DELAYED TREATMENT OF BREAST CANCER

I’m always amazed when a woman who knows she has breast cancer asks if she can wait to start treatment.   There isn’t a perfect answer to this question, but we know some things about delayed treatment of breast cancer. 

Some delay between biopsy and treatment is acceptable.

Fifty years ago, when a biopsy identified cancer, surgeons removed the rest of the breast as soon as possible, usually within hours. 

When we started doing breast biopsies as independent, separate procedures, the surgery would be at least a day or two later.

The so called “two-step procedure” was initially adopted because it allowed women the time to find a surgeon who would treat them without a mastectomy.   But in the process we learned that doing the biopsy and the mastectomy at different times did not harm women. 

Separation of a week or two between biopsy and surgery does not risk a woman’s healthBut we still don’t have a good answer on how much delay is too much.

There is limited information on the effects of delayed treatment.

For ethical reasons, there will probably never be a planned trial of delayed surgery, so our information comes from observing women who had delay for a variety of unplanned reasons.  

Researchers have looked at delayed treatment three ways:  1.  Delay of surgery when surgery is the only treatment.  2.  The effect of delayed surgery when the patient receives chemotherapy in a timely manner.  3. Reduced benefits if chemotherapy or hormone therapy is delayed for women with higher risk of spread of disease, for example stage II breast cancer.

1.  A long delay may reduce survival of women who have surgery alone.

A study of 2,384 California women all under 40 years of age found that delay of over six weeks adversely affect survival if the women received no anti-cancer drugs [click for abstract]. Younger women tend to have more aggressive cancers so it seems that earlier surgery is important for more aggressive cancers.  However, this is not a major problem today because chemotherapy is offered to most younger women with breast cancer.

In contrast, a study of 1,065 North Carolina women average age 61 years old with early stage breast cancer found that a delay of up to 60 days did not reduce survival [click for abstract].  This agrees with a study of 648 Malaysian women almost all over age 40 (only a few received anti-cancer drugs ) for whom up to two months delay did not reduce survival [click for abstract]

A separate study of 2,045 Korean women extended the delay with no effect to 120 days [click for abstract].  However, a delay of over 120 days to surgery did reduce survival if the woman depended on surgery alone for her treatment. 

Thus, for aggressive cancers in younger women, a delay over six weeks seems to reduce survival.  For less aggressive cancers, reduced survival is seen after a 120-day delay. 

It must be remembered that almost none of these women had any anti-cancer drugs.

2.  Delay of surgery has no effect if the patient receives timely drug therapy.

The same California study that looked at delayed surgery without chemotherapy found that if patients had chemotherapy before surgery – neoadjuvant therapy – or chemotherapy after surgery, delaying the surgery itself did not adversely affect survival [click for abstract]

3.  Delay of drug therapy reduces survival.

Drugs are often given after surgery before there is any evidence of cancer growing anywhere else in the body.   The idea is that cancers that are too small to find will be less established and thus more sensitive, to the drugs.  Giving drugs before detecting any spread of cancer is called adjuvant therapy.

The North Carolina study mentioned above included 721 separate women diagnosed with locally advanced breast cancer.  For these women, a delay of over 60 days to the beginning of treatment – usually chemotherapy – significantly reduced survival [click for abstract].

This agrees with a study of chemotherapy given to 2,549 British Columbia women.  A delay of 12 to 24 weeks to the start of chemotherapy significantly reduced five-year survival from a range of 83 to 88 percent (for various time intervals up to 12 weeks) down to 78 percent for a delay of 12 to 24 weeks [click for abstract]

Can adjuvant therapy be delayed and only given if the cancer comes back?

A possible planned delay of treatment is to withhold therapy intentionally and not give it unless the cancer returns some time later.

In underdeveloped countries, money is scarce, even for drugs such as tamoxifen.  This has led to studies of whether it is necessary to treat everyone at the time of diagnosis – thus spending money treating everyone – or whether it works to treat only the women whose cancer comes back.

A study randomized 709 Vietnamese and Chinese women with Stage II breast cancer to answer just this question. Half the women received intense hormonal treatment with removal of their ovaries and tamoxifen pills beginning right after their surgery.  The other randomly selected young women were closely followed but did not receive any treatment after surgery unless the cancer came back [click for abstract]. 

If a woman in the second, close observation group had a recurrence, she was offered the same ovary removal and tomoxifen that the other group had received right after surgery (three-quarters of women with recurrent cancer actually received the treatment offered). 

In essence, women had the same treatment.  The difference was the timing.  Some women had adjuvant treatment before metastases grew, and some women only had treatment after their metastases grew enough to be detected.  Importantly, most women in the second, closely observed group never needed any further treatment, so money was not spent giving them hormone treatment.

Earlier therapy before metastases grew improved survival.

There were 24 percent fewer deaths among the women who received early, adjuvant therapy compared to those whose treatment was intentionally delayed. When women who did not receive adjuvant treatment had a recurrence, they responded less well to treatment. This caused an absolute increase of 6 more women alive for every 100 women who had adjuvant therapy compared to delayed therapy. 

This is the only study I can find comparing the same treatments given early or later.   The available information, however, suggests that if treatment is delayed until the cancer grows back – or if a cancer is left in place and allowed to grow – the woman never has the opportunity for optimal response to treatment again. 

Don’t panic, but make decisions and start getting care.

There is almost always treatment to help women with recurrence of cancer, but the best thing is to reduce the risk of recurrence by treating within a reasonable time.

A woman can use some time to decide what is the right treatment for her.  However, she will have her best chance for disease-free survival if she gathers her information and starts treatment as soon as she is comfortable with her decisions. 

CANCER AND CHEMICAL MIXTURES

We are often told environmental chemicals are safe because we are exposed to concentrations “too low” to cause harm.  Toxicologists call such a low concentration the no-observed-effect-concentration or NOEC. [Some experts use the acronym NOEL for no-observed-effect-level.]

The counter argument is that we are not exposed to one chemical at a time.  Instead, we are constantly exposed to mixtures of chemicals.  Each chemical by itself might not cause harm – that is, each chemical might be present below its NOEC/ NOEL – but the overall effect of the chemical mixture comes from the combination of individual chemicals acting together.

A good metaphor is how adding salt to a recipe makes you taste the sugar more.  Salt changes how our bodies respond to the sugar.

Until recently, the importance of chemical mixtures has been debated without much evidence.

New Information on Chemical Mixtures

Recently, Professor Philippa Darbre and her colleagues at the University of Reading near London published results showing how mixtures of common chemicals called parabens work on cancer cells in the laboratory. [click here for the abstract]

Parabens are Present in Most Human Breast Tissue

Parabens* are absorbed through the skin from over-the-counter personal care products we buy and use every day.  Parabens accumulate and are stored in breast tissue.  Professor Darbre’s group measured the concentrations in breast tissue that had been removed by mastectomy to treat cancer for 40 different women.  [click here for the abstract]

The levels of parabens varied among the different women and in different parts of the breast (There were higher levels in breast tissue that had been nearer the axilla or armpit), and 40 percent of samples had at least one paraben at a level above the NOEC/ NOEL for that individual paraben.

Effects of Parabens can add up

When they tested the effects on cancer cells of a seven day exposure to each of the five parabens individually, at NOEC/ NOEL concentrations, none of the chemicals had an effect by itself

However, seven days of exposure to a combination of all five chemicals in the same NOEC/ NOEL for each of the parabens showed a trend for increased growth. 

When they exposed the cells for two weeks instead of one week to the same combination of very low levels of the five parabens – with each paraben still at a level too low to have an effect by itself – the combination of parabens made cancer cells grow significantly more.

Cancer Cells and the Chemical Mixtures measured in Individual Women

Next they exposed cancer cells to the exact mixtures of the parabens that were measured in specific individual women. In several, but not all cases, they observed enhanced growth of breast cancer cells after exposure to the chemical mixtures. 

Longer Testing finds Additional Effects

Darbre and her colleagues also exposed cancer cells for four rather than two weeks reasoning that parabens accumulate in tissue so human breast tissue is actually exposed a lot longer than two weeks.

After a longer, four-week exposure, cancer cells grew more than after the shorter, two-week test exposure. 

It’s more Convincing that Not Every Combination caused Cancer Cells to Grow

If every woman’s chemical mixture caused cancer cells to grow, it would not match what happens in real life, and we would wonder if the study was designed incorrectly.

The concentrations measured in some women caused cancer cells to grow, but the concentrations measured in some other, different women did not cause cancer cells to grow, even in mixtures.  

This variation is like real women. Not every woman gets cancer.  

Exposure to chemical mixtures may be like radiation exposure.  Only a portion of women exposed to radiation get cancer from it, but we limit radiation exposure as much as possible.  Similarly, exposure to chemical mixtures is unnecessary, so we should also try to limit exposure to chemical mixtures. 

Cancer, Chemical Mixtures and the Precautionary Principle

Is Professor Darbre’s study the proverbial “smoking gun” linking cancer and chemical mixtures?  Not yet.  Do we have reason to be concerned?  I believe we do

We clearly have reason to question tests that conclude that chemicals are benign when they have been tested as individual chemicals. Human breast tissue is exposed to chemical mixtures all the time.  To determine what effects chemicals might have, it is necessary to test chemical mixtures.  This is rarely done.

Possible Precautions for Now

Until we have better information, I personally try to find paraben-free shampoos and soaps.  It’s difficult, but in my opinion, it is the safest thing to do for the present.  This is called the Precautionary Principle.  Be careful as a precaution. 

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* They tested methylparaben, ethylparaben, propylparaben, butylparaben, and isobutylparaben.  You can look in the fine print on the label of your shampoo, cosmetics, skin creams, etc to find out whether you are exposed to these chemicals.

SMALLER OPERATIONS FOR BREAST CANCER

Recently I gave a talk in St. Petersburg, Russia discussing the place of sentinel lymph node biopsy (SLNB) in breast surgery today.  As I prepared my slides, I was struck by how much breast surgery has changed in the last 25 years.  We’re doing much smaller operations for breast cancer. 

THE OLD PARADIGM

By 1990, breast surgery had made a great leap forward.  Reliable, randomized, controlled trials had proved that, for smaller breast cancers, breast conservation therapy (BCT, often called a “lumpectomy”) gave as good survival as mastectomy. 

The basic rule for breast cancer surgery had become:  Remove all the cancer you can find with negative margins; then treat the rest of the breast with radiation therapy. 

However, we still used axillary lymph node dissection (ALND) to obtain nodes for examination by a pathologist, because looking for cancer in nodes was the best way we had to estimate the risk that cancer might come back in the future. 

If cancer was in the lymph nodes, it indicated enough risk of recurrence to justify treatment with chemotherapy and/ or hormone blocking drugs.  

There was, however, already a trend to remove fewer nodes because removing fewer nodes created fewer problems with persistent arm swelling called lymphedema.

If a woman had a larger cancer, we recommended a mastectomy.

A NEW PLAN FOR LARGER CANCERS 

About this time, physicians asked if giving chemotherapy before surgery — called neoadjuvant chemotherapy — might be better than giving chemotherapy after surgery.  It was a good idea to try, but it turned out survival was about the same whether chemotherapy was given before or after surgery*.

There was, however, a benefit of neoadjuvant chemotherapy for large tumors.  If a cancer was too large for BCT, neoadjuvant chemotherapy could make the tumor shrink enough to make BCT feasible.  

At least one-third of women with large tumors had their cancer shrink enough to allow BCT.  With newer treatment plans, the number of women who become eligible for BCT is greater.

REMOVING FEWER NODES 

Physicians also wondered if it was necessary to remove all the axillary nodes to identify women who would benefit from chemotherapy.   This led to trials of sentinel lymph node biopsy (SLNB) that injected a blue dye and/ or radioactive tracer into the breast and then followed the dye and/ or tracer to identify the sentinel node(s) most closely associated with the cancer.  

If there was no cancer in the so-called “sentinel node(s)”, other nodes were left alone.  Removing only the sentinel node reduced the chance of lymphedema to less than 5 percent in most studies.  

IS A NEGATIVE SENTINEL NODE RELIABLE? 

Or, if the sentinel node is negative, what’s the chance that cancer was present in another node and was missed?  

The best way to answer this question was to follow women who had no cancer in a SLNB and did not have an ALND for that reason. 

Multiple studies have found that, after a negative SLNB, cancer reoccurs in another node less than 1 percent of the time.  This might sound unacceptable for cancer to reoccur in the axilla (armpit) even 1 percent of the time, until we are reminded that cancer can reoccur in the axilla even if the patient has a full ALND.  

Specifically, more surgery does not always guarantee better results, which is why use of ALND dropped by almost 60 percent between 1998 and 2004. 

WHEN THERE IS CANCER IN THE SENTINEL NODE

There is no consensus on whether to do a full ALND on every woman with a positive sentinel node.  There is, however, a strong trend to limit ALND to women with larger amounts of cancer in the node, which means not to do ALND if there is only a little cancer in the sentinel node

For example, a micrometastasis – a spot of cancer between 0.2 and 2.0 millimeters in a node – is uncommon.   When a full ALND was done for micrometastisis, most women did not have more positive nodes.  For this reason, surgeons began to omit ALND if there was only a micrometastasis.  In follow up of these women, the risk of cancer reoccurring in the axilla — if they did not do an ALND — was about the same as when the sentinel node was truly negative.  

More recently, a randomized trial intentionally compared doing an ALND to no ALND for women with a positive SLNB, including metastases larger than a micrometastasis.  This was for women who were having radiation therapy as part of BCT.  Not only was there no decrease in survival when ALND was omitted, but there was no increase in axillary recurrence of cancer even though the study included women with up to two positive nodes.

These results show that chemotherapy and radiation therapy after BCT surgery are sufficient to limit further cancer growth.  This is why use of SLNB alone – even with a small amount of cancer in a node – doubled to nearly 40 percent of cases by 2004. 

THE NEW PARADIGM 

In 2013, if a woman has a small cancer in her breast, the recommended plan is still surgery to remove cancer, leaving the rest of the breast.  This is usually combined with SLNB and radiation therapy.

In contrast, the paradigm has changed significantly for larger tumors.  When the cancer is too big for BCT, biopsies are done to confirm the diagnosis, and the patient is given chemotherapy before surgery because it will often shrink the cancer to a size that will allow preserving the rest of her breast.  

Neoadjuvant chemotherapy is more common, but in some cases, physicians recommend neoadjuvant hormone based treatment instead. 

THE NEXT QUESTION 

After neoadjuvant chemotherapy, SLNB does predict additional positive nodes well.   What is not yet proven is whether SLNB is sufficiently reliable after neoadjuvant chemotherapy to omit ALND.  There is no long-term data that the risk of cancer coming back in the axilla is acceptably low in the situation of a negative sentinel node after neoadjuvant drug therapy.  

BREAST SURGERY FOR 2014

We’ve shifted the way we treat breast cancer. SNLB is part of the story, but one can’t talk about SLNB without also considering the role of neoadjuvant drug therapy in reducing the extent of surgery for breast cancer.

Neoadjuvant treatments have enabled us to do smaller operations for many women who are diagnosed with larger cancers.

Neoadjuvant therapy and SLNB are two parts of the same story.  That’s progress!

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*Breast cancer is usually present – but too small to detect – for several years before it is found.   Because of this several-year time course, moving chemotherapy a month or so earlier or later is relatively minor difference compared to the much longer “life-cycle” of the cancer up to that point. 

MAMMOGRAM SCREENING INTERVAL AFTER LUMPECTOMY

How health policy can delay diagnosis.

“Local Recurrence” is the term used when cancer grows back in a woman’s breast after breast conserving treatment of breast cancer.  Local recurrence means that surgery – usually combined with radiation therapy – did not permanently eliminate the cancer.  Local recurrence is     uncommon, but it can occur. 

Experience has shown that if local recurrence is found early, it will not affect the survival of the majority of women.  For this reason it is important to find local recurrences early.

MAMMOGRAMS IDENTIFY LOCAL RECURENCES

About two-thirds of local recurrences are found by mammograms.  Most experts agree that a mammogram should be done six months after surgery to provide a new baseline that shows       how the breast has changed after surgery. 

There is debate as to whether the screening interval for follow-up mammograms after that first study should be every 6 months or every 12 months.   A big reason for the disagreement is cost. 

Mammograms are not very expensive, but there will be twice as many – costing twice as much      – if mammograms are done every 6 rather than every 12 months.  It is informative that in      recent discussions about what timing interval to adopt, I was told that we should go to every 12 months because, “…the world is changing…we have to put costs in there…[and] we understand      it’s arbitrary….”

ONLY AN OPINION

Until recently, information comparing 6 to 12 month follow up intervals was based on the       opinion of experts (insurance companies, health policy researchers, oncologists, surgeons, and radiologists) who thought about this issue and made their best guess.

NOT PERFECT, BUT BETTER INFORMATION

A recent study from UCSF brings observational data to this debate.

In the 1980s, when I was doing most of the breast conservation surgery at UCSF – and                Dr. Edward Sickles, Chief of Breast Imaging at UCSF, was setting up a program to follow these women with mammograms – he decided that 6 months was a good follow-up interval. 

Admittedly, it was a guess, but it was also a decision that intentionally erred on the side of    caution, trying to be extremely careful of the health of the women who were at risk.

Part of the reason 6 months was chosen was experience that if cancer was missed on a mammogram, changes on subsequent mammograms were unlikely to be recognized if the      follow-up mammograms were less than 6 months apart.  Not enough changed to be detectable       if the interval was less than 6 months.

Other radiologists made the decision that they would do mammograms only every 12 months.       In the mid 1980s, it would have been difficult to say that one doctor was right and the other was wrong.

LEARING FROM WOMEN WHO CHOSE NOT TO FOLLOW THE PROTOCOL

At UCSF, most women were advised to have follow-up mammograms every 6 months, and that      is the protocol I have continued in my own personal practice.  There have, however, been      women who did not follow those recommendations

Radiologists at UCSF have compared how the stage of locally recurrent cancer was affected by whether the woman had mammograms at the recommended 6 month intervals, or if they waited and had mammograms after a longer interval.

A SHORTER SCREENING INTERVAL MEANT RECURRENCES WERE FOUND EARLIER

As expected, not many women had local recurrence, but when recurrence did occur, there were differences in how advanced the cancer had become before detection.

If a woman had a local recurrence – and her breasts had been screened for recurrence using mammograms every 6 months (they included up to 9 months as the cutoff) – 94 percent of   recurrent cancers were very early stage 0 or stage 1 compared to only 73 percent very early    stage if the woman’s last mammogram was 9 to 15 months previously.  [click here for the   abstract]  With the 6 month interval, when a cancer came back, it was found at a lower, more favorable stage.

This is not a perfect study – a perfect study would randomize women to mammograms either   every 6 months or every 12 months – but data is always better than expert opinions. 

Until better data is available, it seems prudent to have biannual, i.e. every 6 month mammograms for the first five years after breast conserving treatment of breast cancer.  No matter what    anyone may tell you to the contrary.

BREAST DENSITY AND CALIFORNIA LAW

California women who have dense breasts on their mammograms are currently receiving written notification that they have “dense breasts.”  Some institutions are notifying all women of their density – both high density and low density – whereas some institutions are notifying only women with dense breasts, the minimum that the law requires.  The law does not stipulate any action that a physician must take, but the letter raises more questions than it answers.

Does breast density correlate with density on clinical examination?

No!  Breast density – both in the context of SB-1538 and as a risk factor discussed below – is a specific finding revealed only by mammograms.  Dense breasts on clinical breast examination may be dense either 1. because of dense gland tissue as seen in radiographically dense breasts, or 2. because of accumulated fatty tissue that can exist in breasts that are almost entirely fat on mammograms, i.e very non-dense.  It is not possible to determine whether tissue or fat causes the palpable density by clinical breast examination alone.

How many women have dense breasts?

Half of women have dense breasts on their mammogram.  This “half” breaks down as approximately 10% of all women with extremely dense breasts and 40% with heterogeneously dense breasts [click here, Table 1].  The breakdown is important because only the 10% of women with extremely dense breasts have the maximum increase in risk, and only one-fifth of women who are told they have dense breasts will have a very high risk.  

For comparison, about 10% of women have almost entirely fatty breasts and 40% have scattered densities.

What is the risk with extremely dense breasts?

Independent of other risk factors, a woman with extremely dense breasts (10% of all women) has roughly twice the risk of developing breast cancer as a woman with scattered densities (40% of all women and the majority of women with non-dense breasts) [click here, Table 5]. 

Similarly- as an approximation – breast density divides any risk group of women – for example those with family history, higher alcohol use, etc. – into higher risk (dense breasts) or lower risk (non-dense breasts) sub-groups.  However, the ability to detect truly low-risk versus truly high-risk groups by mammographic density is limited because the ratio of risk between the highest and the lowest groups is only about two fold.

For example, a woman with atypical duct hyperplasia has about an 8% chance of cancer over 10 years.   This can be divided into higher and lower risk groups, but the ratio between low and high is always two to one and they must average to 8%.  This limits how high the high risk really is, but more importantly, it also limits how low the risk is for lower risk women.  These are real differences, but it is not clear how to apply this information since women with low-density mammograms can still develop breast cancer.  [See previous post on Breast Density.]

Why study breast density?

Wolfe in 1967 reported that breast parenchyma patterns could identify women at high risk of developing breast cancer.  Breast cancer increased with the progression from N1 through P1 and P2 to DY parenchyma patterns.  These patterns correspond roughly – though not exactly – to current breast density classifications ranging from almost entirely fatty to extremely dense.

Predicting risk from parenchyma patterns is complicated because many women do not fit one category or another.  Measuring breast density has the same problem.  Computerized systems help, but there is an unavoidable arbitrariness in selecting the cut points between density groups.  Even using arithmetic quartile groups assumes that the point of separation between quartiles has biological significance. 

Cost cutting is the new goal.

Cost cutting – the opposite of risk identification – is the reason for recent research on breast density.   Instead of finding high-risk women, the goal has become to identify a group of women with an absolute low-risk of cancer – or a low enough risk – for whom mammograms can be done less frequently or omitted altogether [click for abstract]. 

Kerlikowski et al expand on this reasoning advocating biennial (every two years) instead of annual screening for most women [click for abstract].  However, they also note that women 40 to 49 years of age – with extremely dense breasts – are more likely to be diagnosed with advanced breast cancer if they have biennial rather than annual mammograms. 

They contend this risk of more advance cancer is acceptable because annual mammograms for ten years are also associated with a significant possibility of a false positive mammogram with attendant stress and unnecessary testing, perhaps even a benign biopsy. 

Women who undergo any breast diagnostic workup experience stress.  They ignore, however, the likelihood of greater stress from remorse for a woman with delayed cancer diagnosis after skipping her mammogram for a year or more.  Such stress has not been considered in their arguments.

What is recommended for women with dense breasts in 2013?

A group of radiologists representing Stanford, UC Davis, UC Irvine, UC Los Angeles, UC San Francisco, UC San Diego, California Pacific Medical Center, and Alta- Bates Summit Medical Center in Berkeley have created a website with recommendations for representative patient scenarios.  www.breastdensity.info

They advise physicians to base screening recommendations on breast density only when density is considered along with other factors

Their recommendations have a general theme.  If a woman has dense breasts – and after risk assessment of family history and/ or other factors – is at increased risk for reasons in addition to breast density alone, they recommend screening MRI.  Otherwise, mammography should be recommended.  Other modalities, e.g. screening ultrasound and 3-D mammography, are investigational as of March 2013.

New tests are being developed.

Berg and colleagues have evaluated adding hand-held ultrasound to screening for women with at least heterogeneously dense breasts on mammograms [click here].  Ultrasound significantly increased cancer detection by an additional 4.2 cases per 1000 exams, but the false positive rate increased from 4.4% for mammograms alone, to 8.1% for ultrasound alone, and 10.2% for combined mammograms and ultrasound.  Ultrasound helps, but at the cost of more false positive evaluations.

Computerized tomosynthesis or 3-D mammography processes two breast exposures to create a set of multiple tomographic images of the breast.  In preliminary studies, tomosynthesis  detected 27% more cancers with a simultaneous 15% decrease in false positives [click for abstract].  The tomographic study itself has only a little more radiation exposure than a screening mammogram, but interpretation is based on both standard mammograms and tomosynthesis together – done with two different exposures at the same time – so currently the total radiation dose is doubled.  Computer algorithms to use one pair of exposures to create both tomosynthetic and standard whole thickness images are being developed to resolve the problem of increased radiation exposure. 

EXERCISE AND LIVE LONGER – BUT HOW MUCH LONGER?

Would you walk 30 minutes every day to live a year longer?

That ‘s the starting benefit of moderate exercise.  You gain more if you do more strenuous exercise. 

Exercise is measured in METS.

METs – “metabolic equivalents” – are the way exercise physiologists compare energy used by a person doing different activities.  By definition, one “metabolic equivalent” (1.0 MET) equals sitting quietly for an hour.  At the other extreme, for example, running at a speed of 10 miles per hour is 18 METS (if you keep it up for a whole hour).  This means you use 18 times more energy to run at a speed of 10 miles per hour than to sit in a chair.

If the METs are multiplied by the number of minutes you do an exercise, they are called MET minutes.  For example, sitting for one hour is 1 MET energy expenditure for 60 minutes or 60 MET minutes.  Or, 3 METS an hour for 60 minutes equals 180 MET minutes (3 MET hours x 60 minutes/ hour = 180 MET minutes).  MET minutes can be added up to measure exercise for a whole week.

Note: an activity counts only if it is done for a minimum of 10 minutes or in an extremely intense short burst, such as a sprint race.  Doing something for 5 minutes does not have the same clear benefit because it does not make you breathe faster.

METs are measured by how much oxygen you use.

We need oxygen to extract energy from sugar and fat.  Physiologists determine energy use by measuring the oxygen a person uses as they breathe in and out during exercise.  To measure the oxygen a person uses, they measure the oxygen left in the air when the person breathes out.  The amount of oxygen the person used is the difference between what the person breathed in and what is left in the air when they breathe out.   

A person with normal lungs – and normal breathing response – can estimate the relative number of METS they are using by observing how hard or how fast they are breathing.  3.0 METS an hour means you can still carry on a conversation, but you are breathing hard enough that you can’t sing.  7.0 METS an hour means you are breathing hard enough that you can’t talk more than gasping a few words at a time.

MET minutes per week of exercise benefits longevity.

A team of researchers from Canada, Boston, Baton Rouge, and Columbia, South Carolina have used data from NHANES (National Health and Nutrition Examination Survey), the Health Interview Study, and US Life Tables to estimate 5-year survival according to how much a person exercises in their leisure time. 

They found that people who exercised regularly- but not enough to add up to 500 MET minutes per week – had some benefit [click for abstract].  People who did more exercise got more benefit.  As an approximation, 500 METs per week is equivalent to 2½ hours of moderate activity such as brisk walking, or 1¼ hours of vigorous activity such as running hard.

Caucasians and African Americans gained about 1 ½ to 2 years of life for being somewhat active every week (a little more for younger persons and a little less for persons over 60 years old).  If they exercise more than the basic 500 MET minutes per week, they will gain about an additional year.  For reasons that were not clear, neither Hispanic men nor Hispanic women gained life years from increased leisure time activity in this study, but there was no measure of how much activity they already had in their daily lives, so they may have been more active all the time.

Women who are active have a lower risk of getting breast cancer.

The Nurses Health Study previously found that women who get 9 MET hours per week or more of exercise – including those who start exercise after menopause – have about a 10 percent reduction in breast cancer [click here for complete article].   [9 met hours x 60 minutes per hour= 540 MET minutes, about the same as the 500 MET minutes that increases longevity].  Again, this is 30 minutes of brisk walking every day.  Note, if you walk briskly for 45 minutes, you can walk fewer days to get the same number of METs.  More intense exercise provides the same benefit in less time.

Calculate your METs per week.

There is a US Government website that discusses METs, but they only list a limited variety of examples [click here].  A year 2000 article in Medicine and Science in Sports and Medicine gives a wide variety of examples, but you need to pay for the whole article [click here for the abstract and the 2011 update]. 

To help you, I have selected representative activities and calculated the MET minutes for an hour and half an hour of each activity [click here].

To calculate the number of METs you personally expend in a week, list each activity, and how long you do it for.  You get credit for the intensity of each activity, but only for the length of time you do it.  For example, if you swim hard for an hour, that is 480 MET minutes (or 6 METs).  If you only do it for half an hour, that is 240 MET minutes, as in the table.  But if you only do it for 15 minutes, that is half of the 240 or 120 MET minutes. 

The health benefit you receive comes from the total of all of your leisure time activity.  If you swim hard for 30 minutes two days a week, that is 240 MET minutes x 2 or 480 MET minutes.  Suppose you also do an hour of Tai Chi for 240 MET minutes, and take a one-hour, brisk walk on Saturday morning for 228 MET minutes.  Your total would be 948 MET minutes or a total of 15.2 METs (948 MET minutes/ 60 minutes per hour = 15.2 METs) in that week.   

Again, note that you receive the basic benefits of 500 MET minutes a week by walking only 30 minutes per day. 

The benefits of vigorous activity also apply to men.

BREAST LUMPS IN YOUNG WOMEN

There is more advanced breast cancer in women 25 to 39 years of age than 30 years ago [click here for recent television report].  Most often this means that the cancer was missed at an earlier stage. 

The most common scenario for delayed diagnosis is that a young woman feels a mass, her doctor orders a mammogram, the mammogram does not show cancer, everyone feels reassured, nothing else is done, but the cancer is still there

Learning from studying delay.

Several years ago, a colleague and I looked at all the steps in diagnosis of over 400 breast cancers [click here]. 

Young women under 50 years of age were twice as likely to find their own cancer by feeling the lump themselves than by any other method.  Five percent of these women had delayed diagnosis for the reasons just described, i.e. they were misled by a falsely negative mammogram.

We also found that delayed diagnosis was three times more likely when the woman found the mass herself compared to her doctor or a mammogram finding the lump.   It seems, unfortunately, that doctors are more willing to dismiss what a woman feels, than what they or the radiologist finds.   For this reason, you have to insist on a thorough evaluation and not accept the first reassurance that may be offered.

From this study of delay, we can also say that if you are a young woman – and you develop cancer – the person most likely to find your cancer first, will be you.  So, if you find a mass, you need to be certain it is fully evaluated.

How do you keep from being another statistic?

The best way to avoid becoming a statistic of delayed diagnosis is to know what to expect from your doctor if you find a mass. 

Your history may be interesting, but that’s all it tells you.

Your doctor will ask about your general health, pregnancies, what your periods are like, hormones or birth control pills, and your family history.  These are usual things put in your record, but not one of these factors is helpful to decide if the mass you feel is cancer.

Breast examination is more than just a quick touch.

Your doctor should examine your breasts. 

A lot has been said about looking at the visual appearance of your breasts and feeling your nodes, but unless that is where the mass is located, the most important part of your examination is palpation of your breasts while you are lying down

Several years ago, I and several colleagues evaluated the diagnostic tests for 1400 cancers and found that only one cancer would have been missed if the doctor only palpated the woman’s breast while she was lying down [click here].  The other cancer was picked up by a mammogram.  For this reason, your doctor can safely skip looking at your breasts and feeling your nodes.  Those steps are getting information for the chart, but they are little help to diagnose what you have felt. 

What a mass feels like is not a reliable way to know if it is cancer.   Specifically, even for the best experts, palpation is not a reliable way to determine if a mass is cancer.  The only thing the doctor learns from the examination is whether you have a mass.

Expect your breast exam to take a few minutes.

Experts disagree on how long a thorough breast exam should take, but two minutes is pretty much the minimum.  Two minutes sounds short, but very few clinicians actually take that much time [click here to see what a 2 minute breast exam is like] www.2minutebreastexam.com].

In addition to what you have felt, your doctor should examine all of the rest of both breasts and also feel both breasts at the same time to assess if your breasts are symmetric (about 60 percent of women have some asymmetry, but only 10 percent are aware of that asymmetry unless they have checked).   Focal asymmetry in only one part of your breast can be the only sign of cancer.

Mammograms have limited usefulness if you’ve already felt a mass.

Your doctor may order a mammogram and possibly an ultrasound examination.  A positive mammogram can guide a biopsy if it shows a focal area of suspicion, but remember that the most common reason for delayed diagnosis of breast cancer is that the mammogram was “falsely” negative even though cancer was present.

A negative mammogram is not a diagnosis.  Please, do not stop at that step!

You need a sample from the mass for a pathologist to look at with a microscope.

If you have a discrete mass that is different from the rest of the breast, some sort of biopsy should be done.  But also know that lumps in the breast are fairly common, and about 7 to 8 percent of women have some sort of focal area in one breast or the other that is unusual, but not cancer. 

Fortunately, fine needle aspiration (also called FNA) is a great way to diagnose most masses that you can feel.   Used with physical examination and mammograms, FNA by a trained specialist is sensitive enough to identify 99 out of 100 palpable cancers

Should younger women have routine mammograms just to be sure?   

To answer this question, it’s best to consider women who are 40 to 49 years old separately from women who are 25 to 39 years old.  

For women 40 through 49 years of age, most leading groups such as the American College of Radiologists recommend routine mammograms.  Some other groups think routine mammograms should not start until age 50.

It’s all a question of how much it costs to detect one cancer.

The difference of opinion is not about effectiveness.  It’s about how much money is spent on mammograms.

The randomized trials of mammograms for women between age 40 and 49 show a survival benefit with screening mammograms.  However, breast cancer is less common in women under 50 so that more mammograms have to be done to find a fewer cancers.  This means that more money is spent on mammograms to find one cancer in a woman under age 50 than to find one cancer in a woman over age 50.  It’s not a question of benefit, but how much money is spent to get the benefit.

In contrast, routine mammograms have not been tested in women under 40 years old, so most experts do not recommend routine mammograms for women in their 30s.

My personal opinion is to start mammograms at age 40, but remember, a negative mammogram never proves cancer is not there!

 

 

DO WE LIVE IN A “CHEMICAL SOUP”?

A television story last week reported a new analysis that had identified an increase in advanced breast cancer in young women age 25 to 39 [click here for the news story]. 

Why is this happening?  Are doctors missing the signs of cancer when it is small? [see next post] Or are young women doing things that cause them to show up with advanced breast cancer? 

Some persons opine that the increase in breast cancer – not only in young women, but in all women – is the result of choices women have made.  They blame birth control pills, alcohol, delayed childbirth, not breastfeeding when they do have children, hormone replacement in older women, etc.

These “usual suspects” are cited because they influence how hormones have acted on a woman’s body through her life, and breast cancer is influenced by hormones.  For example, most of the increase in younger women is an increase in lobular cancers, and most lobular cancers have estrogen receptors, meaning that they are driven by estrogens.  Likewise, most of the excess of breast cancer in Marin County is of estrogen receptor positive tumors – again the kind that are driven by estrogens.

These observations fit with the idea that breast cancer is increasing because of choices women have made that influence the hormones in their bodies. 

But we shouldn’t jump to conclusions too quickly.  There’s a big catch to that interpretation. 

Men are getting more breast cancer, too!

Breast cancer has gone up in men just like in women, and over 90 percent of male breast cancers have estrogen receptors.  This means not only that most male breast cancers are driven by estrogens, but you can’t assert this is because of decisions that men made that raised their estrogens or changed their reproductive history.   Men don’t take birth control pills, delay having a full term pregnancy, not breastfeed their babies, take hormones at menopause, etc. 

The parallel between men and women gets even more puzzling when you see that the rate of breast cancer in men [click here] has the same proportional increase, and the curve has the same shape, as for women [click here].  [Note that the line graph for men is more irregular, but the overall shape of the curves is the same.  Men have experienced the same increase as women.  Click here for a longer article about the increase in men.]

Some argue that breast cancer has gone up in women because of more detection with mammograms, and that the increase in women is not important because many of these cancers found by mammograms would never have caused any problems.  

However, men don’t get mammograms.  Cancers in men are usually found when the man notices a growing mass that is a real, life-threatenting cancer. So why would we detect more cancers unless there really was more breast cancer? 

And, for both men and women, there is a peak in the incidence on breast cancer just before 2000, a little drop by 2005, and then the number stabilizes at a level about 20 percent higher than in the early 1970s.  Whatever the reason, when the pattern is the same, it seems likely that the causes are related. 

We need to look for a factor that would affect both men and women the same.

The lesson from DDT.

It wasn’t initially obvious that some of the amazing chemicals we’ve allowed into our lives might be harmful.  DDT, for example, kills lice and stopped spread of disease especially during and after World War II.  A recent book published by the NATIONAL GEOGRAPHIC pictures a truck spraying DDT at Jones Beach in New York in 1945.  Kids play in the fog of insecticide, and the sign on the side of the truck reads, “D.D.T.  Powerful Insecticide.  Harmless to Humans.”

Or so everyone thought.

An early warning about DDT came from a Florida swamp where DDT had been spilled.  Researchers began to find fewer and fewer male alligators.  Someone wondered if it might be the DDT and exposed alligator eggs to DDT.  The number of males dropped, but it wasn’t because there were fewer male eggs.  There was the same number of male eggs, but a lot of the male eggs exposed to DDT developed as females.   DDT acted like an estrogen.

Could DDT act like an estrogen in women?

In a serendipitous study, researchers at Kaiser Hospitals in Oakland found some stored blood samples drawn from pregnant women in the 1950s and 1960s.  They analyzed these samples for DDT and compared the levels of DDT to the incidence of breast cancer in the same women over the next 30 years.  If a woman had been exposed to DDT when she was very young – which was literally everyone who grew up in the 1940s and 1950s – and she was in the group with the highest levels of DDT in 1960 – she was five times more likely to develop breast cancer as she grew older.  

Chemicals acting like estrogens isn’t a new idea.

DDT causing breast cancer would not have surprised Rachel Carson, but the chemical industry certainly acts incredulous.  Yet the idea that a chemical that is not estrogen can act like estrogen has been around for a long time.  Eighty years ago, Dr. Edward Charles Dodds, the researcher who led the development of DES (diethylstilbestrol, as in DES babies) wrote an article, “A Synthetic Oestrus-Exciting Compound” [That funny English habit of spelling estrogen with an “o” as in oestrogen].  He’d guessed that a chemical with a structure that looked like natural estrogen on paper might act like an estrogen in real life, and he was right.

Before his laboratory invented DES, Professor Dodds had already demonstrated that bisphenol-A (BPA)  looked a lot like estrogen, and acted like estrogen.  More importantly, Professor Dodds studied more than 20 chemicals that he thought looked enough like estrogen on paper to act like estrogen in his laboratory animals.  And they did, too.

The key feature of many of the chemicals Dodds studied was what chemists call a “ring” structure.  These rings all around us in various commonly used chemicals.  Many of them have the potential to act like estrogens.

So is there a “chemical soup”?  I don’t think anyone can deny that.  The need is to put the effort into figuring out what part of the “soup” is affecting the rate of breast cancer in both men and women. 

But why is there more advanced breast cancer in young women?

The “chemical soup” helps us understand why there is more breast cancer, but the “soup” does not explain why there are more cancers that are advanced.  How do they become advanced?  Why are they missed when they are smaller?  What’s happening with young women? 

Coming next [click here].

 

 

 

 

 

 

 

 

CALCIUM SUPPLEMENTS: LET’S GET THE FACTS RIGHT

Controversial headlines attract readers – which sells more advertising – but it’s wrong to lead with a headline that can cause readers to act against their own interests.  This is what Fox News, US News, and multiple other news sources did with identical headlines on February 13, 2013:  “Calcium Supplements may raise odds of heart death in women.”  Technically, the article (that is the same word for word on multiple websites) states that sometimes a calcium supplement could be harmful, but many women took the headline to mean they should stop taking all calcium supplements because they “… may raise odds of heart death in women.”    

The statement in the headline is true – in very specific circumstances that do not apply to most women – but the headline can also be read to suggest it’s risky to take any calcium supplement whatsoever. 

Yet another study of calcium intake

The press story refers to a Swedish study published February 12, 2013 in the online version of the British Medical Journal.  The abstract is available on line [click here].  The researchers reported cardiovascular mortality in women in relation to their calcium intake.  Calcium intake was estimated based on two surveys:  an initial survey taken between 1987 and 1990 when women were enrolled in the study, and a second survey in 1997. 

For their analysis, researchers classified women into four groups from low to high calcium intake: less than 600 mg per day, 600 to 999 mg per day, 1000 to 1399 per day, and 1400 or more mg per day. 

To put the article in perspective, it is important to know that the Institute of Medicine in the United States recommends 1000 to 1200 mg per day.  And, the same Swedish researchers previously reported that between 750 and 1025 mg calcium per day is enough to prevent osteoporotic fractures, i.e. broken bones because of weak bones [click here].

Very low and very high amounts of calcium are associated with higher mortality.

When they looked at death in relation to calcium intake, women in the very low group (less than 600 mg per day) and in the very high group (1400 or more mg per day) had an increased chance of dying from heart disease.

In contrast, there was no significant difference between the two middle groups, the women who had 600 to 999 mg per day and those who had 1000 to 1399 mg per day.  In fact, there was a consistent hint that the 1000 to 1399 did slightly better overall, but this did not reach statistical significance.

The effect of calcium supplements specifically

These results were the same whether a woman got her calcium through food in her usual diet (typically with a lot of dairy products) or used a calcium supplement or both.

They also looked at women who took calcium tablets (which are usually 500 mg per tablet in Sweden).  Women in the 1000 to 1399 group still had slightly lower risk of death even if part of their calcium was from a calcium supplement or calcium included in a multivitamin. 

Who increased their risk with calcium supplements?

Women who took over 1400 mg of calcium per day and had part of that calcium in the form of a calcium pill, had an increased risk of dying of heart disease. 

Who takes over 1400 mg calcium of calcium per day anyway?

The guidelines for dietary calcium are 1000 to 1200 mg per day.  However, some physicians and some nutritionists recommend much higher intake.  There is no data to support benefit from a higher daily intake of calcium, and as just reported, high amounts of daily calcium intake may be risky.

Confirmation from the AARP

In a quirk of timing, a separate study of 169,170 AARP women members published February 4, 2013 found no relation of total calcium to mortality [click here].  They also looked specifically at calcium supplements separate from total calcium, and, although it was not statistically significant, observed a slight trend toward higher heart death with more than 1000 mg of calcium supplement per day.  [The same study followed 219,059 men and found that over 1000 mg of calcium supplement per day was significantly associated with increased heart attack death, especially in men who smoked tobacco.]

Should I take a calcium supplement?

The key to whether you need a calcium supplement is how much calcium you already get through your usual diet.

As discussed extensively in a previous Perspective on Women’s Health [click here], your personal decision should be based on how much you use dairy products, broccoli and kale, or canned sardines on a regular basis.  (And believe it or not, according to the USDA, General Mills Total Raisin Bran Flakes have a lot of calcium).  You can estimate your daily calcium using the US Department of Agriculture website [click here]. 

If you eat sufficient dairy products daily – which means at least two servings of milk, cheese, yogurt, cottage cheese, or ice cream, etc. each day as part of your regular diet – you may not need a calcium supplement.  If you get less than two servings of dairy per day, it’s difficult to get enough calcium consistently, and your total intake may be less than 600 mg per day. According to this article, such low calcium intake would increase your risk of cardiovascular death, and you would benefit from a calcium supplement.

What should have been the headline?

An accurate headline for Fox News, US News, and the others would have been, “Super high dose calcium supplements appear harmful: usual recommendations for calcium intake are confirmed.”

It would not have drawn as much attention, but it also would not have been misleading.

BPA AND CURCUMIN: EAT MORE CURRY?

We have recently published further studies of the effects of BPA, including the observation that curcumin, the active ingredient in the spice turmeric, can reduce the effects of BPA (bisphenol-A). Both the abstract [click here] and the full article [click here] are on line and can be downloaded free. 

This article underscores the connection between BPA and increased cell growth that we suspected from our first studies over five years ago and suggests that curcumin, or a similar drug, may be useful to reverse the effects of BPA.

Looking at cells before they are cancerous.

There is a lot of research looking at how BPA affects cancer cells, but that doesn’t help us understand the origins of cancer because the cells are already cancer.  To study the origins of cancer you have to start with benign cells.

In our research, we start with cells that are not cancerous and look at what BPA does to these cells.  We have identified two ways that BPA changes non-cancerous cells and makes them behave like cancer cells.

BPA stimulates cell growth.

Non-cancerous breast cells usually grow slowly.   Estrogens stimulate these cells to grow faster, and this is part of the way that estrogens and the synthetic estrogen, DES, contribute to breast cancer.

BPA stimulates growth of non-cancerous breast cells just like estrogens. 

The worry is that, once stimulated by BPA, some cells will continue to grow on their own.

Encountering our worst fear.

In this paper we report the event that we all fear:  some non-cancerous cells continued to grow unusually well even after the BPA was gone.  This is the kind of uncontrolled cell growth that could lead to cancer.

Fortunately, this was a rare event, but remember that not everyone exposed to any cancer-causing agent gets cancer.   For example, radiation exposure is a risk factor for many cancers, but only a small fraction of the people who are exposed to radiation go on to get cancer.  In fact, it would be suspicious if all of our cells continued to grow after BPA was removed.   However, that it happened even one time reinforces the parallel to other dangerous exposures. 

BPA helps cells stay alive.

When the body is functioning normally, damaged cells go away by a process called apoptisis (ay-pah-TOE-sis) or programmed cell death.  Although it is called “cell death” apoptosis is really a special way that damaged or unnecessary cells break up and go away.  All cells are capable of this.  It is a little like a scuttle on a ship.

Apoptosis is important because it is the way that cells damaged by radiation, chemotherapy, or hormone therapy go away.  If apoptosis does not work, cells can continue to grow abnormally and not die.  This happens in cancer, and in fact, evasion of apoptosis is a prerequisite for a cell to become malignant. 

BPA causes cells to evade apoptosis

When we exposed cells to tamoxifen, they should have undergone apoptosis, but they did not.  This means that BPA gives cells the ability to grow when they should be stopped by anti-cancer or cancer preventing drugs.   This brings these non-cancerous cells potentially closer to being malignant, especially if the effects persist after the BPA is gone, as we found for growth of some cells. 

The Curcumin Connection

Curcumin is the chemical in the spice, turmeric, that makes curry yellow.  It is a traditional remedy in many cultures, and it has thousands of years of use to suggest that it is safe.

For the last 20 years, researchers have wondered if curcumin might have direct anti-cancer effects.   Relevant to our research, these researchers found that curcumin directly affects the same genes that are controlled by mTOR, but it has the opposite effects from BPA.  Curcumin makes cells less likely to grow and more likely to undergo apoptosis. 

This research suggested that, even if BPA activated mTOR, curcumin might reverse the effects because it directly blocks the same genes that mTOR activates – in essence, it looked like curcumin might “do an end run” and reverse the effects of BPA.

We found just that.  Curcumin reversed the effects of BPA that made cells grow abnormally and survive if they were damaged.  Most important, the cells that kept growing after the BPA was removed, were also stopped by curcumin.

There are two important conclusions from this study. 

Convince the skeptics.

Scientists influence official beliefs about environmental chemicals.  However, scientists tend to be skeptical.  They want to know, “How does BPA work?”   We can now answer their question.  We can show that BPA modifies activity of known genes, and then we add that a known blocker of those genes, i.e. curcumin, reverses the effects of BPA.  This is the kind of add-then-subtract double proof that scientists demand.  

The situation is not hopeless.

It may not be possible to eat enough curry to reverse the effects of BPA, but it is important to know that the effects are not irreversible.  [Supplements of curcumin are on the market, but there is no data yet on how much curcumin you would need to take to protect yourself from BPA.]

Demonstrating reversal of the effects of BPA provides a tangible goal as we try to prevent breast cancer and other effects of endocrine disruption in humans.   We need to know it is possible to help.

Should we eat more curry?

Yes, eat more curry if you like it.  Know that it might help, but we don’t know yet how much it might take to be beneficial.  Researchers are working on that.

A complete pathway.

This study completes a picture of how abnormal activation of a series of genes in a whole pathway can cause cells to grow abnormally.  For more discussion of cell pathways, see Perspectives on Womens’ Health from August 21, 2012.  [click here]

For those who want to read more, the effects of BPA on major genes include:

Increased PI3K, AKT, mTOR, and cyclins and decreased PTEN and p53.