CRBCM KEEPS ADVANCING!

History at CRBCM has shown that our Blog has reached now over 6000 hits and is being followed internationally.  This a testimony to the efforts we put into the science we discuss here.  We should also recognize that the CPRIT story has attracted people internationally because we have noted a steady following by international readers every time the CPRIT name is mentioned.  CPRIT with its up and down remains a game changer attracting the eyes of the world.  And the CPRIT seal is coveted right here in Texas and of course around the world as companies attracted by the CPRIT emblem are fighting to move to Texas.  CRBCM would also want to merit the CPRIT Seal so it can break free and really fight for the cure.
The fight is ahead, we believe we can win.  At time we, at CRBCM, feel we cannot gather enough political muscle to convince those who review our project.  But every time we remember the mission, every time we look around and remember the dead from cancer, our resolve comes back and we go again banging doors.

Our clinic has been given new wind, so we are not going anywhere but up and in their face until we are heard.  The CRBCM is a Coalition and Coalition by definition fight until those who are resisting this mission get it!  With the cancer Center advancing by the Glory of the almighty, and so his our mission.  We are not backing down.  We have a plan, our knowledge and insufficiencies  can be helped, we will get there! The future is brighter by the day...with every resistance, we double our efforts!   

As of 1/7/2013, ----------------------  United States	5497
Germany	160
United Kingdom	93
Russia	57
France	37
Sweden	24
Latvia	22
South Korea	15
Poland	15
Ukraine	15

Commentary: This information is highly important.
Often patients will arrive with an outside biopsy. The biopsy should be processed for p16 testing and a reflex HPV test if p16+. There are no other molecular markers that are indicated for routine testing yet.

 

HPV-related cancers have some distinct characteristics such as they are caused by high-risk HPV (HPV16), restricted to oropharynx, have distinct molecular markers, usually have "good" prognosis, and patients are typically younger and in general good health (Goon et al, 2009).¹ Tumor HPV testing is now "recommended" by NCCN in 2012,² which changed from being "suggested" in 2011. NCCN recommends either immunohistochemistry for analysis of p16 expression or HPV in situ hybridization (ISH) for HPV DNA detection in tumor cell nuclei. The prognosis of HPV status is defined by RTOG 0129 study that compared accelerated concomitant boost radiotherapy to standard radiotherapy. Of the 323 oropharyngeal tumors that were tested 64% were HPV+ and of those, 96% were HPV16+. P16 is a marker of Rb inactivation (Gillison et al, 2009).³ Another study that assessed HPV positivity was TAX324 study where demographics by HPV status showed that from the 110 patients tested, 50% were HPV+, were younger, higher lymph node burden, smaller primary tumors, and better performance status (Posner et al, 2011).⁴ The survival was significantly different for HPV+ compared to HPV- patients. The HPV+ patients also demonstrated better local regional control (Posner et al, 2011).⁴

 

A recent study is consistent with the detection of HPV16 status using a combination of tests such as in Ned's example where IHC and PCR were used. This study evaluated the importance of accurate testing of HPV16. While the tests were comparable in sensitivity, there were significant disparities in specificity when p16IHC, HR HPV ISH, or DNA qPCR was used independently (Schache et al, 2011).⁵

Marshall R. Posner, MD
Director, Head and Neck Medical Oncology, Division of Hematology/Medical Oncology, Mount Sinai School of Medicine
Professor of Medicine, and Professor of Gene and Cell Medicine, The Tisch Cancer Institute
New York, NY

After the initial workup and additional requests, we asked about the most feasible treatment for Ned: surgery with post-op CRT; CRT only; sequential chemotherapy; or palliative chemotherapy/supportive care.

While surgery could be accomplished initially, it does not address the biology of this disease, which will require post-operative CRT and possesses a high risk of distant metastases. In addition, the functional consequences of the surgery would significantly reduce this patient's quality of life (NCCN, 2012).¹

 

CRT offers a standard of care for this stage of disease, and is associated with improved survival compared to radiotherapy alone (Sharma et al, 2010).² Data from randomized phase III trials supports the use of weekly or bolus cisplatin (Adelstein et al, 2003),³ carboplatin and 5-FU (Denis et al, 2004⁴; Bourhis et al, 2012⁵), or cetuximab (Bonner et al, 2010)⁶ with standard fractionated radiotherapy. IMRT would not offer much in terms of salivary sparing given the extent of disease. Radiation would be delivered over 7 weeks (NCCN, 2012).¹

 

Sequential therapy with TPF followed by CRT also represents a standard of care. Phase III trials have demonstrated that TPF (docetaxel, cisplatin, 5-FU) regimens are well tolerated and improve survival and organ preservation compared to PF (Cisplatin, 5-FU; Van Herpen et al, 2007⁷; Posner et al, 2007⁸). There are no completed trials comparing TPF sequential therapy to CRT (Haddad et al, 2012⁹; Lorch et al, 2012¹⁰). Sequential therapy can reduce tumor volume and improve the functional outcome of subsequent definitive CRT, improve local regional control, reduce the risk of distant metastases, and provide response data to inform later treatment decisions.

 

Palliative/supportive therapy might be considered if the patient is not motivated to undertake an aggressive course of therapy, or has significant psychological barriers to completing and rehabilitating from an aggressive therapeutic course.

 

Statement of Participation
The Postgraduate Institute for Medicine certifies that
Mutombo Kankonde, MD
has participated in the enduring material titled
Ned Visit 1: A 57-year-old Man with Human Papillomavirus (HPV) Negative Oropharynx Cancer
on 07-Jan-13 and is awarded 0.5 AMA PRA Category 1 Credit(s)™.
	The Postgraduate Institute for Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
Postgraduate Institute for Medicine 304 Inverness Way South, Suite 100 Englewood, CO 80112 (303) 799-1930 (303) 858-8848 - Fax	Trace Hutchison, PharmD Director of Medical Education Postgraduate Institute for Medicine

 

 

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Downstream from the MAP-Kinase is located the JNK patways with C-JUN as main member. 
This pathway is usually stimulated by stress whether the stress is radiation or a Tumor Necrosis factor.
Antibody to C-jun arrest the cell cycle at G1 to S phase.  Speculation is this how DNA alteration, which is perceived as a stress by the cell, though this pathway, activate P53 and induce cell cycle arrest.  This pathways seems to participate in tissue differentiation.  Formation of the brain is particularly compromised by mutations at C-jun (most likely located at Chromosome One).  C-jun may regulate few promoter gene expression and interact with Cyclin D1.  C-jun is to be tested for mutation in cancer naturally responsive to growth factors and interleukins  (And response to Radiation therapy).  We are digging deeper to clarify some of these assumptions!

Rita Levi-Montalcini Dies

Jan 1, 2013

Rita Levi-Montalcini speaking at the international NGF meeting 2008: Katzir Conference on Life and Death in the Nervous System, at Kfar Blum, ...(from science blog)

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Nobel laureate and pioneer scientist died.she discovered and described Nerve Growth Factor at a time when current evaluation instrument did not exist. Reportedly, even during the war, she continued her work in a makeshift lab at home.  No need for large Biotech companies or large university lab. These are the pioneer that inspires work at CRBCM!  Discovery can be achieved by anyone who believes their cause is right and the problem is here to be solved.  We are inspired by Rita.  May God bless her soul!

Mutombo --

As a Marylander, you probably know all about the huge crowds a presidential inauguration brings.

Every four years, people from across the country come to D.C. and Maryland for inaugural events -- and thousands of amazing people like you step up to be world-class hosts, and make sure everyone has a great time.

This year, I'm asking you to offer that hospitality in an official capacity by lending a hand as an inauguration volunteer. Volunteers will play an important role in making the events before, after, and including the inauguration ceremony a success. We won't be able to do it without you.

Can you volunteer to help out at an event during Inauguration Weekend, or on the big day?

We're going to need a lot of solid people to help make sure we put on an event worthy of the president we'll be swearing in -- and I know we'll be needing some of that Maryland charm, too.

There are a number of events you can be a part of -- take a look, and sign up if you can help out:

http://action.2013pic.org/Volunteer-at-the-Inauguration

Thanks,

Marlon

Marlon Marshall
Senior Adviser
2013 Presidential Inaugural Committee

P.S. -- If you sign up to volunteer, you'll get to be a part of this historic event. More than that though, I guarantee you'll have fun, too.


NOTE:  The Obama Campaign has not realized I moved to El Paso, TX. I am a Texan now!
still own my house in MD waiting for the market to improve a bit!
GO MINERS!

MAP KINASES /ERK
THE MAP KINASES OR MITOGEN ACTIVATED PROTEIN KINASE WHICH WE SPOKE ABOUT RECENTLY AS THEY RELATE TO PANCREATIC, RENAL, AND BRAIN TUMORS,
are downstream from the Epidermal Growth Factor (EGFR) pathways.  When speaking about a pathway,  it is  like a dance where A will dance with B,  A will flirt with B, and B will then leave A and go dance with C and flirt again, and C will the move to D and Flirt and so on.  With each Flirting, there is an exchange of all kinds of things including emotions (and I am not kidding) . Down this pathway is found Molecule involved with Schizoaffective disoders such as bipolar state.  The Actual Pathways is as follow:

EGF--EGFR--GRB2--SOS (My favorite Sons Of the Sevenless) which switch on or excite RAS--RAF--MEK--MAPK (our MITOGEN Activated Protein) which switch a number of Molecules depending on location including MYC and the action goes into the Nucleus to stimulate transcription genes and production of growth proteins.

At each flirt contact, we can intervene and spoil the moment with a Target therapy.
At RAS-RAf we can spoil it by sending Sorafenib or Vemurafenib and treat lung cancer.
At the Raf-MEK, we can send in Selumetinib or Trametinib to inhibit MEK and so on.

At each level, the flirting is actually a chemical reaction mostly involving phosphorylation.  Spoiling the language of phosphorylation is achievable but the challenge is that even normal cells uses this language so it is hard to be selective.  Altering phosphorylation will affect many other normal functions of cells including energy production.  This is an area of intense investigation. It would be a lack of respect if we did not of memtion EGFR inhibition which is the main action in treatment of many important cancer from Head and neck to lung, colon, gastric and so on so forth. And you know the drugs!

ELF5 A NEW PROGNOSIS PREDICTOR OF BREAST CANCER THAT MAY BE SIGNIFICANT IN TRIPLE NEGATIVE BREAST CANCER.  ELF5 IS REPORTED TO BE THE PROTEIN STIMULATING MILK PRODUCTION. IN A BREAST CANCER CELL, IT FAILS TO DO ITS MILK PRODUCTION WORK BUT REPORTEDLY INDUCES GROWTH OF THE CELL PARTICULARLY IN HORMONE RECEPTOR NEGATIVE TUMORS.  POTENTIAL FOR TARGET THERAPY IS INFERRED.  

"CYP2D6 Has Impact on Effectiveness of Tamoxifen

Roxanne Nelson

Dec 31, 2012

Although previous studies have been somewhat inconsistent, a new study shows that breast cancer patients taking tamoxifen who have genetic alterations in CYP2D6 have a higher likelihood of both disease recurrence and death.
Approximately 5% to 7% of European and North American populations are considered to be poor metabolizers of tamoxifen, and there is a simple test that can identify these"
 FROM MEDSCAPE

ABOUT LYMPHOMA

A simpler 2-drug regimen of bendamustine plus rituximab has the potential to become the new standard first-line therapy for indolent NHL, in place of the current standard regimen of rituximab plus cyclophosphamide, hydroxydaunorubicin, vincristine (Oncovin), and prednisone (R-CHOP). Adverse events for the two drug regimens are shown. The 2-drug combination significantly improved progression-free survival to 54.8 months, compared to 34.8 months with R-CHOP—a gain of 20 months.^[13]


FROM MEDSCAPE
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NEW FUNDING STRATEGIES ARE NEEDED FOR CPRIT.

The experience we have had with CPRIT clearly calls for new funding policies at CPRIT.  CPRIT has chosen to mimic NCI, a national organization that answer to a broad range of universities, investors and individual researcher of all colors, size, shape, and dimensions.  At a state level, the pool of Universities and potential applicants is clearly much smaller and the pool of people with powers and connections is much smaller.  The risk of cronyism and abuses is much higher.   People with University background and connections will be biased by their training, connections and prior exposure.  This is not to suggest that their choices are necessarily bad.  But by definition, being BIASED means you miss certain opportunities and perspectives that may have had a critical impact to yours programs. It is important that the new CPRIT think outside this box!  The new leadership should look at Texas as a global State that need a network of prevention ready systems where new discoveries can be quickly implemented and used.  Whether that discovery is new healthy behavior, drug or target therapy.  It needs regional relays and community network centers sharing CPRIT news,views and outlook, ready to broaden the reach of the new findings.  This conspiratory disconnected current system has no clear future and set a path to a limited impact of CPRIT. It is only good for politicians and Biotech owners.  It is not a state structure responding to state needs.  The cure should not benefit a few but a well distributed state network.

We believe that CPRIT should invest in a statewide network, distribute the wealth statewide, and relocate new biotech companies through a network of locations in the whole Texas, to dilute the club mentality prominent in Houston.  We also agree with the Democratic State Representative Craig Eiland statement: 'This was Cancer prevention research, not and Hedge fund or Venture Capital".

The current system is a prime opportunity for backdoor deals and its implementation fragmentary and disconnected because it does not own a state network.  The Citizen of the lone Star state have been duped into signing for a few university funding source.  CPRIT should have had regional offices, with regional competitions throughout the entire state, not 3 cities taking 80 percent of state money!   Were is the fairness.  All the Biotech companies coming to the State  should not go into 3 cities. Work benefit distribution is unequal and only political power towns are benefiting.   There are tissue banks in Houston unknown to most people in Texas including researchers in the field.  Why?  information is not flowing through a network which does not exist.  Only CPRIT office workers know about these banks!

Reviewers coming from outside the State may provide an independent scientific opinion but how do they know enough about the need and impact of such program in a specific location.  Is need of community an important criteria for a prevention program?  How does an outsider evaluate such a need?

Suffice is to say that we need to take advantage of this pause to reshape and reload for a greater impact or larger CPRIT foot print in Texas!

Stickability. Focus. That's CRBCM. Never giving up.

CPRIT's appeal procedure currently being unworkable, we will simply re-submit our research projects for the "Intervention and research through flowcytometry and cytogenetic studies of basal cell type breast cancer in African American women and ways to reverse mortality"
and for the creation of a
"Comprehensive Health Intervention Program to Reverse Breast Cancer Mortality in El Paso, Texas" that includes the construction of a Cancer Center for education, prevention, screening, treatment and survivorship programs open to all El Pasoans (instead of having to travel to Houston or even out of state).

Targeting of MAPK-associated molecules identifies SON as a prime target to attenuate the proliferation and tumorigenicity of pancreatic cancer cells Full Text
Molecular Cancer, 01/05/2013

Furukawa T et al. – Pancreatic cancer is characterized by constitutive activation of mitogen–activated protein kinase (MAPK). Activation of MAPK is associated with the upregulation of genes implicated in the proliferation and survival of pancreatic cancer cells. The authors hypothesized that knockdown of these MAPK–associated molecules could produce notable anticancer phenotypes. The results indicate that SON plays a critical role in the proliferation, survival, and tumorigenicity of pancreatic cancer cells, suggesting that SON is a novel therapeutic molecular target for pancreatic cancer.

High levels of phosphorylated MAP kinase are associated with poor survival among patients with glioblastoma during the temozolomide era
Neuro-Oncology, 01/04/2013

Patil CG et al. – This study provides quantitative means of evaluating p-MAPK in patients with GBM. It confirms the significant and independent prognostic relevance of p-MAPK in predicting survival of patients with GBM treated in the temozolomide era and highlights the need for therapies targeting the p-MAPK oncogenic pathway.
Methods

• Nuclear p-MAPK expression of 108 patients with GBM was quantified and categorized in the following levels: low (0%–10%), medium (11%–40%), and high (41%–100%).
• Independent predictors of overall survival were determined using a multivariate Cox proportional hazards model.
• Our study included 108 patients with newly diagnosed GBM. Median age was 65 years, and 74% had high Karnofsky performance status (KPS ? 80).

Results

• Median overall survival among all patients was 19.5 months.
• Activated MAPK expression levels of <10%, 11%–40%, and ?41% were observed in 33 (30.6%), 37 (34.3%), and 38 (35.2%) patients, respectively.
• Median survival for low, medium, and high p-MAPK expression was 32.4, 18.2, and 12.5 months, respectively.
• Multivariate analysis showed 2.4-times hazard of death among patients with intermediate p-MAPK than low p-MAPK expression (hazard ratio [HR], 2.4; P = .02); high-expression patients were 3.9 times more likely to die, compared with patients with low p-MAPK (HR, 3.9; P = .007). Patients aged ?65 years (HR, 2.8; P = .002) with KPS < 80 (HR, 3.1; P = .0003) and biopsy or partial resection (HR, 1.9; P = .02) had higher hazard of death.
• MGMT and PTEN expression were not associated with survival differences.

REVISITING THE FIRST LAW OF NATURE AND IDENTIFYING THERAPEUTIC TARGETS.

As we proposed earlier, there are major forces in the cell that once unleashed drive cellular metabolic pathways in certain direction to preserve life. We coined these laws of nature because they cannot be changed fundamentally.  The first one is that DNA aberrancies will trigger activation of P53 and stoppage of cell cycle to allow correction.  If those corrections are insufficient, cell death is triggered both downstream (toward the nucleus), but also upstream (toward death receptors).  Indeed, one of the ways the P53 leads to cell death is through modulation of death receptors to induce the Caspase 8 machinery of programmed death.

Modulation of Death receptor is an interesting phenomenon.  it goes to the basic notion of sensitization and desensitization.  Dilute active receptors and you have less effect.  Death receptors once stimulated usually by Tumor Necrosis Factor, lead to Caspase 8 activation (through FADD dependent or independent route).  To decrease the chance of Random stimulation of Death Domains, the cell makes Decoy Receptors which divert the stimulant toward them instead of the Death Domain.  The more the decoy or mimic receptors, the less the chance the stimulant will reach the Death Receptor (DR).  The best Dummy (Decoy) Receptor does not have any intracellular portion of the Receptor, therefore no induction of intracellular signals is initiated. Another protection is the Silencer Of the Death Domain (SODD) which does exactly what its name says!
Toning down the TNF machinery is one of the modulation mechanism.

4 important observations:

1.  Activated Caspases attack
-laminins reportedly leading to Nuclear Shrinkage and Chromatin condensation
-destroy inhibitors to Endonucleases release leading to further DNA Break down
-MOST importantly, Caspases attack the Cytoskeleton (Actin, Pletin, ROCK1, Gelsolin,Microtubules and all filamentous structures, THIS TRIGGERS THE UNFOLDING OF THE 2ND LAW OF NATURE WITH LIBERATION OF CYTOCHROME C FROM THE MITOCHONDRIAL MEMBRANE INTO THE CYTOSOL, AND ACTIVATION OF CASPASE 9 AND ALL SUBSEQUENT CASPASES, SETTING AN IRREVERSIBLE COURSE TO PROGRAMMED DEATH.

2. You note that the 2nd law is downstream the 1st law, therefore targets driving the 2nd law will bypass the mechanisms of resistance in place to stop the progression of the 1st law.  This includes the Bcl-2.

3.Many targets are located here in the functions of Death Receptors.  These include the Receptor itself (CD95),  but they also include CD 120, AP03, P55, P60, P75 (NERVE), C-JUN (STRESS), FADD, APO2L, AND OF COURSE THE SILENCER (SODD).

4. The gene encoding the Death Receptor and several Decoys has been traced to 8p21-24.  THE QUESTION IS, WILL PRESENCE OF MUTATION OF 8p PREDICT FOR RESPONSE TO INTERLEUKINS, INTERFERON OR TO SOME BIOLOGIC INTERVENTION?  IS OSTEOPROTEGERIN (8q23-24) PRESENCE SUCH A PREDICTOR?

FOR BASAL CELL LIKE BREAST CANCER PATIENTS, IS MYC  (8q24.12) PRESENCE A SIGNAL THAT TUMOR GROWTH FACTOR ARE THE MAIN DRIVING FORCE?  IS AVASTIN AND RELATED ANTI-GROWTH FACTORS IMPORTANT IN THE THERAPEUTIC STRATEGY?

WE ARE HARD AT WORK AT CRBCM!

PARADIGM SHIFT IN HEMATOLOGIC MALIGNANCY
"NO MORE CHEMOTHERAPY"
FROM A DISCUSSION BY DR BRUCE CHESON, GEORGETOWN UNIVERSITY.
===========================================================
1.IBRUTINIB

-A Bruton Thyrokinase Inhibitor, working downstream B Cell Receptor
-active in Indolent lymphoma, showing 40% Response Rates in relapse / refractory setting where Activated B cell B  (ABC) phenotype is expressed.
-Here also Revlimid is being used
-and now being tried in Follicular lymphoma
-It is being given in combination with or after failure of Bendamustine and Rituxan.

2.IDELALISIB

-It is an inhibitor of PI3 kinase (in its Delta form)
-shows significant Activity in Indolent Lymphoma, CLL, and Mantle cell
-It is given after or in lieu of HYPERCVAD in Mantle cell lymphoma

3. BRENTUXIMAB VEDOTIN

-AN ANTIBODY CONJUGATE
-Indicated in Hodgkin Lymphoma, Anaplastic large cell lymphoma, CD 30 positive, and may have activity in Diffuse Large cell Lymphoma

No chemotherapy needed, and certain of these products have minimal Thrombocytopenic side effects, allowing easy combination with other drugs!

New Genetic Links to Colorectal Cancer Identified

 By Anna Azvolinsky, PhD¹ | January 2, 2013

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

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Three new genetic links to colorectal cancer have been identified using a large genome-wide study of more than 28,000 individuals. The three new variants may hold potential new therapeutic targets and are helping researchers better understand the biology of colorectal cancer as well as the differential genetic basis of colorectal cancer in European and Asian populations. The study is published in Nature Genetics.

Researchers at the Vanderbilt-Ingram Cancer Center in Nashville, and colleagues in China, South Korea, and Japan analyzed 5,252 colorectal cancer cases and 9,071 control samples from the Asia Colorectal Cancer Consortium (ACCC) to identify novel colorectal cancer risk factors. The samples studied came from China, Japan, and Korea. The results were compared to the known genetic variants identified from European population results.
“This kind of work would not be possible without the support of investigators from multiple centers,” said Wei Zheng, MD, PhD, an Ingram professor of cancer research and lead author of the study.
The top four genetic loci were compared to two previous data sets—the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colon Cancer Family Registry (CCFR). Three of these were also identified in these previous European analyses, although the three loci were more strongly associated with the East Asian populations than the European population.
“A lot of work has been done in European descendants,” said Zheng. “Our study is the first one conducted in multiple East Asian populations. Looking at different ethnic groups is important because the genetic structures can be different enough that variants identified in one population do not explain risk in other populations Sometimes—it is much easier to identify some genetic variants in East Asian populations than European descendants.”
One of the loci is in close proximity to the CCND2 gene, a cyclin that has a critical role in cell cycle progression and has been shown to be overexpressed in colorectal tumors in various studies including The Cancer Genome Atlas (TCGA). Another variant is located proximal to the PITXI gene, a tumor suppressor gene that may activate TP53 and regulate the activity of the enzyme telomerase, which adds telomeres to the ends of chromosomes. A third genetic variant includes two genes—HAO1, which encodes a hydroxyacid oxidase; and PLCB1, which encodes phospholipase C-β1. PLCB1 has been previously shown to be overexpressed in colorectal cancer tissue.
Further genetic analyses of colorectal cancer continue to be necessary. Previous genome-wide studies have isolated 15 common genetic susceptibility loci in colorectal cancer but only 15% of heritable colorectal cancer is explained by these loci. All but one of these colorectal cancer studies analyzed samples from European populations even though genetic variants from non-European populations differ from those of other populations, including Asian populations.
Moreover, only 6% of colorectal cancer cases are explained by the genetic variants previously identified and associated with a high risk of the disease.
In addition to its work on colorectal cancer, the team is working on breast cancer genetics to identify additional genetic loci that confer risk of developing cancer, leading a consortium that has identified multiple susceptibility loci for breast cancer in Asians. “Interestingly,” said Zheng, “these loci were not discovered in previous studies conducted in European descendants, even with a very large sample size.”

Surgical Margins for Breast Cancer: Current Controversies in Oncology

20 Dec 2012 5:21 PM

Experts debate how to achieve both clear margins and the best cosmesis

Introduction
Anees B. Chagpar, MD, MSc, MA, MPH, FACS, FRCS(C)
Breast Center—Smilow Cancer Hospital at Yale-New Haven and Yale University School of Medicine

In a past column on ASCOconnection.org, I talked about a debate that had occurred in our tumor board in which a patient had a margin <1 mm from ink. While “technically negative,” it was a little too close for comfort for me; the surgeon whose case it was, however, argued based on evidence from the NSABP B-06 trial that if a tumor did not touch ink, outcomes were equivalent to the alternative of mastectomy—at least for survival. It brought up how we interpret data—and the difference between what we know and what we think we know; or as the comedian Stephen Colbert would put it, between “truth” and “truthiness.” We like to think that what we do is “evidence-based,” but we can almost always find data to support any position we wish to take.

My two good friends, Dr. Mel Silverstein and Dr. Mike Dixon, have duked out the margins debate in many public forums and settle the score here once and for all. Here is what we know for sure: (1) obtaining negative margins reduces local recurrence rates; (2) there is no consensus on what constitutes an adequate negative margin (although many would be happy with >1 mm); (3) radiation therapy continues to play a role in breast-conserving surgery (although there may be exceptions in tiny areas of estrogen receptor-positive ductal carcinoma in situ excised with widely clear margins); (4) there are ways to take out large segments of breast tissue without compromising cosmesis (although taking out less may yield excellent cosmetic outcomes without needing a contralateral symmetry procedure); and finally, (5) for the record, Mel is not a Republican (not that it matters).

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Dr. Chagpar is Director of the Breast Center at Smilow Cancer Hospital, Assistant Director for Diversity and Health Equity at Yale Comprehensive Cancer Center, Program Director of the Yale Interdisciplinary Breast Fellowship, and an Associate Professor in the Department of Surgery at Yale University School of Medicine. She currently serves on ASCO’s International Affairs Committee and is a columnist for ASCOconnection.org.

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Less Is More
J. Michael Dixon, BSc, MBChB, MD, FRCS, FRCS(Ed), FRCP(Hon)
Western General Hospital Edinburgh

More than 20 years after randomized trials demonstrated that breast-conserving surgery followed by post-operative radiotherapy has the same outcome as mastectomy, there still remains controversy as to how much of the breast should be excised when performing breast-conserving surgery. The aim of breast-conserving surgery is to excise the cancer to clear margins.^1,2

The controversy surrounds what constitutes a clear margin. The margin width is the distance from the cancer to the ink painted on the surface of the excision specimen. In surveys of surgeons and radiation oncologists, no one margin width was endorsed by more than 50% of respondents.^3-5 Thus, there is no consensus, and one consequence of this is that given a distance to the nearest margin of 1 mm, some surgeons and oncologists will accept this whereas others advise re-excision to achieve a wider margin.

A major problem in the published literature is that there are large numbers of single-center series that have all used different margin widths to define what constitutes complete excision.⁶ This allows any individual surgeon to quote a paper that supports his or her personal view.

The first review of surgical margins was conducted by Eva Singletary, MD, and published in the American Journal of Surgery in 2002.⁷ What Dr. Singletary established was that leaving disease at margins was unacceptable and significantly increased local recurrence rates. She established that wider margins did not reduce local recurrence rates and concluded that some of the best local recurrence rates were in series that had used a 1- to 2-mm margin width. This was endorsed by a more recent comprehensive review and meta-analysis of 21 retrospective studies.⁸ This analysis included 14,571 patients with breast cancer and demonstrated that a positive margin was associated with an odds ratio for local recurrence of 2.42. If the margin width was <1 mm this increased local recurrence by 1.8 times. There was, however, no statistical difference in local recurrence rates associated when comparing margin widths of >1 mm, >2 mm, and >5 mm when studies were adjusted for the use of radiation boost and endocrine therapy. The finding of this comprehensive meta-analysis was that a 1-mm negative margin is as good as a wider margin if patients receive optimal adjuvant therapy. The conclusion was that there is no justification for demanding margins greater than 1 mm.

Some have found difficulty in believing that recurrence rates are not reduced when margins are wider. This is in part because detailed whole-breast studies have shown disease extending 2 to 3 cm from the edge of the primary cancer.⁹ What a “clear 1-mm margin” indicates is not that there is no residual disease in the breast, but that any residual tumor burden is low and will be controlled with radiotherapy. Although mastectomy is offered to many patients, and patients choose it in the belief that this reduces local recurrence rates, mastectomy does not eliminate local recurrence. Randomized trials comparing mastectomy alone with breast-conserving surgery and radiotherapy have in fact shown similar local recurrence rates with both breast-conserving surgery followed by radiotherapy and mastectomy.¹⁰

Systemic treatment reduces local recurrence
The rates of local recurrence after breast-conserving surgery continue to fall.⁸ In NSABP B-06, the 20-year recurrence rate was 14.3%,1 whereas the NSABP trials conducted in the 1990s showed 10-year local recurrence rates ranging between 3.5% to 6.5%.¹¹ One of the major reasons for this is that systemic treatment reduces local recurrence significantly. In-breast recurrence was reduced in NSABP B-14 from 14.7% in the placebo group to 4.3% in patients receiving tamoxifen,¹² and in NSABP B-13, which included patients with ER-negative tumors, there was a 10-year recurrence rate of 13.4% in the no-treatment group compared with 2.6% in patients receiving chemotherapy.¹³

Studies from Edinburgh in more than 1,300 patients have confirmed that local recurrence rates do not fall with increasing margin width. In breast tumors, recurrence rates also did not increase when front and back margins were less than 1 mm, provided that full thickness of breast tissue was taken and radiotherapy boost was delivered. There were in fact no local recurrences at five years in patients who had a positive deep margin even though pectoral fascia was not removed routinely.

Importance of cosmetic outcome
It is important to limit the amount of breast tissue removed during breast-conserving surgery because the single most important factor affecting cosmetic outcome is the volume of breast tissue removed.¹⁴ Wider excisions remove more tissue and so produce significantly poorer cosmetic outcomes. There is a direct correlation between cosmetic outcome and psychological well-being—anxiety and depression scores, body image, sexuality, and self-esteem are reported as being significantly better in patients with excellent or very good cosmetic results; only patients who get a good cosmetic outcome gain the full benefits of breast-conserving surgery.¹⁵

The evidence shows that wider margins have no benefit in breast-conserving surgery. Wider margins have an adverse effect on the cosmetic outcome. Surgeons must abandon their obsession with wide margins and accept 1 mm as sufficient. Such a change will reduce health care costs, reduce the number of women having re-excisions, improve cosmetic outcomes, and thus significantly benefit patients.

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Dr. Dixon is a Professor of Breast Surgery and Consultant Surgeon, Edinburgh Breast Unit, Western General Hospital Edinburgh, UK. He currently serves on the editorial boards of Breast Cancer Management and Annals of Surgical Oncology and is Co-Chair of the Miami Breast Cancer Conference.

---

References

1. Fisher B, Anderson S, Bryant J, et al. N Engl J Med. 2002;347:1233-41. PMID: 12393820.
2. Veronesi U, Cascinelli N, Mariani L, et al. N Engl J Med. 2002;347:1227-32. PMID: 12393819.
3. Vallasiadou K, Young OE, Dixon JM. Br J Surg. 2003;90:44.
4. Azu M, Abrahamse P, Katz SJ, et al. Ann Surg Oncol. 2010;17:558-63. PMID: 19847566.
5. Taghian A, Mohiuddin M, Jagsi R, et al. Ann Surg. 2005;241:629-39. PMID: 15798465.
6. Morrow M, Harris JR, Schnitt SJ. N Engl J Med. 2012; 367:79-82. PMID: 22762325.
7. Singletary SE. Am J Surg. 2002;184: 383-93. PMID: 12433599.
8. Houssami N, Macaskill P, Marinovich ML, et al. Eur J Cancer. 2010;46:3219-32. PMID: 20817513.
9. Holland R, Veling SH, Mravunac M, et al. Cancer. 1985;56:979-90. PMID: 2990668.
10. Morris AD, Morris RD, Wilson JF, et al. Cancer J Sci Am. 1997;3:6-12. PMID: 9072310.
11. Anderson SJ, Wapnir I, Dignam JJ, et al. J Clin Oncol. 2009;27:2466-73. PMID: 19349544.
12. Fisher B, Dignam J, Bryant J, et al. J Natl Cancer Inst. 1996;88:1529-42. PMID: 8901851.
13. Fisher B, Dignam J, Mamounas EP, et al. J Clin Oncol. 1996;14:1982-92. PMID: 8683228.
14. Dixon JM. “Breast-conserving surgery: the balance between good cosmesis and local control,” in A Companion to Specialist Surgical Practice: Breast Surgery. Ed. Dixon JM. Edinburgh: Elsevier, 2009.
15. Al-Ghazal SK, Blamey RW. Breast. 1999;8:162-8. PMID: 14731434.

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More Is Better
Melvin J. Silverstein, MD
Hoag Memorial Hospital Presbyterian; Keck School of Medicine, University of Southern California

In 1999, my colleagues and I published a paper in the New England Journal of Medicine showing that patients with ductal carcinoma in situ (DCIS) treated by excision alone had a very low local recurrence rate (about 5% at 10 years), if clear margins of 10 mm or more were achieved.¹

Following that paper and the presentation of those data at numerous meetings, word spread that I no longer used radiation therapy (even for invasive cancer), that I required 10-mm margins for all cases or I returned to the operating room for re-excision or mastectomy, and that I voted Republican. None of those were true. But somehow, erroneously, I became the guru for 10-mm margins without breast irradiation for all patients with breast cancer, both noninvasive and invasive.

So, let me set the record straight. I always recommend breast irradiation for patients with invasive cancer receiving breast-conserving therapy and for about half of my patients with DCIS. The exception, which follows NCCN guidelines,² are patients with DCIS with small, well-excised, low-grade lesions (low University of Southern California/Van Nuys Prognostic Index scores).^3-5 Moreover, I routinely accept 1 mm as a clear margin, and I do not require re-excision, if radiation therapy is going to be used. While I intuitively prefer wider margins, I’m willing to accept narrow but clear margins. With that said, can I prove that wider margins are better?

I admit that in 2001, while giving the Keynote Lecture at the American Society of Breast Surgeons Annual Meeting, I did say, “Margins are like money. More is better.” I still feel that way, but Mike Dixon is right. I cannot prove that 2 mm is better than 1 mm, nor that 3 mm is better than 2 mm. I cannot prove an incremental benefit because the precise measurement of margin width was not common until recently, and the prospective, level I evidence that would be required to prove an incremental benefit simply does not exist. Nevertheless, wider margins make sense, and most surgeons and radiation oncologists would prefer a wider margin, if there were no cosmetic cost.

For patients with DCIS treated with excision alone (no radiation therapy), wider margins correlate with less residual disease and a lower local recurrence rate.^6-8 Those benefits may not be so apparent for patients with invasive cancer because the value of wider surgical margins is blunted by both radiation therapy and the addition of other adjuvant treatments.

I do not want wider margins at significant cosmetic cost. What I do want is wider margins and better cosmesis. I want both. In support of that, and dating back to the 1980s and the Van Nuys Breast Center, I have always been a champion of oncoplastic breast conservation. I have always trained residents and breast fellows to believe that the appearance of the breast after breast preservation is important and that it should be equal or better than before the initial excision, if possible.

Gains from wider excisions
In an attempt to understand what is gained by wider excision, my colleagues and I recently analyzed 100 consecutive excisions using a simple ellipse and compared those cases with 100 consecutive excisions using an oncologically designed reduction mammoplasty, in which a larger amount of tissue could be removed while achieving a better cosmetic result.⁹ The data are outlined in the Table below:



In this series, when compared with a conventional elliptical excision, oncoplastic reduction routinely produced larger specimens, wider margins, a lower percentage of close or transected margins, and a lower re-excision rate. Oncoplastic reduction achieved all these benefits while routinely producing better cosmetic results.

When wider margins = better cosmesis

	Fig. 1: Preoperative (L); Two years postoperative (R): A patient with a large upper central left breast carcinoma treated with neoadjuvant chemotherapy and wide segmental resection, using a split reduction excision, followed by radiation therapy. Complete excision with wide margins as well as excellent cosmesis were achieved.

Figure 1 shows a woman with a large upper central left breast cancer. She would have been deformed with a standard excision, or, more likely, she would have been treated with a mastectomy and her reconstruction compromised by post-mastectomy radiation therapy. The use of neoadjuvant chemotherapy followed by an oncoplastic split reduction excision and radiation therapy yielded widely clear margins and a far superior cosmetic result (a win-win: wider margins and better cosmesis). Her long-term survival will be equivalent to standard lumpectomy or mastectomy, and she will be a far happier patient.

A reduction excision offers additional benefits. When clear margins are achieved during the first operative procedure, re-excision or conversion to mastectomy is eliminated, resulting in substantial cost savings and the elimination of the additional psychic trauma of a second procedure. The removal of excess breast tissue from the contralateral breast, while achieving symmetry, also appears to lower the overall risk of a future contralateral breast cancer.^10,11

I cannot prove to you that wider excision leads to a lower local recurrence rate when radiation therapy and modern adjuvant treatment is given, although I believe that it does, in a small fraction of patients; but it clearly leads to fewer re-excisions and fewer mastectomies. However, if wider excisions affect your cosmetic results negatively, then I agree, you should not be doing wider excisions. Perhaps you should not be doing breast surgery. After all, it is 2013.

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Dr. Silverstein is Director of the Hoag Breast Program at Hoag Memorial Hospital Presbyterian, and Clinical Professor of Surgery at the Keck School of Medicine, University of Southern California. He has served on ASCO’s Scientific Program Committee.

---

References

1. Silverstein MJ, Lagios M, Groshen S, et al. New Engl J Med. 1999;340:1455-61. PMID: 10320383.
2. Carlson RW, Allred DC, Anderson BO, et al. NCCN Clincal Practice Guidelines in Oncology: Breast Cancer. 2008; nccn.org.
3. Silverstein MJ. Am J Surg. 2003;186:337-43. PMID: 14553846.
4. Silverstein MJ, Buchanan C. Breast. 2003;12:457-71. PMID: 14659122.
5. Silverstein MJ, Lagios M. J Natl Cancer Inst Monogr. 2010;41:193-96. PMID: 20956828.
6. Silverstein M. Women’s Health. 2008;4: 565-77. PMID: 19072459.
7. Silverstein MJ. “Margin width as the sole predictor of local recurrence in patients with ductal carcinoma in situ of the breast,” in Silverstein MJ, Recht A, Lagios M, eds. Ductal Carcinoma in Situ of the Breast. 2nd ed. Philadelphia: Lippincott, Williams and Wilkins; 2002.
8. Silverstein MJ, Lagios M, Lewinsky B, et al. Breast Cancer Res Treat. 1997;46:23.
9. Kopkash K, Savalia N, Silverstein MJ. A Comparison of Breast Conservation Methods: Ellipse Verses Reduction Excision. Submitted American Society of Breast Surgeons Annual Meeting 2013.
10. Boice J, Persson I, Brinton L, et al. Plast Reconst Surg. 2000;106:755-62. PMID: 11007385.
11. Brinton L, Persson I, Boice J, et al. Cancer. 2001;91:478-83. PMID: 11169929.

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The views and opinions expressed in Current Controversies in Oncology are those of the authors alone. They do not necessarily reflect the views or positions of the Editor or of the American Society of Clinical Oncology.

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Number of Comments: 1

Mehmet Copur

Wednesday, December 26, 2012 1:53 AM

Thank you for the nice review. Most references quoted involves patients treated 10 years or earlier and some large meta-analysis data. We need to remember that breast cancer care continuum is changing rapidly and constantly. Now we do more breast MRIs and MRI guided biopsises which can detect multifocal disease more frequently. There is also increasing use of partial breast radiation therapy despite the lack of consensus. The data quoted may not differentiate local recurrence versus recurrence from another focus/foci left behind and was not properly treated by radiation because of the partial breast irradiation. It would be nice to know how much of the recurences were true local recurrence versus growth of tumor from another focus left behind.

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Triple-Negative BRCA Has Higher Mortality Risk

This report is part of a 12-month Clinical Context series.

By Michael Smith, North American Correspondent, MedPage Today

Published: May 03, 2012

Reviewed by Vandana G. Abramson, MD; Assistant Professor of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Take Posttest

Action Points

• Patients with stage I-III triple-negative breast cancer had a significantly higher risk of death (OR 8.3) in the first two years after diagnosis than women with ER+ or HER2+ disease.
• Patients with triple-negative disease were more likely to have metastases to the brain or lung, and less likely to have recurrence in the bones compared with ER+ or HER2+ patients.

Women with so-called triple-negative breast cancer had nearly three times the risk of death from the disease as women with the most common form of the disease, researchers reported.
And the risk was even higher in the first two years after diagnosis -- eight-fold compared with women with the most common form, they also had a markedly higher rate of death from any cause, according to Nancy Lin, MD, of the Dana-Farber Cancer Institute in Boston, and colleagues.
They were also more likely to have distant metastases in the brain or lung, but less likely to see the disease recur in bone, Lin and colleagues reported online in Cancer.
The findings come from an analysis of 15,204 women who were diagnosed and treated for stage I through III breast cancer between January 2000 and December 2006 in eight major hospitals that are part of the National Comprehensive Cancer Network centers.
For the analysis, tumors were classified as:

• HR-positive/HER2 negative if they had an estrogen receptor, a progesterone receptor, or both but were negative for human epidermal growth factor receptor 2 (HER2)
• HER2-positive if they had HER2 and any hormone receptor status
• And triple-negative if they had none of the receptors

Analysis of the cohort showed that 17% of women had triple-negative cancers, 17% were HER2-positive, and 66% were HR-positive/HER2 negative.
The triple-negative subtype was nearly twice as common among African-American women, with an adjusted odds ratio of 1.98 (95% CI 1.72 to 2.27, P<0.0001), Lin and colleagues reported.
Only 29% of women with triple-negative cancers were diagnosed as a result of an abnormal screening mammogram, compared with 48% of women with other types, a difference that was significant at P<0.0001.
In an analysis adjusted for age, disease stage, race, tumor grade, and receipt of adjuvant chemotherapy, triple-negative tumors were associated with a greater risk of breast cancer death than receptor-positive tumors.
Specifically, the odds ratio for death over the whole six-year follow-up period was 2.99 (95% CI 2.59 to 3.45).
The odds ratio for death in the first two years after diagnosis, on the other hand, was sharply higher: 8.30 (95% CI 6.23 to 11.05).
The analysis also showed that, compared with women who had receptor-positive tumors, those with triple-negative disease had odds ratios of 2.17, 3.50, and 0.26 for recurrence in the lung, brain, and bone respectively. The differences were all significant at P<0.001.
The researchers cautioned that the analysis was limited to patients at the eight centers, whose median age was 55, younger than the national median.
They also noted that the six-year follow-up was relatively short for HR-positive/HER2 negative and HER2-positive cancers, and "it is likely that survival estimates will evolve over time in this subset."
On the other hand they argued, the picture of outcomes is likely to be accurate for triple-negative cancer, since recurrences were more frequent and earlier.

The study had support from the National Cancer Institute, the National Comprehensive Cancer Network, the Breast Cancer Research Foundation, the American Society of Clinical Oncology, a Berry Junior Faculty Award, and the Karen Webster and David Evans Research Fund.
The journal said the authors made no disclosures.

Primary source: Cancer
Source reference:
Lin NU, et al "Clinicopathologic features, patterns of recurrence, and survival among women with triple-negative breast cancer in the national comprehensive cancer network" Cancer 2012; DOI: 10.1002/cncr.27581.

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View 1 comment or Add Your Knowledge ™

Michael Smith
North American Correspondent
North American Correspondent for MedPage Today, is a three-time winner of the Science and Society Journalism Award of the Canadian Science Writers' Association. After working for newspapers in several parts of Canada, he was the science writer for the Toronto Star before becoming a freelancer in 1994. His byline has appeared in New Scientist, Science, the Globe and Mail, United Press International, Toronto Life, Canadian Business, the Toronto Star, Marketing Computers, and many others. He is based in Toronto, and when not transforming dense science into compelling prose he can usually be found sailing.

=====================================================================
 01/03/2013.
This discussion occurred today at Tumor board at the El Paso University Medical Center under the Guidance of  DR Zeina Nahley, MD, FACP, Associate Professor, Chief Division of Hematology/Oncology
at the Paul L. Foster School of Medicine.
CRBCM was represented by DR Kankonde.

AND CONTROVERSY KEEPS ON COMING

Study: Being Slightly Heavy Aids Longevity

Tuesday, January 1, 2013 6:07 PM

inShare2

A new international analysis reveals a surprising pattern: while obesity increases the risk of dying early, being slightly overweight reduces it.

These studies included almost 3 million adults from around the world, yet the results were remarkably consistent, the authors of the analysis noted.

"For people with a medical condition, survival is slightly better for people who are slightly heavier," said study author Katherine Flegal, a senior research scientist at the U.S. Centers for Disease Control and Prevention's National Center for Health Statistics.

Several factors may account for this finding, Flegal added.

"Maybe heavier people present to the doctor earlier, or get screened more often," she said. "Heavier people may be more likely to be treated according to guidelines, or fat itself may be cardioprotective, or someone who is heavier might be more resilient and better able to stand a shock to their system."

The report was published Jan. 2 in the Journal of the American Medical Association.

Read more: Study: Being Slightly Heavy Aids Longevity
Important: At Risk For A Heart Attack? Find Out Now.
CONTROVERSY KEEPS ON GOING!
FROM HEALTHNEWS!

AURORA KINASES,

A (like Australis)  is more important then B (like Borealis) because of  lack of therapeutic usefulness of the Borealis kind.

Mark my words, The Aurora Kinase inhibitors, by "disrupting centrosome function, spindle assembly, chromosome alignment" as reported by DR Roger Cohen, professor of Medicine at Perelman School of Medicine in a report by Devera Pine, are probably one of the most significant development target therapy.  These go to compromise of Mitotic division and growth inhibition.  These combine to Actin function (disruption of Microtubules) would trigger the second law of nature, triggering Cytochrome C realease and Caspases activation despite the presence of Bcl-2 presence.  And Alisertib could be the Agent to watch.  We believe a Taxane combination with Alisertib and an anti-kinesin will be a potentially  powerful combination to watch in Oncology!  These drugs certainly will make mitosis impossible and stop multiplying cancer cells in their tracks!   Neutropenia induced by the Aurora inhibitors is a concern in such a combination and growth factors will need to be used.  Cancer treatment is progressing by the day. The future is exciting and promising!   

Cancer Survivorship Center in Dayton, Ohio

To Senator Sherrod Brown,
NEW Member of the Appropriation Committee
Ohio.

The Coalition for the Reversal of Breast cancer Mortality in African American women (CRBCM) would like to congratulate you for a successful electoral campaign, and take this opportunity to bring your attention to the plight of Breast Cancer and its reversible devastating effect in African American Community. 
Breast Cancer is the second leading cause of cancer death. One in 8 American will be diagnosed with this disease before age 85. And Approximately 40-50,000 women and men will die of this disease.  This number will include more than  6,000 African American women!

Ohio: Breast Cancer Deaths per 100,000 Women by Race/Ethnicity, 2009

---

Breast Cancer Deaths per 100,000 Women by Race/Ethnicity,
	OH	US
White	22.8	21.6
Black	30.0	30.5
Hispanic	NSD	14.8

----------------------------------------------------------------------------------------------------------------------------------------

The above statistics points once again to the unfair burden carried by African American in the mortality rates from Breast Cancer.
As a matter of Facts, all epidemiologic studies have suggested that the incidence of breast cancer in African American communities is lower than that of white counterpart.  This well known dichotomy  is well established and even coined "Breast cancer paradox".  Significant and concerted Action against this paradox is bluntantly lacking however!   It is estimated that up to 3000 African Women could be saved YEARLY if such an action is undertaken.

The reasons for this unfair level of death are also well known:
1.  relatively poor rates of screening particularly in low income communities where lack of health education and insurance coverage are the main drivers to poor detection of the disease.   Here Vans outfitted with mammograms ("mammoVans")  have been the most successful venues to combat this problems.
2.  with poor screening and detection, comes the late stage of cancer at the time of diagnosis.  and furthermore, they appears to 
be a an increased rate of poor histology type of breast cancer in African American women.  This type is called Basal cell like Breast cancer which is triple negative, meaning lacking Hormone and Herceptin receptors, making current treatments  almost irrelevant.  New genetic studies have only now revealed this type to be closer to Ovarian cancer and new strategies are only now being devised.
3. Lack of leadership and meaningful comprehensive plan with exclusive focus on this PARADOX.   To date, this reversible fact has not been proclaimed a national emergency.  Despite our progress with Human genome, progress in radiology for early detection, expansion of our knowledge of various molecular targets, No politician has stood before the nation and asked that deaths we know to be reversible, be stopped.  It is an amazing and striking thing for a country with an ambitious incline!  Cure will not come without the Senate committment to a 10 year program.   In Texas, CPRIT is trying to do this.  Ohio should join the race! and create jobs!

The Breast Cancer Coalition, CRBCM, through our representative Amy Mccoulah, based in Greenville OH, is asking for funding to open a CANCER SURVIVORSHIP CENTER IN DAYTON OHIO.  The center is the best approach to offer a comprehensive plan to this problems because it will provide all phases of cancer preventions:

-Primary Prevention:  the Center  will conduct field investigation to detect risk factors predominant in local community and develop adjusted prevention programs to fit people of Ohio.  Reach people through Health Bus for health education.
-Secondary Prevention: have mammovans to meet people in churches, work place and civic centers.  And explore the issue of adequacy of current screening means as it is related to this rare histology (triple negative breast cancer). Is mammogram the best way forward to early detection for this population.
-Tertiary prevention:  which include treatment, patient navigation services, and survivorship programs.
The survivorship programs ultimately provide support services to survivors who are the 50-80 percent of breast cancer patients, these services include nutrition, mental health, fitness program, Lymphedema clinics, etc.   Most of these services are reimbursed by federal insurances, insuring the continuation of the center once created!   With further details of this program, it is easy to see that jobs will be created!

Dear Senator, These type of initiatives work in reducing Breast cancer mortality.   Stopping Hormone replacement therapy and work on BRCA have made a difference in mortality,  and have led to oncology practice changes. And it is in your power to make a difference.  The fiscal cliff has been averted, it is time to put Ohio back to work and this initiative will make a difference in African American communities of Ohio.  We call to your human side to act!

Sincerely,

Amy McCulah and DR Mutombo Kankonde MD, MPh (Oncologist).
The Coalition for the reversal of Breast cancer mortality in
African American Women (CRBCM)
Greenville, OH.

============================================================

MONO-TARGET THERAPY IN SOLID TUMOR, a first step in an actual treatment scenario

Time and again we have seen that targeting the membrane or cytosol individually leads to a 15-30% response.  This is very true in solid tumors. Because of phenotype and genetic heterogeneity, it is hard to break this "ceiling".  Mono-target therapy should serve as a proof of principle.  In actual therapy, the multikinase therapy has shown that hitting multiple targets is always better.  The cancer cell is redundant with loopholes that tend to deviate the negative forces toward survival trends.  The cancer cell produces growth proteins more than inhibitory proteins.  This is also why mutations that protect against protein degradation such as the MDM2 Mutation (12q14 location) are widely found in tough to treat cancers.
In actual treatment, hitting 2 driver Mutations in the same cell, or hitting upstream and downstream targets, would result in better response rates.
In Melanoma, the combination of Ipilimumab, an antibody against the Cytotoxic T-lymphocyte Antigen, and DTIC,or Dacarbazine, an Alkylating agent striking down stream Ipilimumab, has once again confirm this premise.  The experience of adding Everolimus to Tamoxifen in refractory metastatic breast cancer  ascertains this principle.
The key is to pick a combination that makes sense or "go nuclear", meaning attacking nuclear component in combination with the mono-target therapy.
Once again, in every cancer cell there are either Driver Mutation, or Driver pathways.  In some cases, the pathway is upregulated by regulator molecules and amplification of transcription genes.  knocking down these amplifiers (Hedgehog signaling) has proven a legitimate therapeutic target (basal cell cancer).
At CRBCM our focus has been to identify major tangible or non-tangible pathways to cellular destruction.  By non-tangible we mean almost reflex mechanisms.  They appear to be threshold that overwhelm cancer cells.  Threshold beyond which the death or apoptotic processes are immediately begun (we call these uncontrollable cell destruction forces LAW OF NATURE) .  Cancer cell death uses Caspase and non Caspase mechanisms.  This is were the crux of the cure is and anything or pathways leading to this, is our focus.  Time is of the essence, let's keep on progressing!

Happy New Year 2013!

Ki-67 May Predict Renal Cell Carcinoma Progression

Lara C. Pullen, PhD

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October 9, 2012 (Chicago, Illinois) — Ki-67 expression is an independent predictor of renal cell carcinoma (RCC) progression and may serve as a valuable biomarker for patients with RCC, researchers reported at the American College of Surgeons (ACS) 98th Annual Clinical Congress.
Surgery is standard treatment for patients with RCC, yet approximately 1 in 5 patients will subsequently develop metastatic disease. Therefore, Kelvin Wong, MD, from the University of Wisconsin, Madison, and colleagues used tissue microarrays to look for protein biomarkers that predict disease progression and might identify patients who need further adjuvant treatment.
The authors searched an institutional database to identify patients with RCC who underwent radical or partial nephrectomy with no lymph node or distant metastasis at surgery. The database included 223 patients with a median follow-up of 60.5 months. Of those, 40 (18%) patients developed metastatic disease.
The investigators constructed a tissue microarray from patient tumor samples and used immunohistochemistry to measure expression of 6 proteins: C-reactive protein, NFκB, CA 9, HIF1a, HIF2a, and Ki-67.
According to the authors, immunohistochemistry represents a straightforward and relatively cheap way to measure protein expression with automated quantification of fluorescent antibody signal intensity.
"What the computer can do is really separate spatially the different layers for us," Dr. Wong explained. "You can remove a lot of the inter-observer variability [using this type of system]." He acknowledged, however, that "the technology software needs a human element to tell the program what to recognize."
Ki-67 Correlates With Progression
Tumor size, grade, stage, subtype, sarcomatoid features, venous thrombus, perinephric fat invasion, and increased Ki-67 expression correlated with progression in a univariate analysis.
In a multivariate analysis, tumor size, level of thrombus, and Ki-67 remained independent risk factors for RCC recurrence. Of all of the factors identified, Ki-67 overexpression was most predictive of recurrence (hazard ratio, 8.4 [95% confidence interval, 3.8 - 19.0]).
David R. Byrd, MD, from the Seattle Cancer Care Alliance in Washington moderated the session and noted that the data suggest "that Ki-67 is something that should be routinely collected." Currently, physicians do not routinely request the test.
An estimated 65,000 new diagnoses of kidney cancer are expected in the United States in 2012. Kidney cancer is the eighth most common cancer in men and the sixth most common cancer in women. It is often difficult to determine who will progress.
Although to date adjuvant therapy has no known benefit, there may be a benefit if it became possible to predict who is at highest risk for progression.
Dr. Wong and Dr. Byrd have disclosed no relevant financial relationships.
American College of Surgeons (ACS) 98th Annual Clinical Congress. Abstract NP2012-24333. Presented October 3, 2012.

US Cancer Screening Rates Fall in the Last Decade

Laurie Barclay, MD

Dec 28, 2012

• Ultrasound a Viable Screening Option for Breast Cancer
• FDA Panel Endorses New Breast Cancer Screening Option
• Task Force Says No to Routine Screening for Ovarian Cancer

Drug & Reference Information

• Prostate Cancer
• Neoadjuvant Androgen Deprivation Therapy in Prostate Cancer
• Prostate Cancer Diagnosis and Staging

In the last decade, the general US population did not meet Healthy People 2010 (HP2010) goals for cancer screening except for colorectal cancer, according to results from a US survey published online December 27 in Frontiers in Cancer Epidemiology and Prevention. However, cancer survivors met goals for all cancer types except cervical cancer.
"There is a great need for increased cancer prevention efforts in the U.S., especially for screening as it is considered one of the most important preventive behaviors and helps decrease the burden of this disease on society in terms of quality of life, the number of lives lost and insurance costs," lead author Tainya C. Clarke, MPH, a research associate in the Department of Epidemiology and Public Health at the University of Miami, Miller School of Medicine, Florida, said in a news release.
"But despite this, our research has shown that adherence rates for cancer screenings have generally declined with severe implications for the health outlook of our society," Dr. Clarke said.
Despite earlier diagnoses and more effective treatments prolonging survival, cancer is still a leading cause of death and a highly prevalent chronic disease. In 2011, cancer-related deaths in the United States exceeded 570,000.
The objective of this study was to analyze 10-year trends in adherence to screening for site-specific cancers as recommended by the American Cancer Society, using the HP2010 goals as an adherence measure. Participants were 174,393 adults at least 18 years of age who completed the National Health Interview Survey between 1997 and 2010 for whom detailed cancer screening information was available.
The investigators also analyzed data from 7528 working cancer survivors representing 3.8 million US workers, as well as data from 119,374 adults representing more than 100 million working Americans with no history of cancer.
The US population slightly exceeded the HP2010 goal for colorectal screening, with 54.6% of the general public having colorectal screening compared with the HP2010 goal of 50%. However, the general US population surveyed failed to meet HP2010 goals for recommended breast, cervical, and prostate cancer screening.
Cervical cancer screening rate was higher in women aged 21 years and older than in those aged 18 years and older, suggesting that increasing human papillomavirus vaccination may contribute to decreasing Papanicolaou tests. The proportion of men older than 50 years receiving prostate-specific antigen (PSA) screening decreased by nearly 20% from 1999 to 2010, which the investigators suggest might reflect questions being raised about the effectiveness of PSA screening.
In contrast to the overall population, cancer survivors met and maintained the HP2010 goal for cancer screening at all sites with the exception of screening for cervical cancer, which decreased to 78% during the last decade. Compared with the general population, cancer survivors had higher screening rates, but there was a decline among cancer survivors who took part in cancer screenings during the last 3 years. Screening rates among cancer survivors were higher for those employed in white-collar and service occupations than for those employed in blue-collar occupations.
Study Limitations and Implications
Cancer survivors report "higher screening rates than the general population," the study authors write. "Nevertheless, national screening rates are lower than desired, and disparities exist by cancer history and occupation. Understanding existing disparities, and the impact of cancer screening on survivors is crucial as the number of working survivors increases."
Limitations of this study include a reliance on self-report for the main outcome variables, that the sample size of cancer survivors employed in the farming sector was too small for analysis, and a lack of data on what type of Papanicolaou test (liquid-based or glass smear) was performed on women screened for cervical cancer.
"This declining trend foreshadows a future negative impact on mortality from cancers of the breast, and cervix as well as increased morbidity associated with a later diagnosis of prostate cancer," the study authors conclude. "Disagreements among the [US Preventive Services Task Force], the [American Cancer Society] and other recommending bodies over cancer screening guidelines may have contributed to the decline in screening throughout the decade. A decline in worker insurance rates over the decade under study could also be a contributing factor."
This study was supported by a National Cancer Institute fellowship at the National Institutes of Health and the National Institute for Occupational Safety and Health. The authors have disclosed no relevant financial relationships.
Front Oncol. Published online December 27, 2012. Full text
===========================================================

Who believed we are better off now?
and who thought Prevention programs are no longer needed?
Prevention is the cheapest was to protect against cancer!