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Statins May Improve Survival for TNBC

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123Donna View Drop Down
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    Posted: Jan 22 2012 at 10:08am

Cholesterol-Lowering Statins May Treat Breast Cancer

Cholesterol-lowering statins seem to keep breast cancer at bay in some patients. Now researchers reporting in the January 20th issue of the journalCell, a Cell Press publication, provide clues about how statins might yield those unexpected benefits. The findings also suggest that mutations in a single gene could be used to identify tumors likely to respond to statin therapy. 

"The data raises the possibility that we might identify subsets of patients whose tumors may respond to statins," said Carol Prives of Columbia University. "Of course we can't make any definitive conclusions until we know more." 

Prives said that a clinical trial of statins in breast cancer based on the mutation status of the tumor suppressor, p53, may be in order. The p53 tumor suppressor acts to regulate many aspects of cell proliferation, generally putting the brake on uncontrolled growth. 

More than half of all human cancers carry mutations in the p53 gene. Many of these mutations don't simply disrupt the normal function of p53, they also endow p53 with new functions that promote, instead of inhibit, cancer formation. Mice lacking p53 develop cancer and die, Prives explained, but mice carrying tumor-derived mutant forms of the p53 gene suffer from more aggressive disease. What these mutant forms of p53 are actually doing is a big question in cancer research.

Prives' team designed experiments to sort this mystery out. By studying cancer cells grown in an artificial system that resembles the three-dimensional structures in the human breast, the researchers learned that cells carrying mutant p53 grow in a disorganized and invasive manner, characteristic of human breast cancers. When the researchers lowered the levels of mutant p53, the 3D cell cultures grew more normally. 

Further studies, led by study first author William Freed-Pastor, traced the structural changes to a cholesterol-building pathway (called the mevalonate pathway). This is the same pathway targeted by cholesterol-lowering statins. When the mutant p53 cells were treated with statins, they stopped their disorganized, invasive growth, and in some cases, even died. Importantly, the effects of the drugs were erased when intermediates of the mevalonate pathway were added back in, additional proof that the drug wasn't working in some other, off-target way.

With collaborators in Norway, Prives and Freed-Pastor analyzed breast cancer tissue taken from patients to find that mutations in p53 and elevated activity of mevalonate pathway genes tend to go together in human tumors too. While those findings are encouraging that the cell culture findings may have clinical relevance, Prives emphasizes that it will take considerably more work to confirm that. 

"It is what it is," she says. "There are great implications, but nothing clinical yet. Perhaps one could do a clinical trial, and that may support these findings, or it may be more complicated." 


Edited by 123Donna - Aug 17 2021 at 8:47am
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Post Options Post Options   Thanks (0) Thanks(0)   Quote mainsailset Quote  Post ReplyReply Direct Link To This Post Posted: Jan 22 2012 at 11:09am
Here is a link from the HeathCare.gov site that we should all use as the Bill allows many of us to get the cholesterol and many other preventative tests done with no insurance co-pay. Since high cholesterol is a component of metabolic syndrome which is common amongst TN community it's nice to know that we can get help with these tests as well as counselling with no co-pay.
 
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Jan 22 2012 at 1:48pm
Article referenced by Donna on the role of statins:

Mutant p53 Disrupts Mammary Tissue Architecture via the Mevalonate Pathway

Cell 148 (1) pg 244-258

William A. Freed-Pastor, Hideaki Mizuno, Xi Zhao, Anita Langerød, Sung-Hwan Moon, Ruth Rodriguez-Barrueco, Anthony Barsotti, Agustin Chicas, Wencheng Li, Alla Polotskaia, Mina J. Bissell, Timothy F. Osborne, Bin Tian, Scott W. Lowe, Jose M. Silva, Anne-Lise Børresen-Dale, Arnold J. Levine, Jill Bargonetti, Carol Prives

 

Summary

p53 is a frequent target for mutation in human tumors, and mutant p53 proteins can actively contribute to tumorigenesis. We employed a three-dimensional culture model in which nonmalignant breast epithelial cells form spheroids reminiscent of acinar structures found in vivo, whereas breast cancer cells display highly disorganized morphology. We found that mutant p53 depletion is sufficient to phenotypically revert breast cancer cells to a more acinar-like morphology. Genome-wide expression analysis identified the mevalonate pathway as significantly upregulated by mutant p53. Statins and sterol biosynthesis intermediates reveal that this pathway is both necessary and sufficient for the phenotypic effects of mutant p53 on breast tissue architecture. Mutant p53 associates with sterol gene promoters at least partly via SREBP transcription factors. Finally, p53 mutation correlates with highly expressed sterol biosynthesis genes in human breast tumors. These findings implicate the mevalonate pathway as a therapeutic target for tumors bearing mutations in p53.

Experiments performed on cell lines in culture and correlative data only in human breast cancer patients based on microarrays.

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Aug 17 2021 at 8:48am

Statins may improve survival for triple-negative breast cancer patients

Date:
August 3, 2021
Source:
University of Texas M. D. Anderson Cancer Center
Summary:
A new study found a significant association between cholesterol-lowering drugs commonly known as statins and survival rates of triple-negative breast cancer patients. Since statins are low in cost, easy to access and produce minimal side effects, this could have an important impact on outcomes for this aggressive disease.

A study led by researchers from The University of Texas MD Anderson Cancer Center found a significant association between cholesterol-lowering drugs commonly known as statins and survival rates of triple-negative breast cancer patients. Since statins are low in cost, easy to access and produce minimal side effects, this could have an important impact on outcomes for this aggressive disease.

The study, led by Kevin Nead, M.D., assistant professor of Epidemiology, was published today in Cancer. This research extends the current knowledge of the association between statin use and triple-negative breast cancer (TNBC), and it is the first study that was adequately powered to investigate the association of statins and aggressive breast cancer subtypes.

Researchers found a 58% relative improvement in breast cancer-specific survival and a 30% relative improvement in overall survival with statin use. The median follow-up was 3.3 years for breast cancer-specific survival and 4.4 years for overall survival.

"There is already a body of literature on statins and breast cancer and the results have been inconsistent," Nead said. "Previous research has looked at breast cancer as only one disease, but we know there are many subtypes of breast cancer and we wanted to focus our research on this particularly aggressive form of breast cancer that has limited effective treatment options."

TNBC is an aggressive disease that makes up roughly 10% to 20% of breast cancer diagnoses. Triple-negative means that the breast cancer doesn't have estrogen or progesterone receptors or HER2 positivity, which are the three most common receptors for breast cancer. This combination results in a highly aggressive breast cancer with poor prognosis and limited treatment options since there are few receptors to actively target with existing therapies.

The retrospective study selected patients included in the Surveillance, Epidemiology, and End Results (SEER)-Medicare registry and the Texas Cancer Registry (TCR)-Medicare, two large databases of administrative claims of Medicare-eligible patients. Patients were required to have Medicare Part D prescription coverage to determine their statin use.

The research included data from 23,192 women over age 66 with stage I-III breast cancer. From that patient cohort, 2,281 were incidental statin users, meaning they started a statin within one year following their breast cancer diagnosis. The incidental statin users were 78.1% white, 8.9% Black, 8.4% Hispanic and 4.5% other.

Analysis by breast cancer stage suggested that the association of incidental statin use with improved outcomes may be stronger in women with early stage TNBC. When examining statin intensity, high-intensity statin use had the strongest effect on overall survival among women with TNBC. Researchers also found a statistically significant association between lipophilic statins (L-statin: simvastatin, atorvastatin, lovastatin, fluvastatin, pitavastatin) and improved overall survival.

"We know that statins decrease breast cancer cell division and increase cell death," Nead said. "Our study shows that there is an association between statins and improved outcomes in TNBC, and it is time to pursue this idea further in a prospective trial."

Prospective trials are needed to validate these study results and to better define the potential role of statins in TNBC treatment.

This research was supported by the National Institutes of Health CCSG (P30 CA016672). Additional support was provided by the Cancer Prevention Research Institute of Texas (CPRIT) (RR190077) (FP9178) (RP160674) and Komen (SAC150061

https://www.sciencedaily.com/releases/2021/08/210803105520.htm




DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09)
11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15

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