Jill – A 35 year old lady referred for evaluation of left sided breast cancer. She noted a mass in her breast while in the shower. She denied any pain, skin changes, or nipple discharge. She saw her family doctor who ordered a mammogram, revealing a spiculated mass in the upper outer quadrant of the left breast. The solid nature of the mass was confirmed by ultrasound.
A biopsy of the mass was performed using ultrasound guidance and test results revealed invasive duct cell carcinoma – the most common type of breast cancer.
Jill’s past medical history is notable for mild high blood pressure for which she takes the blood pressure medicine, amlodipin (Norvasc). She does not smoke and only drinks occasionally – usually 1 glass of wine every week.
Her family history is significant, having a maternal aunt with breast cancer and a maternal grandmother with ovarian cancer. Because of her age, family and history, it was elected to send a blood test for the BRCA 1 and BRCA 2 mutation to see if there is a genetic component to her breast cancer.
She was found to have a deleterious mutation in the BRCA 1 gene which means she has a mutation in BRCA 1 which is inherited from her mother. Because of the BRCA 1 mutation, Jill elected to have bilateral mastectomies performed by a breast surgeon. She also had reconstruction by a plastic surgeon performed at the time of the surgery.
The pathology report from the right breast revealed no abnormalities. However, the pathology report from the left breast revealed a grade 3 (high grade) invasive duct cell cancer measuring 2.2 cm. Although the anterior margin was close, revealing only a 1 mm distance, all other surgical margins were free of cancer. A total of 11 lymph nodes were examined and none contained evidence of cancer.
Immunohistochemical studies revealed the cancer to be ER (estrogen receptor) PR (progesterone receptor) and Her2 negative (triple negative). The ki-67 or proliferative index (growth rate) was high at 80%. There was evidence of extensive lymphovascular invasion. CAT scans and bone scans revealed no evidence of the cancer spreading. She was staged as T2N0M0 – Stage 2.
Jill was seen by an oncologist who recommended chemotherapy because of the triple negative features of her breast cancer, the size and her young age. Chemotherapy was given for risk reduction – to lower the risk of the breast cancer returning to some other distant part of her body such as the lungs, liver, or bone.
Jill received 4 cycles of chemotherapy with doxorubicin and cytoxan (A.C.) given intravenously once every 2 weeks with Neulasta support to minimize the duration of low white cells. Once the A.C. was complete, she then received paclitaxel (Taxol) once intravenously each week for 12 weeks. Although Jill had bouts of expected fatigue and some mild neuropathy involving her feet due to the Taxol treatment, she tolerated chemotherapy well.
Following chemotherapy, Jill received an opinion from a radiation oncologist who recommended radiation to the chest wall even though she already had a mastectomy. This is because of the close margins, triple negative features and extensive lymphovascular invasion. She tolerated this well.
Jill recovered from her treatments. She did not receive the pill Tamoxifen as she is ER/PR negative. Jill was due to have some further breast reconstruction surgery and knowing that the BRCA 1 mutation increases the risk of ovarian cancer, she elected to undergo a bilateral oophorectomy― removal of the ovaries. There was no cancer in the ovaries.
Today Jill is seen regularly in follow-up without any evidence to suggest recurrent cancer. This case illustrated several interesting issues which I feel, deserves further clarification.
By: Dr. Chris Charlton
Jill was diagnosed with what we refer to as a triple negative breast cancer. A triple negative breast cancer accounts for up to 20% of breast cancers. Breast cancers are not all the same and not treated the same. In a triple negative breast cancer (TNBC) the cancer cell does not have the estrogen receptor, progesterone receptor or the her2 protein on its cell surface.
This means the cancer is not fed by the female hormones and anti-hormonal pills such as Tamoxifen or aromatase inhibitors – anatrazole (Arimidex), letrozole (Femara) or exemestane (Aromasin) will not be helpful. You may think, “Wow! That is great that the cancer is not fed by hormones.”
Unfortunately, this is not the case as we want with the ER/PR receptors. Cancers with these receptors are much less aggressive. Plus, we have another treatment option in the form of the anti-hormonal pills.
In TNBC the only way we can do this is with chemotherapy whereas ER/PR positive breast cancer allows us to use anti-hormonal pills.
Breast cancer itself is rarely fatal. It is when it spreads to other parts of the body such as lung, liver, etc. that it becomes a killer. When a patient comes to me with a TNBC, they have my attention and, assuming the person has good health, it is important to be aggressive upfront with this kind of cancer to prevent return.
By: Dr. Chris Charlton
Researchers over the past few years have found more information about TNBC. They have been able to categorize them based on molecular subtypes. Some cancers are luminal, mainly the ER/PR positive breast cancer, but most
TNBCs are referred to as basal type. I bring this up as some researchers and physicians will use TNBC and basal type interchangeably. When we look at treatment options for TNBC we know that these cancers are more aggressive and we have no options with regards to anti-hormonal pills unlike ER/PR positive breast cancers. As a result, most patients whose tumor size is greater than 5mm and/or lymph node involvement will be offered chemotherapy to lower the risk of cancer return.
Remember, breast cancer is a systemic disease which can affect the whole body, so in addition to surgery for the breast we also have to protect the entire body by eradicating potential microscopic tumor cells that may have escaped the breast.
By: Dr. Chris Charlton
In our case above, Jill did receive chemotherapy for her TNBC. Many chemotherapy treatments in the adjuvant (meaning chemotherapy after breast surgery) setting are designed for one treatment every 3 weeks. However, in Jill’s case, the first four treatments were given once every 2 weeks.
This is called dose dense chemotherapy and is the second concept I would like to review. Dose dense chemotherapy has become more popular over the past few years. It was introduced in an attempt to improve existing treatments for more aggressive cancers.
Dose dense chemotherapy is basically giving the same dose of chemotherapy closer together in an attempt to minimize cancer cell re-growth in between chemotherapy cycles. It is based on the work performed by Dr. Larry Norton at Memorial Sloan Kettering Cancer Center in New York. Some resistant cells may live through chemotherapy but by giving them another slug of chemotherapy sooner (2 versus 3 weeks) before they have fully recovered should improve cell kill. Think of this as kicking the cancer cell while it is still down. Remember, in cancer – don’t fight fair!
Giving the chemotherapy in a dose dense fashion does not allow that extra week of recovery for the patient so it may be a little tougher. It also requires the use of white cell growth factor shots to allow recovery of the white blood cells which help prevent infection. Further research has determined that the dose dense approach yield better benefits for patients with ER/PR negative breast cancer (due to the fact that they are faster growing cancer cells) but not ER/PR positive breast cancers. I rarely use this approach in ER/PR positive breast cancers.
By: Dr. Chris Charlton
The final point I would like to make about this case is Jill testing positive for the BRCA 1 mutation. BRCA 1 and BRCA 2 is Breast Cancer gene 1 and 2, respectively.
They are classified as tumor suppressor genes and are passed to a person by their parents. Everyone has these genes but it is only when there is a mutation that there becomes a problem.
About 7-10% of breast cancers are caused by a mutation in one of these genes. There is nothing you can do to prevent or get rid of a mutation as it is inherited.
A mutation in one of these genes is likely to substantially increase your risk of developing breast or ovarian cancer. However, if you do develop a cancer as a result of one of these mutations it does not mean that the cancer would be more aggressive or treated any differently.
BRCA 1 and 2 mutations will increase the likelihood of breast cancer – from that standard 12% to about 60-70%. The risk of ovarian cancer with these mutations increases from 1-2% in the standard population, to 20-40%. Other cancers may also be increased in mutated patients and include, pancreatic, stomach, gallbladder/bile duct, melanoma uterine, cervical, prostate (men) and testicular (men) cancer.
Patients diagnosed with breast cancer who should be tested for these mutations include the following:
· Women of Ashkenazi Jewish ancestry (usually eastern Europe).
· Breast cancer diagnosed under the age of 50
· Breast cancer diagnosed in both breasts.
· Ovarian cancer at any age
· All male breast cancers
· Triple negative breast cancer under the age of 60.
· Multiple family members with breast or ovarian cancers
In this case, Jill having tested positive for BRCA 1 mutation and elected to have both breasts and ovaries removed. This will significantly minimize the risk but not completely eliminate the risk of future breast or ovarian cancer as not every cell can be removed. Some patients may elect no extra surgery but consider increased surveillance with more frequent mammograms and MRI of the breast. For ovarian cancers trans-vaginal ultrasounds and CA125 tests may be useful in monitoring. SERM (Selective Estrogen Receptor Modulator) drugs such as Tamoxifen and Evista can decrease the risk of breast cancer.
I ask every person considering BRCA testing to have this performed by a genetic counselor. There is so much more to this than just checking a lab. The implications of a negative, positive, and unknown significance result must be discussed with the patient.
Frankly, most oncologists will not be able to explain these in as much detail as an experienced genetic counselor. An unknown significance test is not common but can occur when a mutation in the BRCA gene is found but it is not one of the typical ones known to increase the risk of breast or other cancers.
Many of the unknown tests will not cause an increased risk, but no one really knows. The unknown significance tests are kept in a data bank and if more information becomes available the patient or healthcare provider will be notified.
The BRCA test is a blood test, and quite expensive. Most insurance companies will cover the cost and it is illegal to use these results in determining insurance rates or eligibility. They cannot be used as a pre-existing condition either. There are no documented cases of health care insurance discrimination nationwide.
By: Dr. Chris Charlton