Mutiple Myeloma management notes from training!
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Martha Q. Lacy, MD
Professor of Medicine
Division of Hematology
Mayo Clinic College of Medicine
Rochester, Minnesota

At diagnosis, if patient had no high-risk molecular markers and excellent renal function. In this setting, at Mayo, we prefer to start with lenalidomide and dexamethasone because it has high remission rates, is oral, well tolerated, and unlikely to induce peripheral neuropathy. When using lenalidomide in patients with no personal history of VTE, we favor prophylaxis with aspirin at 325 mg daily. We would use IV bisphosphonates monthly for 12 months and quarterly for 1 additional year. In patients with low-risk disease, we consider risks and benefits of maintenance therapy. If maintenance therapy is chosen, consider limiting the duration to 12-24 months. 

At relapse, if our patient had a good response and a long duration of remission (> 12 months), we favor re-introduction of the initial regimen. If the patient has suboptimal response or a short remission duration, we would change the class of drug used (eg, if initially treated with an immunomodulatory agent [thalidomide, lenalidomide], we would switch to proteasome inhibitor [bortezomib, carfilzomib]. If initially treated with a proteasome inhibitor, we would switch to an immunomodulatory agent). In this particular case, we would need to factor in that the patient now has renal failure and a new bone lesion. We generally re-introduce bisphosphonates quarterly at relapse in patients with new bone lesions. However, since this patient has renal failure, we would wait for renal improvement and favor pamidronate over zoledronic acid with a reduced dose of 30 mg (from 90 mg).¹ Also due to the renal status of this patient, full-dose lenalidomide should not be used. I would favor switching to bortezomib because it can be used at full dose. However, dose-adjusted lenalidomide is also an option.² A second ASCT may also be considered, especially if the initial remission was extremely long (eg, > 4 years).
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SECOND OPINION
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Thomas G. Martin III, MD
Clinical Professor of Medicine
Multiple Myeloma Translational Initiative
UCSF Medical Center, University of California, San Francisco
San Francisco, California

Mr Johnson's presentation was fairly typical and consistent with standard risk myeloma. At UCSF, we would consider this young (< 60 years), standard risk patient to be an excellent candidate for autologous transplantation at presentation. Therefore, we would avoid melphalan containing therapy and limit upfront lenalidomide therapy to 4-6 cycles thus allowing ample marrow reserve for stem cell collection. Lenalidomide/dexamethasone, bortezomib/dexamethasone, and/or lenalidomide with bortezomib would all be considered excellent upfront therapy options. Appropriate supportive care measures would be oral calcium and vitamin D and IV bisphosphonates. Patients receiving proteasome inhibition should receive anti-viral prophylaxis to prevent zoster reactivation and patients receiving immunomodulatory agents should receive venous thromboembolism (VTE) prophylaxis. Patients at increased risk for VTE should receive therapeutic warfarin, while low-risk patients, such as this one, can receive aspirin (325 mg) daily. In patients treated with autologous transplantation, we favor lenalidomide maintenance based on the CALGB 100104 and French randomized post-transplantation maintenance trials.^1,2 The median time to progression in the CALGB study was almost double for the lenalidomide arm (46 months) versus the placebo arm (27 months). The optimal duration of maintenance therapy remains unclear but we attempt to continue maintenance in this setting for at least 1 year and often for 2-3 years depending on tolerability and count suppression.

At relapse, Mr Johnson has developed significant renal insufficiency and this prevents the use of full-dose lenalidomide, as lenalidomide clearance is primarily renal. Since Mr Johnson's remission lasted 24 months, one could choose to use either dose-reduced lenalidomide, or a bortezomib-containing regimen. There are a number of reports describing improved renal function in patients receiving early bortezomib administration and no increased toxicity. Consequently, we would likely recommend a bortezomib-based regimen, like cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in this case. One should consider re-instituting bisphosphonate therapy once the renal function improves (unless the renal insufficiency is due to hypercalcemia for which bisphosphonates should be used right away). At relapse, one always needs to consider toxicity from prior therapy. Since the patient has a history of neuropathy, we would choose to administer bortezomib at weekly intervals and by subcutaneous injection. If the neuropathy increases, option would include switching to carfilzomib or lenalidomide-based therapy.

References

• ¹ McCarthy PL, et al. N Engl J Med. 2012;366(19):1770-1781.
• ² Attal M, et al. N Engl J Med. 2012;366(19):1782-1791.

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follow-up

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Once a patient has achieved remission following upfront therapy, it is important to follow their myeloma for evidence of relapse. Early recognition of disease relapse often can prevent morbid complications including hypercalcemia, compression fractures, and renal failure. For patients on maintenance therapy, we will follow their CBC including neutrophil and platelet counts every 4-6 weeks and adjust dosing accordingly. A history and physical exam and laboratories including serum protein electrophoresis, quantitative immunoglobulins, serum immunofixation electrophoresis, and serum free light chains can be followed every 12 weeks. We will follow 24-hour urine tests (TP, UPEP, UIFE) every 12 weeks if a patient has had disease that is only assessable by urine tests (this is rare). We perform bone marrow biopsies every 12-18 months unless the patient has truly nonsecretory disease for which BMB exams are performed every 3-6 months. We rarely performed routine skeletal surveys but prefer PET/CT or total body MRI exams, every 12-18 months.

Elizabeth Bilotti, MSN, RN, APN

For patients who have achieved a CR post-transplant, we would follow every 3 months or as clinically indicated for reported symptoms, with a change in the frequency of assessments at the time signs of relapse became present. Evaluation would include full laboratory assessment (CBC, chemistry panel, quantitative immunoglobulins, SPEP, free light chain analysis, serum immunofixation with 24-hour urine analysis as appropriate ‒ UTP, UPEP, and urine immunofixation on a 24-hour urine). Radiographic imaging and BM biopsy would be determined based upon medical necessity and only used routinely in patients with non-secretory disease. 

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Patients with the t(4;14) should receive bortezomib containing induction therapy. Often we will include lenalidomide and dexamethasone (thus RVD) as induction therapy in this setting. We would recommend transplantation and consider bortezomib maintenance following transplantation. The CALGB study has yet to evaluate lenalidomide maintenance therapy in the subset of t(4,14) patients, thus lenalidomide maintenance is also acceptable. 

Martha Q. Lacy, MD

I agree, t(4;14) patients have high remission rates with bortezomib. We would likely go with a bortezomib-based regimen and advocate bortezomib maintenance.

Elizabeth Bilotti, MSN, RN, APN

As the patient opted not to receive maintenance therapy, I would not recommend any changes in monitoring or assessments. However, had this cytogenetic information been available at the time of diagnosis, we would have likely recommended bortezomib as part of induction therapy. At relapse, we would opt for a combination regimen, with a bortezomib backbone, and, under the current renal circumstances, would choose VCD (bortezomib, cyclophosphamide, and dexamethasone).

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tougher case
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Martha Q. Lacy, MD
Professor of Medicine
Division of Hematology
Mayo Clinic College of Medicine
Rochester, Minnesota

This patient has intermediate/high-risk molecular markers consisting of the t(4;14), high beta-2 microglobulin, and a short duration of response following ASCT. Patients with the t(4;14) translocation have high response rates to bortezomib, so we prefer starting with a bortezomib-based regimen. If no maintenance therapy is given after the ASCT, remission duration is generally short. In addition, we would prefer bortezomib-based maintenance therapy for this patient. The choice to use bortezomib, 1 dose every other week, as maintenance is based on the HOVON-65/GMMG-HD4 trial that showed patients receiving bortezomib maintenance had improved PFS and OS.¹ Since the remission was a fairly short duration (< 12 months), we at Mayo favor switching class to an immunomodulatory agent-based regimen. A second ASCT generally would not be performed if the first remission was less than 12 months.

This patient is now dual refractory, and historical outcomes for this patient type are poor. Data by Kumar and colleagues found that in 286 multiple myeloma patients refractory to bortezomib and relapsing following, refractory to, or ineligible to receive lenalidomide or thalidomide, the median OS was 9 months and median event-free survival was only 5 months.² Recently, carfilzomib was approved for patients who have failed at least 2 prior therapies including bortezomib and an immunomodulatory agent. In a phase II trial of heavily pre-treated myeloma, carfilzomib monotherapy resulted in 20% overall response rate with a 7.4-month median duration of response in 214 bortezomib and lenalidomide refractory/intolerant patients. In addition to carfilzomib, a clinical trial would also be a reasonable approach for this patient.³ Agents in late stage trials include combination therapy and the immunomodulatory agent, pomalidomide, which produced a 26-29% response rate in patients refractory to both bortezomib and lenalidomide.⁴ Alkylating agents may also be considered for this dual refractory patient.

During treatment, Mrs Anderson developed peripheral neuropathy. There are a number of ways to reduce the risk of treatment-induced peripheral neuropathy. The randomized French trial found that subcutaneous bortezomib is not inferior to IV bortezomib and significantly reduced the risk of peripheral neuropathy.⁵ Efficacy with carfilzomib monotherapy is comparable to that of bortezomib but the risk of PN is greatly reduced.^3,6 Regimens containing melphalan or cyclophosphamide may be active and would not contribute to PN. Thalidomide can cause treatment-induced neuropathy and would not be an option to reduce the risk of neuropathy.

Thomas G. Martin III, MD
Clinical Professor of Medicine
Multiple Myeloma Translational Initiative
UCSF Medical Center, University of California, San Francisco
San Francisco, California

Mrs Anderson initially presented with high-risk disease based on high beta-2 microglubulin, complex cytogenetics, and FISH (+) for t(4,14). She was appropriately treated with a bortezomib-containing regimen and went on to receive an ASCT. Unfortunately, she relapsed within 1 year of transplant, which suggests very aggressive disease and poor OS. She was treated appropriately with salvage RVD but only enjoyed remission for approximately 5 months. At this point, one could consider using carfilzomib since the patient has received 2 prior regimens including both an immunomodulatory agent and proteasome inhibitor. Data recently published in Blood suggests an anticipated response rate of 23.7% and median duration of response of approximately 8 months.¹ A clinical trial would also be an excellent option for this patient. Aggressive chemotherapy including alkylator-based therapy like hyperCAD or PACE could also be considered in a robust patient.
  

When is a second transplant indicated?

Thomas G. Martin III, MD

Patients who clearly benefit from second autologous stem cell transplant (ASCT) are those who enjoy a remission duration longer than 24 months. Patients achieving a remission duration less than 12 months should not be considered for second transplant. Patients who achieved remission following ASCT between 12 and 24 months fall in the grey zone and should be considered for second transplant on a case by case basis. Obviously, patients should have good performance status and be in remission (chemoresponsive) at the time of second transplant.

Elizabeth Bilotti, MSN, RN, APN

At this time, the indication for a second transplant, outside of a novel conditioning regimen on protocol, would not be recommended. The patient got less than 12 months remission out of the first transplant, presumably when the disease would be more sensitive.

 

Martha Q. Lacy, MD

If you chose a clinical trial for this patient, what agents would you focus on?

Thomas G. Martin III, MD

The 2 most promising drugs on the horizon are carfilzomib and pomalidomide. I would focus on clinical trials that include one or both of these 2 agents. Impressive preliminary results were presented by Dr Richardson at ASCO 2012 utilizing a novel naked anti-CD38 monoclonal antibody.¹ To date monoclonal antibody therapy for myeloma has had limited success but these agents may be more potent when combined with immunomodulatory agents.² A number of phase II and III trials are now underway evaluating the potency of these new monoclonal antibodies. Additional studies combining proteasome inhibitors to mTOR, AKT, and HDAC inhibitors are underway and may demonstrate positive results.
 

References

Elizabeth Bilotti, MSN, RN, APN

In evaluating clinical trials we would focus on pomalidomide, a combination regimen that includes carfilzomib, monoclonal antibodies, and AKT inhibitors.¹

 

References

Katherine Sanvidge Shah, PharmD, BCOP

Our team would likely focus on novel agents with potential mechanisms differing from those she has seen previously such as the monoclonal antibody, elotuzumab (in combination with agents such as lenalidomide and dexamethasone). We would avoid agents known to cause or worsen PN as this patient has experienced grade 2 PN previously. Also, though now FDA-approved for the treatment of myeloma, I would also consider phase II or III carfilzomib combination trials (± lenalidomide, pomalidomide, dexamethasone, etc) trials as most patients do not experience new onset or worsening of their PN. One could also consider AKT or HDAC investigational agents.

Mrs Anderson - Idea Exchange #4

 

High-Risk Cytogenetics

Martha Q. Lacy, MD

What are options for patients who have or develop a deletion of 17p?

Thomas G. Martin III, MD

Those patients who develop del(17p) have a very poor prognosis. Transplantation has limited role as salvage therapy. The most promising agent is carfilzomib as the phase II data suggested that the 17p deleted patient responded equally as well as non-17p deleted subjects. I would treat with carfilzomib as a single agent or on a clinical trial in combination with other agents (ie, carfilzomib + cyclophosphamide, carfilzomib + pomalidomide, carfilzomib + histone deacetylase inhibitor).¹
 

References

Elizabeth Bilotti, MSN, RN, APN

del(17p) suggests poor prognosis at this point in time, but there is no evidence in this setting that it is clinically useful. Thus, with the current mature data, knowledge that the patient has developed a del(17p) would be purely scientific, as it would not provide any assistance in the determination of clinical intervention.

Katherine Sanvidge Shah, PharmD, BCOP

del(17p) confers an especially poor prognostic outcome (lower response rate and shorter PFS and OS). Currently there are no definitive treatments, and thus, would use agents with novel mechanisms of action or those not used previously.

CERTIFICATE OF
CONTINUING EDUCATION
AMA PRA Category 1 Credit(s)™
Educational Concepts Group, LLC verifies that
Mutombo Kankonde, MD
has participated in the enduring material titled
Optimizing Care for Patients with Relapsed/Refractory Multiple Myeloma
on 20-Jan-13 and is awarded 1 AMA PRA Category 1 Credit(s)™
Educational Concepts Group, LLC 1300 Parkwood Circle SE Suite 325 Atlanta, GA 30339 1.770.933.1681 - Main 1.770.933.1692 - Fax www.educationalconcepts.net	Educational Concepts Group, LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Tina Stacy, PharmD, BCOP, CCMEP President Educational Concepts Group, LLC
©2012 Designed and produced by Educational Concepts Group, LLC

NOMENCLATURE OF GENES INVOLVED IN THE 3RD LAW.

1.BIRC5  A CELL CYCLE GENE MAKING A PROTEIN REGULATOR OF CELL CYCLE AND APOPTOSIS MODULATION, SURVIVIN, IN BREAST CANCER IT IS A VALIDATED BAD PROGNOSIS INDICATOR.

2. BUB1
BUDDING UNINHIBITED BENZIMIDAZOLES 1
A SERINE THREONINE PROTEIN KINASE IMPORTANT A CHECK POINT.
LISTEN TO THIS, MUTATION OF BUB1 CAUSES ANEUPLOIDY, CHROMOSOME INSTABILITY AND PREMATURE SENESCENCE
DOES THIS SOUND LIKE A TARGET, I BET YOU!

3.  CCNB1
WIKEPEDIA SUGGESTS:
"
Cyclin B1 is a regulatory protein involved in mitosis. The gene product complexes with p34(cdc2) to form the maturation-promoting factor (MPF). Two alternative transcripts have been found, a constitutively expressed transcript and a cell cycle-regulated transcript, that is expressed predominantly during G2/M phase of the cell cycle. The different transcripts result from the use of alternate transcription initiation sites.^[2]
Cyclin B1 contributes to the switch-like all or none behavior of the cell in deciding to commit to mitosis. Its activation is well regulated, and positive feedback loops ensure that once the cyclin B1-Cdk1 complex is activated it is not deactivated. Cyclin B1-Cdk1 is involved in the early events of mitosis such as chromosome condensation, nuclear envelope breakdown, and spindle pole assembly."

IF YOU DON'T SEE A TARGET HERE, CLOSE YOUR EYES!
CYCLIN B1 BEING AT THE "SWITCH" IS THE LATCH OF THE EXIT DOOR TOWARD CELL PROLIFERATION.  PRESENCE OF CYCLIN B1 COULD SIGNAL MALIGNANT PROLIFERATION.

4.CDC, CELL DIVISION CYCLE------MCM2  (TO BE CONTINUED)

Monitoring Circulating Tumor Cells with the Cellsearch® System Can Predict Prognosis in Metastatic Breast Cancer

New Study Reinforces Important Role of Integrating Therapeutic Monitoring Tools Raritan, NJ (July 13, 2009) – Measuring the change in circulating tumor cell (CTC) count can accurately predict the prognosis and survival in patients with metastatic breast cancer (MBC), according to a newly published report in the July 10 issue of the Journal of Clinical Oncology. The retrospective study compared how well CTCs and a more sensitive than conventional modality, fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), predicted survival in MBC patients on standard therapies. The comparison showed that both technologies significantly correlate to overall MBC patient survival (p<0.001 for CTCs and p=0.001 for FDG-PET/CT). However, a CTC count of five or more could better predict the prognosis and survival in MBC patients.

The CellSearch® System is the first 510(k) diagnostic test used to automate the capture and detection of CTCs, tumor cells that have detached from solid tumors and entered the patient’s blood.

“Measuring CTCs in metastatic breast cancer patients provides oncologists with an additional tool to help us better monitor patient outcomes,” said one of the lead authors, Dr. Massimo Cristofanilli*, associate professor in the Department of Breast Medical Oncology at The University of Texas M. D. Anderson Cancer Center. “The CellSearch® CTC test provides an early indication about patients’ disease progression and overall survival.”

CTCs and FDG-PET/CT are two of the most promising new tools for therapeutic monitoring in patients with MBC. The number of CTCs identified in patients with MBC is related to patient prognosis; a high number of CTCs at any time during treatment is associated with poor prognosis.

“Veridex is committed to providing oncologists with high-value in vitro diagnostic solutions, such as the CellSearch® CTC test, to help them make informed patient care decisions,” said Ken Berlin, general manager of Veridex. “This study demonstrates the utility of integrating the CellSearch® CTC test in therapeutic monitoring of patients with metastatic disease.”


Study Design
A retrospective study was performed on 115 patients with MBC who had the CellSearch test performed as part of their initial staging process at M.D. Anderson over a three-year period. CTC count and FDG-PET/CT imaging were performed at baseline in 102 evaluable patients before starting a new therapy and then again at the midpoint of their therapies (9 - 12 weeks). Patients outcomes were categorized according to midtherapy CTC counts as favorable (< five CTCs/7.5 mL blood) or unfavorable (≥ five CTCs/7.5 mL blood). Based on FDG-PET/CT, patients were considered responders if metabolic activity of target lesions decreased more than 25% compared to baseline, and if there was no change or a decrease in size. Patients were considered nonresponders if the FDG uptake was similar or higher and/or if target lesions had increased in size. CTC counts and FDG-PET/CT response at midtherapy were compared, and univariate and multivariate analyses were performed to identify factors associated with survival.


Study Findings
A total of 115 patients with metastatic breast cancer were considered for the study and 102 were evaluable for efficacy. The median overall survival time was 14 months (range, 1 to > 41 months). In univariate analysis, both midtherapy CTC counts and FDG-PET/CT response predicated overall patient survival (p<.001 and p=.001, respectively). The overall concordance between the CTC counts at midtherapy and FDG-PET/CT was 67% for response/nonresponse and 74% for progression/nonprogression. In the discordant category, detection of five or more CTCs during therapeutic monitoring accurately predicted prognosis in MBC beyond metabolic response. FDG-PET/CT was able to predict outcome in discordant instances of patients with less than five CTCs at midtherapy. Midtherapy CTC levels remained significant in a multivariate analysis (p=.004). These results suggest a higher and independent predictive value of CTCs compared with FDG-PET/CT among patients with a CTC count of five or more. In addition, there was a strong correlation between complete response and the absence of significant levels of CTCs (median CTC level zero).
* Dr. Cristofanilli is a principal investigator for a CellSearch® validation study and received honoraria from Veridex, LLC.


About CellSearch®
The CellSearch® test works by using antibodies that are joined to microscopic iron particles, called ferrofluid. These antibody/ferrofluid combinations attach very specifically to CTCs. Powerful magnets then draw the CTCs out of the blood sample and they are then stained with additional bio-molecules and chemicals so that they can be positively identified as CTCs.

CellSearch® test results should be used in conjunction with all clinical information derived from diagnostic tests (e.g., imaging, laboratory tests), physical examination and complete medical history in accordance with appropriate patient management procedures. For further information on intended use, warnings and limitations, please refer to the CellSearch® CTC Test Instructions for Use, or visit www.veridex.com.


About Veridex, LLC
Veridex, LLC, a Johnson & Johnson company, is an organization dedicated to providing physicians with high-value in vitro diagnostic oncology products. Veridex's products may significantly benefit patients through earlier disease detection and may enable personalized strategies to help improve patient management and outcomes. For more information, visit www.veridex.com.

# # #

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from Johnson and Johnson site!

IN METASTATIC DISEASE THAT IS ADVANCED, ONE OF THE GENE MENTIONED IS THE NME1/NM23A

This gene (Non Metastatic Cell 1) is expressed at 17q21.3 and produces protein NM23A.Contrary to its name, it is noted to be expressed in advanced Metastatic disease and as such could have prognosis indication.
Remember, there is that notion that if a Molecule found in Metastatic state is present in the early stage of a cancer, it is predictive of more advanced cancer, higher recurrence rate and higher mortality risk.

CPRIT BACK IN THE NEWS!

IN AN INTERVIEW JUST FEW DAYS AGO WITH THE HOUSTON CHRONICLE,
Governor Perry was wrongfully condemned and attacked by the newspaper when he stated: "CPRIT' job is not just to fight cancer, but to create economic avenues from which wealth can be created".  At CRBCM we believe that any investment does that.  And investment in health does create wealth no matter how you want to sugar coated it.  They are Cities across the country which would be empty without health enterprise money. Fighting cancer is a noble thing but fighting cancer and changing lives by creating opportunities is even better.  You can't advance this noble cause without putting brains to work.  When you pay brains to work you create opportunities and wealth whether you like it or not.   The wrong way to invest however is to become biased, distributing the wealth to Universities exclusively and their cronies at each CPRIT fund allocation sessions.  And all this based on assumptions that Universities are the only media of scientific research.  We argue that CPRIT can create scientific research in new locations as long as qualified people can be hired to do the work.  Universities have funds from their vast pool of donors.  They should be the number one beneficiaries we agree, but not the only one.  Also the distribution of wealth should not exclude some cities, Biotech companies benefiting from grant should not locate only to Houston, Dallas or Austin.  That's the argument El Paso, the fourth city (population wise) in this State, is making!  So yes CPRIT should improve its policy.  New requirements need to be put in place to allow a fairness in this system!   And a bigger pool of beneficiaries is called for to expand the pool of ingenuity in the race for cancer  cure


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 Referenced Article

Mission creep

CPRIT is supposed to help find treatments for cancer, not 'create wealth.'

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FOLLOWING UP ON THE 3RD LAW. (SWING OF THE PENDULUM)

WITH CELL DIFFERENTIATION AT ONE EXTREME, AND CELL PROLIFERATION AT THE OTHER SIDE.  During Malignant transformation, the pendulum swings from de-differentiation to proliferation.  Pushing the EXIT-door open.  At the molecular level, there is an increased expression of genes involved in promoter regulation (TTK, E2F1), but also a gene is involved with the resumption of mitotic phases BUB1, MCM2,CDC.  Microfilament formation and Histone related molecules also reappear ((NUSAP1,ZWINT,CENPA), but also CEP55, CKAP).  Activity at the promoter region is proven by overexpression of EZH.  Relevent cyclins involved are proven by activation of CDKN2 .   Over-expression of any combination of these genes marks the first sign of a Cancerous trend in a differentiated cell.

Of all these, E2F1 and NUSAP-1 seem to be the focus of target therapy as interactions with HMGA are suggested in the literature!

THIRD LAW OF NATURE, NO PROLIFERATION AND CONCURRENT DIFFERENTIATION. HOW THIS LAW CAN BE USED FOR CANCER CURE

While the first and second law refer to the well being of the nucleus for protection of the cell division and its integrity, the 3rd law pertain to cell differentiation.  Basically the first law say that if DNA is altered, cell need to be stopped to allow correction.  And the powerful P53 Activation has been put in place for that.   Significant alteration of DNA will send powerful signal to P53, cause itS activation, and lead to cell cycle arrest.  This is where the power of Cisplatin based combinations reside.  And sure enough, this the basis of the notion that strong repair system will weaken this type of drug.  The all notion of Microsatellite Instability and its role in cancer is based on this law.

The 2nd law, is significant destruction of the scaffold of Mitosis, the Microtuble and all actinic or actinic like molecules which makes mitosis impossible should lead to cell destruction no matter what.  The intergrity of this system of Microtubule and filament not only control the critical phases of Mitosis (Metaphase, Anaphase), it control the integrity of membrane but also the cytoskeleton and cell mobility.  It is the nervous system of the cell and the control of various anchors.  Organelles of the cell are not just free flowing in general, they are anchored  to the Reticulum membrane most of the time (unless destined to Autophagia for cell preservation) and important Molecules involved in Apoptosis such as Cytochrome are attached to Mitochondrial membranes.   Suffice is to say that major alteration to these line of proteins will bypass major Cytosol based protection including the Bcl-2.  This is the strenghth  base of Taxol and Ixabepilone.  It is the explanation for neuropathy and cardiac toxicity of Adriamycin. It is partially the explanation of Q-T prolongation etc.

The 3rd law is more complex, cell differentiation should not go with full proliferation.  Cell that are fully differentiated should not be multiplying like crazy. and for sure, we do not want hundred  of livers, 3 brain or 99 lungs.  Have wonder why Atypia goes along with cancer transformation.  Well you have to lose differentiation to restart multiplying again!  And the poorly differentiated, the worse the magnitude of cancer.
The story of differentiation goes like this:

All cells have the same genome.  But based on their position, internal and external stimuli, they will  go one way or the other to specialize in a certain function for tissue and organ specialty.  The external stimuli could be a change of Oxygen content, Ph, or messages from your neighbor cells sending growth messages etc.  Internal stimuli are cytokines, morphogens, growth factors and signaling molecules or intracellular particulates.  These will stimulate Receptors or pathways (such as the NF-kB) and cause genetic and epigenetic consequences in the Nucleus.  Expression of genes which the cell want and need to be specialized will be achieved through heavy duty transcription of genes.  On the other hand, to control the uniqueness of the tissue, epigenetic closure of  multiplying capability genes is first completed to seal the deal on the fate of the cell.  Differentiation is like an EXIT door.   you can enter, but don't try coming back.  And once you enter, immediately you are taking care by the transcription machinery directing you to where you should be going and you lose multiplication ability.   The door however is not fully irreversibly closed.  In cancer the flow of force reverse and instead of moving forward, the door is reopen and the differentiation machinery is reversed or disabled (poor differentiation), the door is reopen, and the cell start to multiply again as part of the cancerous process.   Studies of Estrogen effect Vs Progesterone has shed some light in this case.  When one look at estrogen, it has more effect on the Exit door, constantly pushing that door toward Multiplication than Progesterone that has little effect of the door but with similar effect on the terminal differentiation.  Making Estrogen more cancer inducing than progesterone.  Yes taking Estrogen gives you the relief of symptoms but it is the push toward reversing the Exit door flow (toward proliferation transcription) that is the problem!
Is expression of H3K or FG2 the markers of Exit door tinkering, we are working hard to determine this.

AS ONE LOOK AT THIS FLOW TOWARD DIFFERENTIATION, A SLEW OF THERAPEUTIC TARGETS  EMERGE, THE ARRAY GOES FROM :

1. NEIGHBOR MESSAGES
2. ENVIRONMENT CHANGES
3. BLOCKING RECEPTOR UPSTREAM THE NF-kB AND COMPARABLE PATHWAYS
4. BLOCKING  THE PATHWAYS
5. SEALING THE DOOR
6. METHYLATION OF GENES, AND PARALYZING OR MODULATING ENZYMES INVOLVED IN EPIGENETIC CHANGES (PCAF, p300 MAY BE)
7. BLOCKING TRANSCRIPTION MACHINERY, EXPRESSION OR GENES DIRECTLY.

CERTAINLY, SIGNS OF RESUMPTION IN ACTIVITY OF GENES MEANT FOR PROLIFERATION IS AN EARLY SIGN OF CANCEROUS TRANSFORMATION, AND The BEST WAY TO DETERMINE THAT A DRUG IS CANCER PRODUCING.

AS A MATTER OF FACT, THIS IS HOW PAMIDRONATE AND OTHER BIPHOSPHONATE ACT TO CONTROL CANCER, BY INCREASING DIFFERENTIATION AND RELIEVING PRESSURE ON THE EXIT DOOR.

WELL DIFFERENTIATED TUMORS WILL HAVE A BETTER PROGNOSIS BECAUSE THEIR GENERAL FLOW OF FORCE IS STILL TOWARD DIFFERENTIATION AND NOT THROUGH THE PROLIFERATION DOOR .

WE ARE WORKING HARD AT CRBCM!

An usere Leser aus Deutschland

Guten Tag ... oder ist's noch Nacht in Deutschland?
Jedenfalls, es ist toll unsere Mitleser aus fernen Landen begruessen zu koennen, wissenschaftliche Denkanstoesse kennen nun mal keine Grenzen: teilen Sie uns Ihre Hypothesen, Beobachtungen und Interessengebiete mit! Wir sind ganz Ohr... Bis bald. Tschuess!

TALKING DE-ACETYLATION, PANOBINOSTAT

Panobinostat is a De-acetylator inhibitor for Histone, meaning that it paralyzes a few enzymes perinuclearly, therefore blocking Mitosis this way.
It has demonstrated Activity in Relapsed/Refractory Hodgkin's disease post transplantation. An area where it does not have much competition.   And here it is actually pretty good at achieving like most target therapies a 30% effectiveness and  with additional stable diseases.  A respectable effectiveness.
Now  it is being tried in Non Hodgkin's disease with Rituxan.  We will update you on this!

JAK SIGNALING, STIMULATED BY INTERFERON AND OTHER GROWTH FACTORS AND RELEVENT CYTOKINES CANNOT DO ITS WORK UNTIL IT REACHES TRANSCRIPTION FACTORS OF WHICH AMPLIFICATION IS TRANSLATED IN MODULATION OF REGULATORS OF PROMOTOR GENES.
This links the JAK signaling Pathway to the STAT.
In a recent article by Lee et al.,
"Acetylation of STAT3 is crucial to Methylation of tumor suppressor gene promoters", the authors, tying their work to Breast cancer, state: "Furthermore, reduction of acetylated STAT3 in triple-negative breast cancer cells leads to demethylation and activation of the estrogen receptor-α gene, sensitizing the tumor cells to antiestrogens. Our results also demonstrate a correlation between STAT3 acetylation and methylation of estrogen receptor-α in melanoma, which predicts melanoma progression. Taken together, these results suggest a role of STAT3 acetylation in regulating CpG island methylation,"
 These could be used as further supporting evidence for our proposed combination of mTOR with Interferon in triple negative Breast Cancer.
There is another important issue raised here that depression in STAT level may activate Estrogen receptor with a possibility of causing Breast cancer or progression thereof!

1.Is STAT genetic amplification a predictor of Hormonal manipulation response to intervention
2. Is activation of these STAT an effective prevention therapy in patient with BRCA positivity, in otherway should STAT status be assessed in patient participating in prevention with Tamoxifen and Raloxifen to really measure and understand subset variances.
3.Does inclusion of mTor and Cytokines break the need of testing ER positivity, or at least weaken the need of such determination so long as the STAT is depressed?
4.Role of Deacetylation of STAT in Breast Cancer/Target of therapy.  De-Methylation of promoter gene to stop their silencing.?

NEW LIPOSOMAL VINCRISTINE WITH EFFICACY IN RELAPSE/REFRACTORY PHILADELPHIA POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA

AT 2.25 MG/m2 IV WEEKLY
COMPLETE REMISSION RATE 4.6%
WITH OF COURSE NEUROPATHY IN ALMOST 40% OF PATIENTS
BUT EFFECTIVE EVEN WITHOUT ASPARAGINASE
Liposomal encapsulation prolongs its presence in the blood and ability to penetrate the marrow, lymph nodes and spleen).
------------------------------------------------------------------
Jakafi, for your Myelofibrosis patient with positive JAK2V617F positive and negative patient
with a 35% reduction in splenomegaly at 24 weeks occurring in 41% of patients.
will check out the JAK signaling!

PUTTING THINGS TOGETHER IN TRIPLE NEGATIVE BREAST CANCER BRCA TESTING AND THE MTOR UNVEIL NEW PARADIGM SHIFT AT CRBCM

Now that we know that up to 85% of triple negative Breast cancers could have the BRCA Mutation in some cohort,  it is becoming a guideline shift that this test be performed not only for prognosis, but also for therapeutic information.  The presence of BRCA positivity generally imparts worse prognosis of this disease.
But knowing if it is BRCA1 positive will give it an atypical morphology as per  the article from Stanford suggests:

"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."

BRCA 2 is mostly of Luminal histology and therefore will be more susceptible to PIK3CA/MTOR blockade which will explain their better prognosis.  We still believe that as we move forward, the role of interferon and Mtor is still to be explored.  As that in Luminal triple negative BRAC2 positive hormone manipulation with MTOR could still be tried. We still believe that EGFR inhibitor in combination to MTOR inhibitor and inhibitor of NK-kB or antiproteasome are all potential add-ons!

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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. (MORE: How to Maximize the Potential of mTOR Inhibitors in Breast Cancer—More Questions Than Answers) 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.

Medscape Hematology-Oncology > Kris on Oncology

Learning to Swim in the Pool of Genetic Data

Mark G. Kris, MD

Drug & Reference Information

• Non-Small Cell Lung Cancer Staging
• Imaging in Non-Small Cell Lung Cancer
• Genetics of Non-Small Cell Lung Cancer

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

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!