocal in his criticism of SLN biopsy and has published maybe 15 or 16 papers on the subject, Dr. Cochran explained. "This is a picture of a tennis match.... We publish something and then Dr. Thomas prints a rebuttal. We have eventually left him to it and figured time will tell," he noted.
"I don't know if bias is the right word, but the paper seems to only represent 1 side of the debate," said Dr. Wong. "That side is a very minority opinion, and Dr. Thomas is a vocal critic," she added.
Dr. Wong noted that when "we try to set up debates at national meetings, we can never get anyone to take the con side. Not even a 'soft' con."
This report is not offering any new information or insight, said Daniel Coit, MD, a surgical oncologist at Memorial Sloan-Kettering Cancer Center in New York City. It "is really just a rehash of arguments and commentaries that have been made for quite some time," he explained.
Dr. Coit emphasized Donald Morton, who introduced the technique and who has, so to speak, the biggest stake in it "is the one person who has done more than anyone else to critically evaluate the technique, with these 2 large randomized prospective trials.... While there are many critics — and Steve Rosenberg [mentioned in the report] and Meiron Thomas have an absolute right to interpret the data of others — neither has actually created any data of their own to contribute to this," he explained.
"It is very easy to take pot shots, but very hard to create new data," Dr. Coit added. "And Don Morton has created a wealth of data."
All of the arguments made in the report are cogent. "This is not a procedure that affects survival, it is a procedure that provides important prognostic information," he noted.
"As a society, we have to decide if we want to pay for it, just as we decide if we are going to pay for CT scans or PET scans," Dr. Coit added.
Professional Advancement and Company Profits?
Torjesen implies that the uptake of SLN biopsy has been largely driven by professional advancement and commercial profit. She states that "whole professional careers and businesses have been built on sentinel node biopsy for melanoma. Professional pride and company profits are now at stake."
Dr. Cochran explained that it is highly doubtful that the use of SLN biopsy has been endorsed simply to advance careers or to generate profit. "I don't think that the popularity of the technique can be put down to the commercialization," he said. "I'm sure that there is some money to be made, but nothing like the money that can be made by pharmaceutical companies from some of their new drugs."
Dr. Wong agrees that there is some cost associated with the procedure, but it is not very expensive overall and not a huge profit maker. "It's not like chemotherapy or using excessive imaging," she noted.
"If you're really cynical, you can say that if melanoma surgeons stopped doing this, they would lose a large part of their practice," she added. "But that's cynical because this is a procedure that can help overall survival or help make an accurate diagnosis," she said.
Harms of Overtreatment
Torjesen raises concerns about overtreatment in her report. "It is generally accepted that only 20% of patients who have sentinel node biopsy will have positive sentinel nodes, and only 20% of those will have metastatic disease in the nonsentinel nodes," she states. "Therefore, 96% of patients who have sentinel node biopsy will have unnecessary surgery," she writes.
Dr. Cochran agrees that the prophylactic removal of lymph nodes can cause serious morbidity, but pointed out that some people can be saved by it. "The other alternative is to watch and wait, but we've found that the number of involved lymph nodes in patients who have been observed is about 3 times as high as those treated with sentinel node biopsy," he said. "We know that with time, the disease progresses. I think most physicians are uncomfortable with letting things be and letting nature take its course," he explained.
Dr. Cochran added that at some point it will be possible to tell which patients with a positive SLN have metastatic disease, "but we are not there yet."
It is hoped that the follow-up MSLT-II will answer some of those questions. That study is also being run by Dr. Morton, and will evaluate the potential benefits of regional lymphadenectomy for melanoma patients with positive sentinel nodes.
The MSLT-II will establish whether "every patient with a positive SLN needs a full dissection," said Dr. Wong.
If lymph node surgery in melanoma is ultimately scaled back, it would not be without precedent. In recent years, surgical oncologists have learned that not all women with positive sentinel axillary lymph nodes need completion dissection. The Z0011 trial, conducted by the American College of Surgeons Oncology Group, showed that women with minimal lymph node involvement did not suffer from inferior survival when they only underwent sentinel node biopsy and did not undergo completion dissection.
In addition, new agents have been shown to be very effective in metastatic disease; that's why the staging is so important, Dr. Wong explained. "You may have a patient who walks in with a stage I melanoma clinically, but may actually be a stage III once we do the procedure. If we lose these data, we won't know which patients will benefit from these new treatments," she noted.
In general, the jury is still out as far as SLN biopsy goes. "But everyone is doing it, and I don't think there is too much debate," Dr. Wong said. "It is hard to tell a patient that you don't want to do it if they are in the 1 to 4 mm stage. They want to know."
Dr. Coit agrees. "I don't think any clinicians regularly using this procedure propose it to patients as anything other than a method that will provide more information on how likely melanoma is to occur," he said.
The main question right now is which patients are least likely to benefit from the procedure, he added. "We are taking a long hard look at who this prognostic information will likely help, this procedure will help, but also who it will not be of benefit to."
Medscape Medical News requested a comment on this report from BMJ, but had not received a response by press time.
BMJ. 2013;346:e8645. Full text
===========================
FROM MEDSCAPE NEWS, BE AWARE OF THIS CONTROVERSY!

Sunday, January 13, 2013

Effective Treatment of Psoriasis with Narrow-Band UVB Phototherapy Is Linked to Suppression of the IFN and Th17 Pathways

Emőke Rácz, Errol P Prens, Dorota Kurek, Marius Kant, Dick de Ridder, Sabine Mourits, Ewout M Baerveldt, Zeliha Ozgur, Wilfred F J van IJcken, Jon D Laman, Frank J Staal and Leslie van der Fits

BACK TO ARTICLE

Table 2. Effect of narrow-band ultraviolet-B (NB-UVB) phototherapy on pathways known to be therapeutic targets in psoriasis, or targets of UVB radiation

Previous tableFigures and tables index

		Molecules affected by NB-UVB within these pathways
Pathway	P-value	Upregulated	Downregulated
Therapeutic target in psoriasis
Glucocorticoid receptor signaling	1.1E−03	PIK3R1, PIK3C2G, HSPA2, BCL2, IL1R2, TGFBR2, TSC22D3, KAT2B, AKT3, NCOR2, ADRB2, UBE2I	IL8, STAT3, STAT1
VDR/RXR activation	4.2E−03	IGFBP5, NCOR2, CST6	DEFB4, SERPINB1, KLK6, HSD17B2
NF-κB signaling	2.3E−02	IL1R2, CSNK2A2, IL18, PIK3R1, PIK3C2G, AKT3, IL1F7	IL1F9

Induced by UV in normal skin
p53 signaling	2.1E−03	KAT2B, TP53INP1, PIK3R1, PIK3C2G, AKT3, CCND1, BCL2	SCO2
p38 MAPK signaling	3.5E−03	IL1R2, TGFBR2, IL18, H3F3B, IL1F7, EEF2K	IL1F9, STAT1
EGF signaling	5.4E−03	CSNK2A2, PIK3R1, PIK3C2G	STAT3, STAT1
IGF-1 signaling	2.4E−02	CSNK2A2, PIK3R1, PIK3C2G, AKT3, IGFBP5, IGFBP7

Proposed as therapeutic target in psoriasis
LXR/RXR activation	2.5E−04	IL1R2, APOE, IL18, IL1F7, NCOR2	IL1F9, LDLR, CCL7
IL-10 signaling	4.2E−03	IL1R2, IL18, IL1F7	IL4R, IL1F9, STAT3
PPAR signaling	1.8E−02	IL1R2, IL18, IL1F7, NCOR2, PDGFC	IL1F9
IL-4 signaling	2.2E−02	PIK3R1, PIK3C2G, AKT3	IL4R, IL13RA1

Other
GM-CSF signaling	1.5E−04	PIK3R1, PIK3C2G, AKT3, CCND1	CSF2RB, LYN, STAT3, STAT1
Acute-phase response signaling	3.2E−04	PIK3R1, SOCS6, IL1F7, IL18, AKT3	C1S, SERPINA3, STAT3, C1R, IL1F9, SOD2, CRABP2, CFB
IFN signaling	6.3E−04		IFIT1, OAS1, IFNGR1, MX1, STAT1
PDGF signaling	2.1E−03	CSNK2A2, PIK3R1, CAV1, PIK3C2G, PDGFC	STAT3, STAT1
JAK/Stat signaling	4.2E−03	PIK3R1, SOCS6, PIK3C2G, AKT3,	STAT3, STAT1
IL-6 signaling	7.2E−03	IL1R2, CSNK2A2, IL18, IL1F7	IL8, IL1F9, STAT3
Complement system	9.5E−03	CD59	C1R, C1S, CFB
LPS/IL-1-mediated inhibition of RXR function	1.9E−02	IL1R2, GSTA3, APOE, ALDH3A2, CAT, HS3ST6, ABCC4	ALDH1A3, PAPSS2, HS3ST3A1
VEGF signaling	1.9E−02	PIK3R1, PIK3C2G, AKT3, BCL2	HIF1A, ACTN1
Wnt/β-catenin signaling	2.2E−02	TGFBR2, CSNK2A2, FRZB, DKK3, SOX10, AKT3, CCND1	SOX9, FZD5
Xenobiotic metabolism signaling	3.2E−02	GSTA3, ALDH3A2, PIK3R1, MAF, CAT, PIK3C2G, HS3ST6, NCOR2,	ALDH1A3, UGT1A9, HS3ST3A1
Fc ∑ RI signaling	3.6E−02	FYN, VAV3, PIK3R1, PIK3C2G, AKT3	LYN
IL-2 signaling	4.3E−02	CSNK2A2, PIK3R1, PIK3C2G, AKT3

Previous tableFigures and tables index

BACK TO ARTICLE

ASPECTS OF TARGET THERAPY IN TRIPLE NEGATIVE BREAST CANCER.

As one goes in deeper into treating Breast cancer with triple negative characteristics, one quickly realize it is imperative to further assess genome and pathway drivers in order to get to effective therapy. This type of Breast cancer is driven by polygenic stimulators and prognostic factors. Recent developments has pointed to STAT1 and its relationship with AKT3 and MAP3-K1. In the article posted here, MAGI3-AKT3 reshuffling is plenty discussed. One of the challenge is to find an effective AKT3 inhibitor. The potential inhibitors have been tested in Melanoma where AKT3 pathway is amplified in 70% of cancer cells. Generally, an amplification of pathways is linked to overexpression of promoter genes and transcription genes. This is were gene Methylation can help silence these promoters, and can prove an effective way controlling these disease processes. Once again, we believe that an Interfeon and /or Interleukin combined to an mTor (Afinitor), plus or minus a Taxane would be effective in Triple Negative Breast Cancer.

Breast cancer’s many drivers

By Elizabeth Cooney, Broad Communications, June 20th, 2012

A breast cancer cell, shown in a color-enhanced scanning electron
micrograph.
Image courtesy of Anne Weston via Wellcome Images

Breast cancer is not a single disease, but a collection of diseases with dozens of different mutations that crop up with varying frequency across different breast cancer subtypes. Deeper exploration of the genetic changes that drive breast cancer is revealing new complexity in the leading cause of cancer death in women worldwide.
In one of the largest breast cancer sequencing efforts to date, scientists from the Broad Institute, the National Institute of Genomic Medicine in Mexico City, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute have discovered surprising alterations in genes that were not previously associated with breast cancer. They report their results in the June 21 issue of Nature, which is publishing a series of papers characterizing the genomic landscape of breast cancer.
One of the team’s new findings, a recurrent fusion of the genes MAGI3 and AKT3 in what is known as a translocation event, was observed in tumors from a rare but aggressive form of breast cancer known as triple-negative breast cancer. This cancer does not respond to conventional hormone therapy because its tumors lack three receptors that fuel most breast cancers: estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (known as HER2). But the biological pathway that is affected by the MAGI3-AKT3 reshuffling is already the target of experimental drugs.
The other new alteration reported by the team occurred in two transcription factor genes. Recurrent mutations were detected in the gene CBFB and deletions of its partner RUNX1. Cancer-causing rearrangements of these two genes are common in blood cancers, such as acute myeloid leukemia, but their discovery in breast cancer marks the first time they have been seen in a solid cancer.
“These genes wouldn’t top the list of genes you think would be mutated in breast cancer,” said Alfredo Hidalgo Miranda, co-senior author of the paper and head of the cancer genomics laboratory at the National Institute of Genomic Medicine, known by its Spanish acronym INMEGEN. “That’s exactly the point of doing this type of analysis. It gives you the opportunity to find those genes that you never thought would be involved in the breast cancer process.”
The scientists studied two kinds of samples. They sequenced the whole exomes – the tiny fraction of the genome that encodes proteins – of 103 breast cancer tumors and DNA from normal tissue from patients in Mexico and Vietnam. They also sequenced the entire genomes of 22 breast cancer tumors and matched normal tissue.
Their analysis confirmed the presence of previously known mutations, but it also turned up the unsuspected alterations.
“One of the lessons here is the real diversity of mutations in breast cancer. I think it’s clear there are going to be roughly 50 or so different mutated genes in breast cancer,” said Matthew Meyerson, co-senior author of the paper, Broad senior associate member, and professor of pathology at Dana-Farber Cancer Institute and Harvard Medical School. “There’s a big diversity of driver genes in cancer. We don’t understand what all of them are, but larger data sets will enable us to identify them.”
The mutations in CBFB and RUNX1 point to the importance of understanding cell differentiation – how cells become specialized – and transcription factors that regulate that process of cell differentiation in epithelial tissue, which lines the inner and outer surfaces of the body. Further studies are needed to unravel that relationship, the authors concluded.
For the current study, inspecting the novel fusion gene MAGI1-AKT3 more closely showed not only that the translocation can transform normal cells into cancer cells, but also that the protein produced by the gene is insensitive to certain drugs now in clinical trials, yet sensitive to others.
In general, fusion genes are created within the same chromosome or across different chromosomes when parts of one gene join parts of another to become a novel gene that wouldn’t normally exist. Like the CBFB and RUNX1 mutations, translocations are also more common in blood cancers but until now have rarely been detected in solid tumors, especially breast cancer.
This particular MAGI1-AKT3 fusion gene produces a fusion protein that acts in the PI 3-kinase pathway as an oncogene, or a gene that drives cancer, revealing a new target for potential therapy. The kinase pathway controls a multitude of cellular functions. When a gene is mutated in this pathway, the result is uncontrolled cell growth, a hallmark of cancer.
Other gene mutations in this pathway are well-known, but MAGI1-AKT3 is a first.
“This is the first translocation event resulting in an oncogenic fusion protein that has been identified in this pathway,” said Alex Toker, a professor in the department of pathology at Beth Israel Deaconess and Harvard Medical School. “That’s important because this is one of the most frequently mutated pathways in human cancer, especially in women’s cancers such as breast, ovarian, and endometrial cancer.”
The most frequently mutated pathway is also the most studied and, from a pharmaceutical perspective, among the most “druggable.”
In laboratory dishes, tests confirmed that the novel structure of proteins encoded by the fusion gene provided no place for some drugs to bind but offered targets for other drugs.
“There are many additional studies that need to be performed using mouse models of disease that would recapitulate the expression of this protein in the mammary gland, in addition to the mechanism by which this protein promotes the effects associated with malignancy,” Toker said. “These are all experiments that are under way.”
Once the mechanism at work in triple-negative breast cancer is understood through animal models, the next step would be to test chemical compounds to see how effective they might be at targeting cells that harbor this fusion gene’s protein.

Beyond these scientific findings, the study also represents a closer look at the Latino population, thanks to the collaboration between the Broad and INMEGEN forged through the Slim Initiative in Genomic Medicine.
“The Slim Initiative in Genomic Medicine aims to support the discovery of the genetic basis of diseases such as type 2 diabetes mellitus and several types of cancer which have a profound public health impact in Mexico and Latin America,” said Roberto Tapia-Conyer, director general of the Carlos Slim Health Institute. “This novel bi-national scientific collaboration is contributing to put the Latin American genome on the map of the second generation worldwide genome studies.”
INMEGEN scientists had previously built a large breast cancer study and then scientists at both the Broad and INMEGEN exchanged clinical, biological, and computational information.
“From the Mexican point of view, you can say the Latino population has not been extensively characterized using genomic methods,” Hidalgo Miranda said. “This is a significant contribution to the knowledge of the architecture of breast tumors in this particular population.”
The study represented a first opportunity to study the genetic basis of breast cancer in Mexico. Larger studies will be required to determine whether differences in the spectrum of mutations exist between different populations, but this was an important first step toward that goal.
Contributors to the work also include, from the Broad and its Harvard-affiliated hospitals: Shantanu Banerji (co-first author), Kristian Cibulskis (co-first author), Kristin K. Brown (co-first author), Scott L. Carter, Abbie M. Frederick, Michael S. Lawrence, Andrey Y. Sivachenko, Carrie Sougnez, Lihua Zou, Maria L. Cortes, Shouyong Peng, Kristin G. Ardlie, Daniel Auclair, Fujiko Duke, Joshua Francis, Joonil Jung, Robert C. Onofrio, Melissa Parkin, Nam H. Pho, Alex. H. Ramos, Steven E. Schumacher, Nicolas Stransky, Kristin M. Thompson, Jose Baselga, Rameen Beroukhim, Kornelia Polyak, Dennis C. Sgroi, Andrea L. Richardson, Eric S. Lander, Stacey B. Gabriel, Levi A. Garraway, Todd R. Golub, and Gad Getz (co-senior author). From Mexico: Claudia Rangel-Escareno (co-first author), Juan C. Fernandez-Lopez, Veronica Bautista-Pina, Antonio Maffuz-Aziz, Valeria Quintanar-Jurado, Rosa Rebollar-Vega, Sergio Rodriguez-Cuevas, Sandra L. Romero-Cordoba, Laura Uribe-Figueroa, Gerardo Jimenez-Sanchez, and Jorge Melendez-Zajgla.
The research was conducted as part of the Slim Initiative in Genomic Medicine, a project funded by the Carlos Slim Health Institute in Mexico. The work was also supported by grants from the National Institutes of Health and the National Cancer Institute.
About the Broad Institute of Harvard and MIT
The Eli and Edythe L. Broad Institute of Harvard and MIT was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.
Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to http://www.broadinstitute.org.
About the Carlos Slim Health Institute
The Carlos Slim Health Institute is a non-profit organization created in 2007 by the initiative of Mr. Carlos Slim-Helú with the purpose of generating solutions in order to help solving Mexico’s and Latin America’s main public health problems focusing on the most deprived populations.
The institute seeks to achieve its objectives by fostering alliances with Mexican and foreign public, private and social institutions in order to support the adoption of innovative, sustainable and replicable solutions aimed at improving the health of the population, such as the use of mobile technologies in health care, on-line based distance learning, translating scientific research into applicable tools, etc. http://www.salud.carlosslim.org
About the National Institute of Genomic Medicine
The National Institute of Genomic Medicine (INMEGEN) was founded in 2004 and became the 11th National Institute of Health in Mexico. INMEGEN's mission is to contribute to the healthcare of the Mexican population by developing cutting-edge scientific research and well-trained human resources. The goal is to apply the knowledge of genomic medicine through innovation, state-of-the-art technology, and strategic partnerships, all the while complying with universal ethical principles.
INMEGEN's main research areas focus on principal complex diseases in Mexico, all based on the genomic characterization of the Mexican population. Examples of these areas are genomics of metabolic diseases (diabetes mellitus and obesity), cancer research, infectious and cardiovascular diseases, as well as nutrigenomics and pharmacogenomics.
One of the features of INMEGEN¹s innovative culture is scientific research and development of technology, which leads to goods and services that can then be used to contribute to better health care for the Mexican people in the knowledge-based economy.
www.inmegen.gob.mx
About Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center is a patient care, research and teaching affiliate of Harvard Medical School and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.harvard.edu.
About Dana-Farber Cancer Institute
Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women’s Hospital as Dana-Farber/Brigham and Women’s Cancer Center and it provides pediatric care with Boston Children’s Hospital as Dana-Farber/Children’s Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Twitter: @danafarber or Facebook: facebook.com/danafarbercancerinstitute.

Paper(s) cited:

Banerji S et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature DOI: 10.1038/nature11154

A network module-based method for identifying cancer prognostic signatures

Guanming Wu^* and Lincoln Stein

* Corresponding author: Guanming Wu guanmingwu@gmail.com

For all author emails, please log on.

Genome Biology 2012, 13:R112 doi:10.1186/gb-2012-13-12-r112
Published: 10 December 2012

Abstract (provisional)

Discovering robust prognostic gene signatures as biomarkers using genomics data can be challenging. We have developed a simple but efficient method for discovering prognostic biomarkers in cancer gene expression data sets using modules derived from a highly reliable gene functional interaction network. When applied to breast cancer, we discover a novel 31-gene signature associated with patient survival. The signature replicates across five independent gene expression studies, and outperforms 48 published gene signatures. When applied to ovarian cancer, the algorithm identifies a 75-gene signature associated with patient survival. A Cytoscape plugin implementation of the signature discovery method is available at http://wiki.reactome.org/index.php/Reactome_FI_Cytoscape_Plugin.

Coalition for the Reversal of Breast Cancer Mortality in African American Women