Breast Cancer Screening for Childhood Cancer Survivors

Early MRI screening may cut breast cancer deaths in half

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Screening for breast cancer in childhood cancer survivors is important as the risk can be significant. In fact, some survivors of childhood cancers have a risk of developing breast cancer as high as women who carry BRCA mutations. Fortunately, it's been determined that yearly screening beginning at age 25 with both breast MRI and mammography can cut breast cancer deaths by 50%.

Not everyone who survives childhood cancer has the same risk. Having received chest radiation, certain chemotherapy drugs, having a gene mutation associated with breast cancer, or family history of breast cancer are all associated with a greater risk (but the risk remains high even in survivors who do not have these risk factors).

The issue of breast cancer screening after childhood cancer will only become more important. There are currently over 400,000 childhood cancer survivors in the United States, and that number is growing due to better treatments and survival rates. At the same time, while fewer people receive radiation than in the past and delivery has improved, the risk of secondary cancers has not declined. Breast cancer still takes far too many women each year, and those who develop the disease after childhood cancer have lower survival rates.

We will look at the incidence of breast cancer in survivors, at what age you should be concerned, the types of screening methods recommended, and what the latest research is showing.

Breast Cancer in Childhood Cancer Survivors

It's not uncommon for people to have to face a second primary cancer (a separate and unrelated cancer), as roughly 20% of people diagnosed with cancer today have already survived another cancer. Yet the incidence is higher in childhood cancer survivors.

While there are increased risks of several types of cancer, the risk of breast cancer can be particularly high. A 2014 study compared the cumulative risk of breast cancer in childhood cancer to those who carry BRCA mutations. The cumulative risk of breast cancer in women who had a BRCA1 or BRCA2 gene mutation was 31%, while that of women who had Hodgkin lymphoma as a child (but did not carry a BRCA mutation) was 35%. Data at age 50 was not available for survivors of other childhood cancers, but women with these other cancers had a cumulative breast cancer risk of 15% by age 45.

Women who received radiation for childhood cancer have a risk of breast cancer similar to that of women who carry a BRCA mutation.

Other studies have noted this risk as well (see below).

Breast cancer tends to occur at a significantly younger age in survivors of childhood cancer than in women who have not, and women who develop one breast cancer after childhood cancer have a high risk of developing another.

Incidence in Survivors Who Did Not Receive Radiation

Even without radiation, the risk of breast cancer in childhood survivors is high. A 2016 study of over 3500 women who had survived childhood cancer but did not receive radiation therapy made this clear. In this study, the childhood survivors were 4.0 times more likely to develop breast cancer than the general population. The median age of diagnosis was age 38 (range from 22 to 47), with a median gap of 24 years (10 years to 34 years) between the original childhood cancer and the diagnosis of breast cancer. The risk was highest for survivors of sarcoma (5.3 times) and leukemia (4.1 times average risk).

The magnitude of a four-fold elevated risk is more easily understood when looking at the overall incidence of breast cancer. It's thought that 1 in 8 women, or roughly 12%, will develop breast cancer during their lifetime. Multiplying this number by 4 results in almost 50-50 odds that these women will face breast cancer in their lifetime.

Incidence in Survivors Who Received Radiation

In childhood cancer survivors who received chest radiation (10 Gy or more), roughly 30% developed breast cancer by the age of 50. (The incidence was somewhat higher among those who had Hodgkin lymphoma at 35%.) To put this in perspective, among the general population women have roughly a 4% risk of developing breast cancer by age 50. This was seen with lower doses of radiation delivered to a large area (for example, an entire lung), or high doses of radiation to the mantle field. The risk of death related specifically to breast cancer was 12% at five years and 19% at 10 years.

When Does Breast Cancer Occur in Survivors?

As noted, breast cancer often occurs at an earlier age in childhood cancer survivors, with the increased risk becoming appreciable at 10 years out of diagnosis.

Changes in Incidence With Changes in Treatment

Since less radiation is usually used for people with Hodgkin lymphoma than in the past (and when radiation is used, it is often more focused and of lower dose), it was thought that secondary cancers such as breast cancer would decrease. This doesn't appear to be the case, however, and the incidence of secondary cancers in Hodgkin lymphoma survivors actually seems to be increasing.

Impact

Not only is a diagnosis of breast cancer after surviving childhood cancer disheartening (some people claim that it's tougher the second time around, but this is debated), but it's discouraging from a survival standpiont as well. Women who were diagnosed with a childhood cancer and later developed breast cancer as an adult were more likely to die than women diagnosed with breast cancer who did not have childhood cancer.

According to a 2019 study, the risk of death after breast cancer was higher (twice as high) in women who were childhood cancer survivors than in those who did not experience childhood cancer. The risk of dying from breast cancer was somewhat higher, but the risk of other causes of death, such as other cancers, heart disease, and lung disease was significantly higher.

Women who were diagnosed with a childhood cancer and later developed breast cancer as an adult were more likely to die than women diagnosed with breast cancer who did not have childhood cancer.

Risk Factors

Certainly, women who have survived childhood cancer may have the same risk factors for breast cancer as those who have not faced childhood cancer, but having and being treated for cancer poses additional risk factors. While both chemotherapy and radiation therapy can sometimes cure childhood cancers, they are in themselves carcinogens (agents that can cause cancer). A genetic predisposition that increases the risk of one cancer may also raise the risk of other cancers.

Chemotherapy

Chemotherapy drugs work by causing cell damage, but can also cause the mutations (and other genetic alterations) that increase the chance of developing cancer. That said, not all chemotherapy drugs are of equal concern. In particular, it appears that two categories of chemotherapy drugs pose the most risk:

Alkylating agents:

  • Cytoxan or Neosar (cyclophosphamide)
  • Leukeran (chlorambucil)
  • Myleran or Busulfex (busulfan)
  • Mustargen (mechlorethamine)
  • Alkeran or Avomela (melphalan)
  • BiCNU or Gliadel (carmustine)
  • CeeNU, CCNSB, or Gleostine (lomustine)

Anthracyclines:

  • Adriamycin (doxorubicin)
  • Cerbidine (daunorubicin)

The risk is greater when the drugs are given in high doses, when they are given in a "dose dense" manner (infusions are closer together), or the drugs are used for a longer period of time.

Radiation Therapy

People who receive chest radiation for childhood cancer have the greatest risk of developing a secondary breast cancer. Those who received 20 Gy or more of radiation to the chest had 7.6 times the risk of later breast cancer than those who did not receive any radiation.

Not everyone who receives radiation has the same risk, however, and in the future genomic testing may help predict who is at the greatest risk.

Genetics

Women who have a gene mutation that increases the risk of breast cancer and also experience childhood cancer have the highest risk of developing a secondary breast cancer. In the St. Jude study, women who had survived childhood cancer and also had a breast cancer predisposition gene mutation were at very high risk (23 times higher).

In some cases, a genomic alteration (such as a hereditary gene mutation) may predispose a person to both childhood cancer and breast cancer. This appears to be the case with BRCA2 mutations, that not only raise the risk of breast cancer, but may predispose children to developing non-Hodgkin lymphoma as well.

Earlier data had found that BRCA2 was the third most commonly mutated gene among a group of childhood cancer survivors.

Less is known about several of the non-BRCA mutations that raise breast cancer risk, but it's likely that more will be known about any association with childhood cancers in the future. With the associations that have been noted thus far, however, some argue that all childhood survivors should be referred for genetic counseling.

Most of the time, however, the connection is less well understood, but genetics is still important. In some cases, risk could be related to an underlying gene-environment interaction. At others, variations in a number of genes that are fairly common in the general population may play a role.

Genome-Wide Association Studies

In contrast to testing for single gene mutations, genome-wide association studies (GWAS) look for variations in loci on chromosomes that may be associated with a disease. A 2014 study genome-wide association study done with survivors of Hodgkin lymphoma who received radiation therapy identified a loci (an area) on chromosome 6 that was associated with an increased risk of secondary cancers.

A 2017 GWAS study detected additional loci that may be associated with breast cancer risk after radiation.

Further genome-wide association studies as well as next-generation sequencing are in progress and promise to expand our understanding such that we will likely have much clearer answers in the future.

Breast Cancer Screening in Childhood Cancer Survivors

Due to the increased risk of secondary breast cancer, it's recommended that childhood cancer survivors undergo earlier and more intense screening. Guidelines have been developed, but as with all aspects of cancer care, these do not take into account the multitude of differences among women, and should be interpreted along with an evaluation of an individual's risk factors, either positive or negative for developing the disease.

Screening vs. Diagnostic Studies

It's important to note that screening recommendations are designed for people who are asymptomatic (have no symptoms). If signs or symptoms are present, evaluation isn't considered screening, but rather diagnostic. Screening recommendations may not be sufficient to rule out breast cancer in people who don't have any symptoms.

Breast Cancer Gene Mutations or a Family History of Breast Cancer

Both women who have a gene mutation associated with breast cancer and those who have a family history of the disease may require testing above and beyond that recommended for childhood cancer survivors without a genetic predisposition.

It's important to note that testing for BRCA (and other mutations) cannot detect all genetic risk, and BRCA mutations are associated with at most 29% of familial breast cancers. Working with a genetic counselor can be extremely helpful in understanding potential risk for those who have a positive family history but test negative.

Screening for Survivors at Average Risk

Current screening recommendations (Children's Oncology Group Survivorship Guidelines) for childhood cancer survivors (female) who do not have a breast cancer gene mutation or family history include:

  • Monthly self breast exams
  • Clinical breast exams (exams done by a physician) yearly until the age of 25, and then every six months
  • Yearly mammogram and MRI beginning at age 25 or eight years after radiation, whichever comes last

MRI vs. Mammography

Breast MRI is more accurate than mammography in detecting breast cancer early, and is why MRI studies rather than mammography are recommended for people with BRCA mutations. (MRI is much more costly and does not appear to be cost effective for people who have not had cancer and who are at average risk.)

At an abstract presented at the 2019 annual meeting of the American Society of Clinical Oncology, it was shown that annual MRI and mammography could avert 56% to 71% of breast cancer deaths. Between 56% and 62% of deaths could be averted with annual MRI alone (without mammography), and 23% to 25% of deaths could be averted by mammography alone every other year. Annual MRI and mammography beginning at age 25 was also found to be cost effective.

In addition to saving lives, breast cancer detected by screening are smaller, meaning they are less likely to have spread to lymph nodes and may be less likely to require chemotherapy.

Compared to no screening, yearly MRI and mammography can avert over 50% of breast cancer deaths, and is cost effective as well.

While guidelines currently recommend screening begin at age 25, and, there's some evidence that delaying screening until age 30 may be appropriate for some people, and further research weighing the survival benefit vs. the risk of false positives (and the accompanying anxiety and invasive testing) is needed.

It bears emphasizing again that guidelines are only suggestions and do not take into account many different nuances among different people. You and your doctor may choose to screen at an earlier age or more frequently (or possibly at a later age or less frequently in some cases).

Barriers to Screening

Despite the ability of screening to save lives, far too few childhood cancer survivors receive regular screening. A 2019 study looked at the ability of mailed materials followed by telephone counseling to improve rates of screening. It was found that the intervention increased the rate of screening mammography, but not MRI screening. Barriers to screening found in the study need to be addressed.

In women aged 25 to 39, reported barriers to screening included:

  • "Putting it off" (36%)
  • "Too expensive" (34.3%)
  • "Doctor didn't order it" (29.4%)

Among women aged 40 to 50, barriers included:

  • "Too busy" (50%)
  • "Haven't had any problems" (46.7%)
  • "Put it off" (43.8%)
  • "Doctor didn't order it" (37.5%)
  • "Too expensive" (37.5%)

Clearly, efforts to educate both survivors and physicians are needed, as well as options to reduce the cost of regular follow-up.

Reducing Your Risk

In addition to following screening guidelines, there are several things childhood cancer survivors can do to lower their risk of developing breast cancer:

  • Engage in regular exercise (at least 30 minutes daily)
  • Lose weight if you are overweight
  • Minimize alcohol intake (no more than one drink daily, and preferably less)
  • Don't smoke
  • Discuss the risk of birth control pills or hormone replacement therapy with your doctor before using these medications
  • Eat a healthy diet (at least five servings of vegetables and fruits daily)
  • If you have a child or children, try to breastfeed (the Children's Oncology Group recommends breastfeeding for at least four months)

In addition, be your own advocate and stay updated on screening recommendations as they may change. As noted, a significant percentage of people did not undergo screening because it was not recommended by their physician. Medicine is changing so rapidly that it is difficult for physicians to stay abreast of all the changes. If cost is an issue with screening, talk to an oncology social worker about free or low-cost options.

Prevention?

Noting that childhood cancer survivors who had radiation have a risk profile similar to that of people with BRCA mutations, you may be interested in preventive options. There are currently no guidelines (as to preventive surgery, the cost of prophylactic tamoxifen, etc.), but you may wish to discuss options with your oncologist.

For those who develop breast cancer after childhood cancer, it's important to have a thorough discussion with your doctor as well. Hereditary breast cancer is one situation in which the benefits of a double mastectomy likely outweigh the risks, though there is no data on benefits and risks for people who have had childhood cancer and radiation.

A Word From Verywell

Women who have survived childhood cancer have a significantly increased risk of developing breast cancer, especially if they received radiation to the chest or a few particular chemotherapy drugs. Fortunately, regular screening beginning at an early age can avert many breast cancer deaths. Just as precision medicine has led to advances in the treatment of many cancers, a better understanding of genetic risk factors will likely help physicians further define who is at the greatest risk of breast cancer in the future.

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Article Sources

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