Abstract

Triple-negative breast cancer (TNBC) is one of the aggressive subtypes of breast cancer that occurs in women. Unfortunately, the prognosis and management of TNBC pose great difficulty. However, a new study by the University of Texas M. D. Anderson Cancer Center reports an association between statin use and improved survival rates among TNBC affected individuals.

Triple-Negative Breast Cancer (TNBC)

TNBC is a subtype of breast cancer that lacks any receptors generally found in breast cancer cells. The other types of breast cancers have receptors for any of these hormones: 

• Estrogen
• Progesterone
• Human Epidermal Growth Factor (HER2)

*Note: Receptors are proteins that receive chemical signals by binding to specific molecules.

TNBC represents about 10-15 % of all breast cancers.

The presence of even one of the receptors makes treating breast cancer easier. Doctors can then treat cancer by targeting these receptors to get inside the cancerous cell and destroy it.

However, in TNBC, the lack of receptors limits the treatment options.

According to the American Cancer Society, based on diagnosis information between 2010-2016, the 5-year survival rate for TNBC affected individuals is 77%. However, these statistics are subject to variation depending on the cancer progression stage and grade of the tumor.

Risk Factors for Triple-Negative Breast Cancer

1. The most significant risk factor for TNBC is genetics. People having a BRCA mutation are at higher risk of developing TNBC. Almost 80% of BRCA mutations are triple-negative. 

Know about your BRCA status and risk for breast cancer using Xcode Life’s BRCA and Breast Cancer Report.

2. Women under the age of 40 years are at a higher risk, as are women in their premenopausal phase.

3. Ethnicity and ancestry play a significant role in TNBC. For example, people from African American and Hispanic backgrounds are more likely to be diagnosed with TNBC.

4. Socioeconomic status may also contribute to TNBC diagnosis. For example, a study reported that disparities in income levels and prejudiced healthcare facilities due to socioeconomic status prominently affected TNBC mortality. 

5. Among other body conditions, obesity is one of the most significant risk factors for TNBC. Therefore, the implication of obesity in TNBC prediction can be used to modify diet and lifestyle choices which will help prevent the development of TNBC. 

What are statins?

Statins represent a class of drugs usually prescribed for heart attacks and stroke. Statins help in lowering blood cholesterol levels. 

Statins can be broadly classified into lipophilic and hydrophilic statins. Lipophilic statins are fat-soluble, and hydrophilic are water-soluble. 

• Lipophilic statins: Simvastatin, fluvastatin, pitavastatin, lovastatin, and atorvastatin
• Hydrophilic Statins: rosuvastatin and pravastatin

Notably, lipophilic statins quickly enter the cells and communicate with cell membranes. In contrast, hydrophilic statins show more selectivity to liver cells.

Explore your body’s response to different types of statins with Xcode Life’s Personalized Medicine report. 

Statins & TNBC

The earliest research to report a link between statin and TNBC was a study in 2013. According to the study, statins activate the inhibition of TNBC through the PI3K pathway. They also suggested Simvastatin as a potent candidate for the treatment of TNBC, especially for wild-type (a form of the gene occurring naturally and predominating a population) expression of PTEN in the TNBC tumors. 

Another study, done in 2017, to investigate the outcome of statin use on TNBC produced mixed results. The study observed no apparent association between statin use and overall survival (OS) in an unselected cohort of TNBC patients. 

However, statin use significantly improved OS within a specific group of test subjects whose cholesterol and triglyceride levels were controlled. In addition, statin use showed a pronounced effect on survival rate even for another group of triple-negative patients who experienced metastatic failure. 

*Note: 1. Overall survival: Length of time from the diagnosis date or start of treatment that a patient is still alive.

2. Metastasis: Stage of cancer where the cancerous cells start migrating from their origin site and infect other healthy parts of the body.

In 2019, a study found that the effect of statin use on breast cancer survival depended on the duration of statin use. In the test subject group, patients who had a medical history of statin use for more than five years experienced a conspicuous improvement in survival rate. 

(NB: The findings of the study were irrespective of breast cancer type or receptor subtype)

 In 2020, a statistical study on the clinical outcome of statin use on breast cancer diagnosis involving multiple research studies found a significant association between statin use and decreased recurrence rate and breast-cancer mortality in women. 

The Study - Statins Can Improve Survival Rates for TNBC

A study led by Kevin Nead of the University of Texas M. D. Anderson Cancer Center explored the outcomes of statin use in breast cancer patients. This study was the first to investigate the effect of statin use on all subtypes of cancer, focusing mainly on TNBC. 

According to Nead, “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.” 

Study Conditions

The study analyzed 23,192 female patient data included in the Surveillance, Epidemiology, and End Results (SEER)-Medicare registry and the Texas Cancer Registry (TCR)-Medicare databases between 2008-2015. Patients were at least 66 years of age and diagnosed with stage I-III breast cancer.

2281 patients out of 23,192 were individuals who commenced statin use within 12 months of a breast cancer diagnosis. Out of these 2281 patients, 78.1% were white, 8.9% were black, 8.4% were Hispanic, and 4.5% belonged to other races. 

The study also assessed the type-specific effect of statin on breast cancer outcomes.

Results of The Study

• In a specific TNBC subgroup of 1534 patients, statin use influenced a 58% relative improvement in breast cancer-specific survival (BCSS) rate and a 30% relative improvement in OS rate. 

• In a specific TNBC subgroup of 1534 patients, statin use influenced a 58% relative improvement in breast cancer-specific survival (BCSS) rate and a 30% relative improvement in OS rate. 

• In a specific TNBC subgroup of 1534 patients, statin use influenced a 58% relative improvement in breast cancer-specific survival (BCSS) rate and a 30% relative improvement in OS rate. 

• In a specific TNBC subgroup of 1534 patients, statin use influenced a 58% relative improvement in breast cancer-specific survival (BCSS) rate and a 30% relative improvement in OS rate. 

Let’s lower the risk of TNBC!

1. Keeping a check on body weight and/or obesity, especially for women who have undergone menopause, can help in minimizing breast cancer risk. 
2. Adopting a Mediterranean diet and foods containing fiber over “Western-type” diets can help with reducing or managing obesity.
3. Dietary patterns, including plant foods, legumes and/or fish and/or poultry, and unsaturated fats, are associated with a lower risk of cancers and youth mortality.
4. Limiting alcohol consumption to 1 drink per day for women and two drinks per day for men or stopping alcohol consumption minimizes breast cancer risk.
5. Cruciferous vegetables like broccoli, cauliflower, and Brussels sprout, and allium vegetables like onion and garlic can be included in the diet for their anti-cancer properties.

Video

Summary

1. TNBC is the most aggressive of all breast cancers as it lacks all three receptors; it is, therefore, harder to diagnose and treat.
2. Statins can help in prolonging lifespan by improving survival rates in TNBC.
3. Long-term and high-intensity use of statins, predominantly lipophilic statins, increases the OS rate.
4. The stage of cancer and tumor grade is essential to consider while looking at survival rates and statistics.
5. Managing weight by judicious inclusion of dietary elements while cutting down on alcohol can help prevent breast cancer.

References

1. https://doi.org/10.1002/cncr.33797 
2. https://www.cdc.gov/cancer/breast/triple-negative.htm  
3. https://www.cancer.org/cancer/breast-cancer/about/types-of-breast-cancer/triple-negative.html 
4. https://www.healthline.com/health/triple-negative-breast-cancer-outlook-survival-rates-stage
5. https://www.sciencedirect.com/science/article/abs/pii/S0006291X13013697?via%3Dihub 
6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559964/ 
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596255/ 
8. https://www.cancer.org/healthy/eat-healthy-get-active/acs-guidelines-nutrition-physical-activity-cancer-prevention/guidelines.html 

ACE gene: An introduction

ACE gene codes for Angiotensin-Converting Enzyme.

This enzyme is a part of the Renin-Angiotensin System, which is responsible for maintaining blood pressure, and fluid and salt balance in the body.

The enzyme cleaves the protein angiotensin I at a particular site, converting it into angiotensin II.

This angiotensin II brings about constriction of blood vessels, thereby increasing the blood pressure.

ACE gene is located on the long arm of chromosome 17.

Mutations in the ACE gene have been associated with a severe form of the renal disease called renal tubular dysgenesis.

What are ACE inhibitors? 

As the name goes, ACE inhibitors are medications that slow down or inhibit the effects of angiotensin-converting enzyme (ACE).

Such medications are involved in relaxing the blood vessels and reducing blood pressure levels.

They are primarily used as anti-hypertensive drugs.

The ACE inhibitors prevent the angiotensin-converting enzyme from producing angiotensin II.

This reduces blood pressure and makes it easier for the heart to pump blood, thereby improving the functioning of the heart.

ACE inhibitors can be used to treat the following conditions:

• High blood pressure
• Heart failure
• Diabetes
• Chronic kidney disease
• Coronary artery disease
• Scleroderma
• Migraines

Common examples of ACE inhibitors are:

• Enalapril
• Captopril
• Ramipril
• Lisinopril

What are the side effects of ACE inhibitors? 

Like any other medication, ACE inhibitors too, have a few side effects. But, most of them are not a cause of worry.

These include:

• Cough
• Red, itchy skin or rash
• Dizziness and lightheadedness
• Metallic taste
• Decreased ability to taste
• Severe vomiting and diarrhea
• Swelling of the neck, tongue, and face
• Hyperkalaemia or excessive potassium in the blood 
• Kidney failure

ACE inhibitors and weight loss 

According to a study conducted by researchers in Australia, it was observed that ACE deficient mice weighed 20% lesser than the mice with ACE activity. It was also observed that the ACE deficient mice had 50% less body fat, especially around the belly area. 

The results from this study have suggested that ACE inhibitors might help in weight loss around the mid-section in humans.

This, along with the other effects of ACE inhibitors, might be cardio-protective.

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Are ACE inhibitors safe for the kidneys? 

ACE inhibitors are cardio and renoprotective.

They reduce systemic vascular resistance in patients with hypertension, chronic renal disease, and heart failure.

ACE inhibitors as we know by now cause a fall in the blood pressure.

Intrarenal efferent vasodilation is also observed along with a fall in the glomerular filtration pressure.

These events are said to be renoprotective.

However, when the glomerular filtration is critically dependent on the angiotensin II-mediated efferent vascular tone, giving ACE inhibitors to the patient can induce acute renal failure.

The systemic and renal hemodynamic consequences, both benefits and adverse effects, are brought about by the depletion of sodium. 

Treating such patients with diuretics and ACE inhibitors, along with some sodium intake restrictions, can improve their therapeutic efficiency.

So, if the patients have a high risk of adverse renal effects to ACE inhibitors, their dosages should be titrated appropriately, and renal function and potassium levels should be closely monitored.

ACE inhibitors vs. beta-blockers 

ACE inhibitors and beta-blockers are both classes of drugs that are used to treat hypertension.

Though their goal is the same, their mechanism of action is entirely different. 

ACE inhibitors work by preventing the conversion of angiotensin I to angiotensin II.

Thus, they cause the relaxation of blood vessels and lower the blood pressure.

Beta-blockers, on the other hand, block epinephrine (adrenaline) and norepinephrine (noradrenaline) from binding to beta receptors on the nerves.

This reduces the heart rate and subsequently lowers blood pressure.

Both these classes of drugs have their side effects and drawbacks.

In most cases, a combination of one or more anti-hypertensive drugs is used to treat high blood pressure.

What is hypertension? 

Hypertension is a widespread and highly prevalent lifestyle disease.

It is a medical term given for consistently high blood pressure over 120mm Hg systolic and 80mm Hg diastolic.

Hypertension is characterized by the flow of blood at high pressure against the walls of the blood vessels. 

As a result, the workload of the blood vessels and the heart increases substantially.

Over a period of time, this force and friction on these tissues end up damaging them, and this can precipitate many conditions.

Some of them include:

• Stroke
• Vision loss
• Heart attack
• Heart failure
• Kidney disease 

What are the leading causes and symptoms of hypertension? 

Hypertension can be of two types: Primary and secondary.

When the rise in blood pressure levels is due to a non-identifiable cause, it is known as primary hypertension.

However, when there is an increase in the blood pressure levels due to an underlying condition, it is called secondary hypertension.

Some common causes of hypertension include:

• Environmental factors such as lack of exercise, stress
• Increase in blood plasma volume
• Hormonal activity
• Some medications
• Smoking
• Familial history of high blood pressure
• Diabetes
• Chronic kidney conditions
• Hyperthyroidism
• Hyperparathyroidism
• Pregnancy
• Obesity
• Pheochromocytoma
• Sleep apnea

Though hypertension is often silent, in some cases, the patient does show some symptoms. Like:

• Sweating
• Anxiety
• Blushing and flushing
• Sleep problems
• Frequent headaches
• Nosebleeds

What are the four stages of hypertension? 

Individuals who are in the prehypertension stage can progress to the other stages if immediate action is not taken.

Untreated cases of hypertension can even be fatal.

Diet recommendations to reduce blood pressure

One of the primary causes that result in hypertension is poor lifestyle choices, which includes an unhealthy diet.

So, to reduce the blood pressure levels and maintain it under the limit, certain dietary recommendations should be followed.

• Count your calories and keep track of what you eat.
  • Reducing caloric intake and eating adequate portions of high fiber foods can help you reduce weight, lose fat, and reduce cholesterol levels in the body.
  • All these together can bring down your blood pressure levels.
• Avoid sodium.
  • Increased sodium in your diet results in increased blood pressure levels.
  • Therefore, reduce your sodium intake and increase the absorption of other minerals, such as potassium and magnesium.
• Increase your intake of fresh fruits and vegetables.
• Consume probiotics.
• Avoid high carbohydrate foods.
• Avoid excessive fatty foods, especially those who are rich in saturated fats.

What is the DASH diet? 

DASH diet is an acronym for Dietary Approaches to Hypertension diet.

The plan includes adopting a diet which includes fruits, vegetables, whole grains, low-fat dairy, nuts and seeds, legumes, fish, and poultry.

The most important aspect is to eat foods that are rich in potassium, calcium, magnesium, protein, and fiber and avoiding foods rich in sodium.

DASH diet is low salt and low sugar diet that does not allow the intake of desserts, sweetened drinks and beverages, red meat, and processed meats and fats.

The diet allows a maximum of 2000 calories a day, which includes:

1. 7-8 servings of grains
2. 4-5 servings each of fruits and vegetables
3. 2-3 servings of low-fat or fat-free dairy products
4. 1-2 servings of lean meat or fish 
5. 4-5 servings of nuts and seeds per week
6. 2-3 servings of oil or fat 
7. Not more than five servings of sweets per week 

Can high blood pressure be cured?

In most cases of primary hypertension, blood pressure levels can be brought down by a combination of medications, dietary changes, regular exercise, and lifestyle modifications.

Once the blood pressure has been controlled, the individual can maintain his/her blood pressure levels within a reasonable range by living and eating healthy.

In many cases, a precautionary medication is advised to prevent the blood pressure from shooting up. 

Salt intake and high blood pressure 

Our kidneys are responsible for water and salt regulation.

More the salt we consume, more the kidneys tend to retain water.

The increased water retention results in an increase in our systemic blood pressure.

This leads to increased pressure on the walls of many blood vessels, which may result in organ damage. 

ACE gene and hypertension 

Of the many factors that can cause hypertension, the ACE gene also plays a role.

We know that the blood pressure in the body is controlled by the kidneys.

But, to be more specific, the Renin-Angiotensin System or RAS system is responsible for regulating it.

Some genetic variations are related to the RAS system, the most common one being the insertion/deletion polymorphism of the ACE gene.

So, essentially, the interactions between the ACE I/D polymorphism, sodium intake the RAS system determine your blood pressure and influence the risk of developing hypertension.

rs2106809

It was observed that the DD genotype of ACE and the TT genotype of ACE2 were significantly high in female hypertensives and the T allele of ACE2 was also linked to male hypertensives.

rs4308

SNP rs4308 is located on chromosome 17.

Presence of the A allele is responsible for the increase in the diastolic blood pressure.

This SNP locus also features as a target of anti-hypertensive drugs.

ACE gene and fitness 

The ACE gene has been linked to athletic performance.

A genetic variation consisting of 287 DNA bases when inserted into the ACE gene causes a decrease in the ACE enzyme activity.

This version of the gene is called the ‘I’ version.

This variation is shown to be present in athletes, especially sprinters.

The presence of this insertion has been seen in many athletes who perform well in endurance sports such as wrestling, swimming, triathlons, etc.

Though the exact mechanism of how the ACE I gene contributes to fitness and athleticism is unknown, it probably has something to do with an increase in the heart rate, blood pressure, and muscle growth during training.

rs4343

SNP rs4343 of the ACE gene has the ‘A’ and ‘G’ allele.

The A allele is associated with the insertion or I variation, whereas the G allele of the gene is associated with deletion or the D variation.

The G allele results in an increased risk of heart disease (GG) whereas, the minor A allele shows an increased association with endurance-based athletes. 

SNP rs4343 has also recently been linked to susceptibility to migraine, where a G/G polymorphism was seen in patients with migraine with aura as compared to patients of migraine without aura.

Does your 23andme, Ancestry DNA, FTDNA raw data have ACE gene variant information?

References:

1. https://ghr.nlm.nih.gov/gene/ACE#synonyms
2. https://www.ncbi.nlm.nih.gov/pubmed/8879974
3. https://www.ncbi.nlm.nih.gov/pubmed/17473847?dopt=Abstract
4. https://www.ncbi.nlm.nih.gov/pubmed/24112034
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972004/

The hepatic lipase gene (LIPC) is associated with the synthesis of hepatic lipase enzyme (LIPC) which catalyzes the hydrolysis of fat. Hepatic lipase converts intermediate-density lipoprotein (IDL) to low-density lipoprotein (LDL).It is expressed in the liver and in the adrenal glands. Specific alleles of this gene are known to either increase or decrease hepatic lipase levels, and due to linkage disequilibrium, the levels of lipoprotein lipase, which is associated with variations in the plasma HDL levels.  People with the T variant of the gene are shown to be associated with higher baseline HDL levels.

Does your 23andme, Ancestry DNA, FTDNA raw data have LIPC gene variant information?

Association with Weight Loss Upon Exercise:

People with the C variant of the gene were associated with reduction in weight, body fat and visceral fat.

Association with Plasma Lipoprotein Levels upon Exercising (atherogenic effects):

In a study investigating the effects of endurance training on plasma lipoprotein levels, people with the C variant of the gene have been found to be associated with exercise mediated reduction in VLDL and increase in HDL. The benefit of exercise was found to be more in men with CC genotype than women.

Association with Childhood Obesity:

In a meta-analysis study conducted on children, boys with the T allele had a higher BMI and higher risk of obesity. In another study, boys with the T variant of the gene were found to be associated with higher HDL level on high fat intake.

Association with Dietary Fat intake:

In a study conducted to determine gene-nutrient interactions, people with the T variant on a low fat diet (less than 30% of energy from fat) have been shown to be associated with higher HDL levels. In a study conducted to identify how Chinese, Malays and Asian Indians in Singapore were exposed to similar environment but where Asian Indians had three times the rates of myocardial infarction compared to Chinese, found that a complex interplay of environmental and genetic factors gave rise to these ethnic differences. A high fat diet was shown to be associated with higher serum triglyceride and lower HDL-cholesterol concentrations in people with the T variant while those with the C variant were shown to be associated with lower serum triglyceride and higher HDL cholesterol under the same dietary conditions. People with the T variant of the gene may have an impaired adaptation to a high fat diet, increasing the risk for cardiovascular disease.

Association with Insulin Sensitivity:

In a study conducted on the LIPC gene variant and insulin sensitivity, the baseline insulin sensitivity was found to be similar between the gene variants but, upon exercising, people with the C variant were shown to be associated with higher insulin sensitivity. In a similar study, men with the T variant were shown to be associated with an improvement in insulin sensitivity when MUFA and carbohydrate rich are consumed instead of SFA fat. There was no association with women with the T variant and between diet and insulin sensitivity among men and women with the C variant.

References:

1. https://www.ncbi.nlm.nih.gov/pubmed/12403660
2. https://ajcn.nutrition.org/content/81/6/1429.full.pdf
3. https://www.ncbi.nlm.nih.gov/pubmed/9114024
4. https://www.ncbi.nlm.nih.gov/pubmed/23550552
5. https://goo.gl/I8cAcl
6. https://apjcn.nhri.org.tw/server/APJCN/14/s/72.pdf
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3053582/

“Nutrigenetics, fitness genetics, health genetics are all nascent but rapidly growing areas within human genetics. The information provided herein is based on preliminary scientific studies and it is to be read and understood in that context.”

I am your heart. I work really hard to keep you alive. Every minute I pump out 5 litres of oxygen rich blood to every cell in your body so you can think, move, speak, work and live. In return all I ask is that you keep me healthy. Not many people around the world do that. In fact approximately 17.3 million people die every year because heart disease. By 2020, it will be the leading cause of death around the world.

So let’s have a conversation. Heart to heart. Here are 7 natural ways you can prevent a heart attack.