Treatment

What is tri-modal treatment and why is it important in inflammatory breast cancer?

Tri-modality treatment in inflammatory breast cancer (IBC) means that treatment consists of 3 modalities – chemotherapy, surgery and radiation.  Chemotherapy is important because it targets both the tumor cells in the breast and skin, as well as tumor cells that have escaped. Chemotherapy is necessary to make the breast suitable for surgery – i.e. reduce the skin involvement so that the surgeon does not need to cut directly into diseased skin. Surgery is important to remove the bulk of the breast tissue and skin which usually contain some disease.  Knowing how much disease (if any) is left over is a prognostic factor. Radiation is the last piece of treatment, and is an important mop-up strategy for scattered left-over tumor nests.  Chemotherapy is an example of a systemic therapy, while surgery and radiation are local therapies. Both of these types of therapies have their roles in IBC care.

Why is chemotherapy given first in IBC treatment?

Inflammatory breast cancer (IBC) is an example of a locally advanced, non-operable breast cancer. This means that cutting into the breast to perform a mastectomy is not advisable due to the presence of widespread tumor emboli.  The purpose of chemotherapy is to shrink these tumor nests as much as possible. Also IBC is known to spread early in the course of disease systemically. Chemotherapy also targets these tumor cells that have migrated away from the primary tumor; these may be micrometastatic (not visible on standard imaging).  This is another reason for prompt initiation of chemotherapy rather than upfront surgery.

What are targeted therapies?

Unlike cytotoxic chemotherapy which kills all dividing cells indiscriminately, targeted therapies are drugs that are specifically designed to inhibit the function of a target protein. Ideally the target is more specific for cancer cells than normal cells, or at least expressed at a much higher level. Some examples of such drugs used in IBC include HER2 targeting antibodies or small molecule inhibitors (Herceptin, Perjeta, Lapatinib/Tykerb, Neratinib etc) or Everolimus (Afinitor) that targets mTOR. Hundreds of targeted drugs are in clinical trials for cancer.

What is a port and why would I want one?

A port is a small disc made of plastic or metal about the size of a €1 coin that sits just under the skin. A soft thin tube called a catheter connects the port to a large vein. Chemotherapy and other liquids are given through a special needle that fits into the port. You also can have blood drawn through the port possibly saving some wear and tear on veins in your arms as you get treatment.  One good tip to know of you are person of petite size, ports do come in more that one size, so discuss this with your surgeon.

Can I do chemo without a port?

Yes it is possible to have your chemotherapy given to you via a peripheral IV. While this might help you begin chemo more promptly, over time, your veins may become damaged and more difficult to find. In addition, some of your chemotherapy drugs can cause tissue damage if the needle accidentally leaks the drug into your skin. A port prevents these from being a problem, and also makes it easier to do routine blood draws.

If I have a complete response to chemotherapy by imaging, do I need to have a mastectomy?

Yes surgery is recommended for all stage III IBC patients who have at least a partial response to chemotherapy. If you have a very good response to chemotherapy, this is excellent news for your long term prognosis. The limitation with relying upon imaging for decision-making is that current imaging modalities are not perfect. Even PET scans which may be the most sensitive type of scan, still require a few millimeters of tumor to detect anything. In addition, due to the scattered/webby nature of IBC, it is impossible to know that all of the tumor is dead without removing the breast surgically and examining it under the microscope for the presence of live tumor cells. If disease is left in the breast, it will just begin growing again once chemo has been stopped, and then potentially seed distant metastasis which will eventually kill you. Ultimately it is much safer to remove the breast which is an obvious source of potential metastases, and then follow through with the post-mastectomy radiation that is part of the consensus IBC treatment protocol.

Why can I not have a sentinel node biopsy at surgery like other breast cancer patients?

Sentinel lymph node biopsy (SLNB) is a newer less invasive way surgeons have developed to stage the regional lymph nodes in different cancers including breast cancer based on the principle that if a breast tumor is injected with a blue radioactive dye, the dye would naturally drain to the first set of lymph nodes that would be the most likely sites for metastatic spread. The concept is that if the blue dye containing nodes (which are evaluated during the surgery by the pathologist) don’t contain tumor cells, the likelihood is that the other nodes are also negative. Based on large studies showing their accuracy and safety in early breast cancer, SLNBs have been accepted as the standard of care to evaluate axillary lymph node status in patients with early breast cancer, as a way to reduce the morbidity from full axillary dissections in patients with limited/no lymph node involvement. However SLNB is not recommended for patients with IBC because of lymphatic blockage by tumor cells and the unreliability of the SLNB procedure after neoadjuvant therapy in the IBC setting. In one study, eight patients with IBC underwent SLNB after neoadjuvant chemotherapy. The rate of identification of SLNs was 70% and the false-negative rate was 40% [67]. This unacceptably high false-negative rate demonstrates the unreliability of SLNB in IBC. In addition, because of the lymphatic issues, sentinel node biopsies frequently fail in IBC patients due to non drainage of the blue dye, making a full axillary dissection necessary anyway.

Do they have to remove all my lymph nodes?

Axillary lymph node dissections are standard of care in all lymph node positive breast cancer patients, including IBC. Since the sentinel lymph node biopsy method is suboptimal in IBC, even if you are in the minority of clinically lymph node negative patients at diagnosis, the entire axilla must be examined for complete staging information. The purpose of determining how many lymph nodes are still pathologically positive for tumor cells is primarily to provide prognostic information, but also helps by removing sources of future metastases/local recurrences. So yes, all of your axillary lymph nodes that reside in what are referred to as level 1 and level 2 must be removed. Level 1 and 2 means all the nodes that lie below/in front of the pectoralis minor muscle. Level 3 nodes which are above the pectoralis minor muscle used to be removed, but they are no longer included because this increases the lymphedema risk considerably without providing any additional prognostic value.

How soon after chemotherapy should I have surgery?

The waiting period between chemotherapy and surgery is about 4 weeks.  This allows time for your immune system to recover from the chemotherapy.  If your surgeon is rushing you to surgery much before this time, with the concern that the IBC may begin to spread again, consider carefully whether this is the optimal plan. If your response to chemotherapy is poor and the surgeon must cut through actively diseased skin, the likelihood for a long-term disease-free life is very small. A second opinion with an IBC specialist center may help guide the decision of whether to go ahead with surgery or receive more, potentially different systemic chemotherapy or radiation.

What is the difference between Herceptin and Perjeta? Why are both needed?

Herceptin is an antibody against HER2. Perjeta is an antibody that blocks HER2 from binding to one of its co-partners in crime, HER3.  Together these 2 antibodies inhibit HER2 signaling better than Herceptin alone, and blocks HER3 from being active. HER3 activity can be a resistance mechanism to Herceptin.

What should I take to my mastectomy? How long will I be in the hospital?

A mastectomy without immediate reconstruction (i.e. the recommended surgery for IBC patients) is usually a short day/overnight surgery – 2-4 hours from start to being returned to recovery/observation room. If all goes well, patients usually get to go home the next day. So a long list of items to bring is unnecessary. One important thing to note is that both pajamas and a casual shirt with buttons or a zip on the front should be brought, since raising arms will not be possible shortly after axillary surgery.  A small pillow or two may be helpful for the journey home.

How long do my drains need to stay in?

This varies from patient to patient.  Surgeons will often say 7-10 days but 2 to 3 weeks is not uncommon. The timing for drain removal is based on the output of fluid but also with caution to not leave them them in so long to allow an infection to set in.  Maintain your fluid log as instructed by your surgeon to insure the drains are removed at an appropriate time based on your body. Importantly, the next step in IBC treatment which is usually radiation cannot begin until the drains can be removed.

How do I interpret my pathology report?

You will receive at least 2 different pathology reports during your cancer experience – one at diagnosis which will describe the biopsies and a full final report after surgery on the removed breast(s) and lymph nodes. Breast cancer pathology reports are one of the more complex pathology reports and can seem quite overwhelming at first glance. Ask your doctor or nurse to explain any terms you are unfamiliar with, and what that means for your treatment or prognosis.  Both types of reports will tell you what histological type of breast cancer you have. Breast cancers are almost all epithelial cancers that arise from glandular tissue. Breasts have lobules, which make the milk and ducts which carry the milk to the nipples. Depending on which type of cells the cancer most resembles, you get a designation of “ductal carcinoma” or “lobular carcinoma” or mixed. There are also a few very rare subtypes that IBC can resemble.  About 85% of IBCs are ductal carcinomas.  The subtype does not affect your treatment, but knowing your subtype gives some additional information about potential biological differences. Lobular carcinomas have some unusual metastatic spreading patterns, such as to the GI organs and gynecological system, but overall the rate of metastasis is not different between ductal and lobular cancers matched stage for stage.

When you are diagnosed, you will be most interested in knowing the aggressiveness of the disease and your ER, PR and HER2 status. Aggressiveness is semi-quantified by a grade, usually 2 or 3 (with 3 being high grade) as well as comments on the punch biopsy sample mentioning tumor cells that have invaded local lymphatic vessels or blood vessels (known as “lymphovascular invasion”). If you see the word “pleomorphic” that means different – ie pleomorphic nuclei means that the tumor cells have nuclei that look different. This is a feature of a high grade cancer.  In the US, ER and PR are usually reported on 1-100 scale representing the percentage of positive cells for these proteins. Any positive number is taken as a sign that your cancer may be driven by the hormones estrogen and progesterone, and therefore endocrine therapies may benefit you.  HER2 testing may be done via 1 of 2 methods. If the test was immunohistochemistry (IHC) then the results are reported as 0, 1+, 2+ or 3+. If you are 3+, then you will be classified as “HER2 positive”. The 2+ status is a grey area, and the guidelines state that the other test should be used to confirm whether HER2 gene copy number is increased.

The mastectomy pathology report is more complex. There will be a lot more details about what was found in each piece of the tumor – since it must be chopped up into small pieces to be processed and made into slides. Not only will you have breast tissue among these specimens, you will have lymph nodes and surrounding tissue. The summary should include the same factors as the diagnosis report as well as the number of positive lymph nodes out of the total number that were removed. If a lymph node metastasis has burst out of the lymph node, then this is called extra-capsular extension, and should be noted. This is a sign of additional aggressiveness and lack of response to chemotherapy. Another thing to note about the breast is that when it is removed from your body, it is marked by different colors of ink representing the orientation. The ink serves as a way for the surgeon to know where to look if the pathologist says that the edge is not free from cancer. The edge is called a margin. If there is cancer in the inked area, then the margin is “positive” and this is not good! The surgeon will be asked to cut more out if this is the case. Your report should state that the final margin is free of cancer. If the margin cannot be made “clean” – this is an important fact for you to glean from your report, since this should influence your radiation and your potential recurrence risk.

The one section of the report that you may be less interested in is what the tissue looked like by the naked eye. This is called the gross description. Microscopic cancer cells can’t be seen by eye unfortunately.

My ER/HER2 status changed after surgery? Why? Is it real? What does this mean for my treatment?

A change in marker status between your biopsy and final pathology after surgery is not uncommon. You may wonder why, and in most cases we do not know for definite. However what we do know is that a biopsy is only a small sample that may only contain a few thousand tumor cells. This is particularly true in IBC because there may not be a solid mass to sample, and the tumor cells may be in small nests throughout the skin.  Another very important thing to know is that not all tumor cells are alike, and so one area may be HER2 positive while the rest is HER2 negative.  If you sampled each area, you could get a different answer.  Therefore at final pathology a larger area of tumor will be examined, and therefore could pick up differences like this.  The scientific terminology for this is “intratumor heterogeneity”.  Another difference may be the relative resistance or sensitivity of different clones to therapy – the surgical sample will only tell us about the cells that survived chemotherapy and targeted therapies (if relevant). We know in general that some ER+ cells are more chemo-resistant (and hormone-sensitive), and so a greater portion of these may be leftover than at the beginning.  So in summary yes, the differences are indeed real.  As for the meaning of these changes, usually if you gain a marker, then you will receive extra drugs that target these proteins (ie endocrine therapy or Herceptin). This is because the potential harms from not treating exceed the tiny risk of unnecessary treatment. In the case of becoming TNBC, the situation is a little more complex. Most oncologists would continue the treatments that have begun or were recommended based on biopsy, in case the already disseminated micro-metastatic cells still have these markers.  However, there is no randomized high quality data that this is the best approach that improves survival.  As with many decisions, your oncologist should personalize the approach based on your circumstances.

Should I get an Oncotype test? What does this test tell you?

You may have heard or read about the Oncotype DX test that is sometimes in used in early stage breast cancer. It is not relevant in inflammatory breast cancer (IBC). The Oncotype DX test is used in patients with early stage cancers that are removed surgically shortly after diagnosis. The reason this test was designed was to identify those patients who do not require systemic chemotherapy because their risk of recurrence is too low to derive a significant benefit. Oncotype DX is a molecular gene expression test that quantifies the aggressiveness of the breast cancer and provides the oncologist a score that can be related to a risk of recurrence. If the score is low enough, then chemotherapy can be skipped, and since these patients are usually ER+, endocrine therapy is the treatment recommended after surgery.  Since in IBC, everyone gets chemotherapy upfront, there is no use for this test.

How soon after surgery should I begin radiation?

About 4 weeks is about the average recovery period between surgery and radiation.  Sometimes range of motion can be impacted by the modified radial mastectomy and if your drains are in for a longer period than usual, sometimes radiation must be postponed.   Your physician will suggest exercises to help retain or regain range of motion, so you can lay comfortably with your arm elevated or extended while receiving radiation.

I’ve read about some inflammatory breast cancer patients getting twice a day radiation? Is this standard or how do they decide?

Radiation is a very important aspect of IBC local treatment. For years, the sub-group of inflammatory breast cancer (IBC) patients who made it to radiation, received the same schedule and dosing of post-mastectomy radiation as regular non-IBC patients. However this strategy did not always provide optimal disease control and resulted in both poor survival and morbidity due to skin metastases. Unfortunately IBC cells are intrinsically more radiation-resistant than other breast cancer cells  For this reason, MD Anderson’s radiation oncologists decided to escalate the total dose received by 10% on average, and reduce the recovery time between treatments so that IBC cells could not start growing again once the DNA damage by radiation is repaired.  This is what led to twice a day treatments.  Upon further research, we have learned which patients really benefit from this more intensive treatment – that is patients that are younger (less than age 45), patients who had tumors that responded poorly to chemotherapy or patients who had surgery and had either positive or close margins (sometimes not possible to avoid this). If you lack all of these high-risk features, then once a day radiation treatments up to a total dose of 66Gy is sufficient. The number of treatments varies a bit from place to place, but generally the idea is that you get a total of 50Gy to the entire chest wall and then a boost of 10-16Gy to the scar line. The scar line is targeted because it is the most susceptible area for local recurrence. You will have radiation every weekday until it is finished. Occasionally you might have to take a break towards the end if your skin breaks down too much.

After radiation, am I radioactive? Can I be near my kids?

It is perfectly safe to be around other people including your children after radiation. External beam radiation enters your body, damages DNA in some cells, and some of the radiation exits your body through your back (yup some women have burns on their back). Your cells do not become radioactive. After radiation you can go about your day as you wish/feel able to. Cumulative fatigue from radiation and the rest of your treatment may limit your stamina for some time, especially if you are expecting to go back to a full active life.

Should I get scans after surgery and radiation to make sure they got everything?

It is common to wonder whether the surgeon got all the remaining tumor out. The current standard of care is not to perform scans such as PET or CT scans after surgery and radiation for stage III patients, in the absence of symptoms of metastasis. On the other hand, if you were diagnosed at stage IV (or developed metastatic disease during the course of chemotherapy-surgery-radiation), then it is normal to continue routine scans once you begin systemic therapy again. The exact frequency and type of imaging will be personalized to your disease behavior. Our best advice for overcoming the anxiety from lack of scans is to maintain good communication with your medical oncologist regarding any unusual symptoms or problems you are having.  Your follow-up appointments during the first 2 years should be relatively frequent (every 3-6 months is reasonable for your medical oncologist) and then after that, you might have less frequent appointments if all is well.

If I had a lot of cancer left over at surgery, should I get more chemo afterwards?

This is a very reasonable concern to voice, given that significant amount of residual disease at surgery is a poor prognostic marker.  However, this assumes that more chemo is better than less. Unfortunately this premise is not valid for standard cytotoxic chemotherapy. Cancers that are highly resistant to the cocktails containing multiple types of chemo upfront, are often cross-resistant. In addition, the side effects are cumulative and begin to outweigh the benefits (eg heart damage, immuno-deficiency).  In certain disease settings there are adjuvant clinical trials using newer targeted drugs that are more commonly used in the metastatic setting, earlier in the course of disease for patients with significant residual disease that may be of interest to you in preventing or delaying possible recurrence. Speak to your medical oncologist about whether any of these trials exist that fit your situation.

How often should my port be flushed?

After your chemotherapy and other infusions have been completed your port may be left unused until you decide to get it removed. Most port manufacturers recommend routine heparin flushing at 4 week intervals, however some variation does occur in practice.  A small retrospective study showed that prolonging the frequency to every 3 months did not increase significantly the rate of complications. These potential problems include clots and infections. If the port is not flushed carefully by trained professionals, serious problems may occur. Follow the guidance of your oncologist about when these flushes need to occur.

When should my port be removed?

There is no hard and fast rule. Some patients with anticipated good responses who no longer have a use for their port get it removed at their mastectomy. Others don’t feel safe removing it for a year or more after that to make sure they are still NED (“No evidence of disease”). If you are HER2 positive, then you need it for several months at a minimum after mastectomy while you finish getting the 1 year total of Herceptin.  The port can remain in for months or years more without problems, but it should be flushed regularly if it is not used for infusions or blood draws to reduce the chance of infections and clogging. Some women have some slight discomfort from the port and get it removed as part of ‘moving on’ from cancer.  If you are stage IV, then usually you would keep your port indefinitely since systemic treatment (chemo/targeted therapy) continues after surgery. Speak with your own oncologist who knows your situation to figure out the best removal time for you.

If I had a lot of cancer left over at surgery, should I get more chemo afterwards?

This is a very reasonable concern to voice, given that significant amount of residual disease at surgery is a poor prognostic marker.  However, this assumes that more chemo is better than less. Unfortunately this premise is not valid for standard cytotoxic chemotherapy. Cancers that are highly resistant to the cocktails containing multiple types of chemo upfront, are often cross-resistant. In addition, the side effects are cumulative and begin to outweigh the benefits (eg heart damage, immuno-deficiency).  In certain disease settings there are adjuvant clinical trials using newer targeted drugs that are more commonly used in the metastatic setting, earlier in the course of disease for patients with significant residual disease that may be of interest to you in preventing or delaying possible recurrence. Speak to your medical oncologist about whether any of these trials exist that fit your situation.

What reconstruction options are available to me? How long must I wait?

Breast reconstruction methods fall into 2 categories – autologous reconstruction or implant based methods. Autologous reconstruction methods use your own tissue and include methods such as the DIEP flap or the TRAM flap or a latissimus dorsi. These methods are best for inflammatory breast cancer (IBC) patients.  Implant-based methods involve the placement of a skin expander at mastectomy and gradual stretching of the skin by filling up the expander with fluid.  Once the skin has stretched sufficiently over multiple months, then the expander is removed and replaced by a saline or silicone-filled implant. While this might sound like a more appealing strategy than taking stomach or back tissue, in IBC it is not recommended due to the damage to the skin from the intensive radiation needed. In addition, trying to radiate in the presence of an expander often compromises the radiation plan. This is particularly a problem in IBC patients since radiation is exceptionally important for reducing the chance of a local/regional recurrence.

The next question is timing. Some surgeons like to talk about immediate reconstruction as a way to potentially get the woman back “whole” again more quickly, and avoid the potential mental anguish due to loss of breasts.  But in IBC, whether or not immediate reconstruction should be encouraged for patients remains controversial. Due to the skin involvement and higher rates of early recurrence, reconstruction is recommended to be delayed 1 to 2 years post completion of treatment.  This can be very hard for a woman to hear and one day research might allow earlier reconstruction. For now though, the recommended schedule is waiting at least 1 year, preferably 2 years before doing an autologous reconstruction method that works for your body (DIEP flaps are the most common technique used nowadays, and since many women with IBC have higher BMIs, this can be a benefit as a source of tissue). Speak with a plastic surgeon about what would be best in your situation. Contact us if you would like to join a closed facebook group we run to discuss reconstruction with fellow IBC survivors.

What are the differences between tamoxifen, and aromatase inhibitors?

Tamoxifen and aromatase inhibitors (AIs) are both examples of endocrine therapy used for ER/PR+ breast cancers to reduce recurrence.  The both act on the estrogen signaling pathway in different ways.  Tamoxifen binds to the estrogen receptor (ER) and stops it from being activated by estrogen.  Aromatase inhibitors such as Femara (Letrozole), Arimidex (Anastrozole) or Aromasin (Exemestane) block the production of estrogen from cells that express aromatase (such as fat cells, uterus, bone, and skin).  The aromatase enzyme converts androgens such as androstendione to estrone, and testosterone to estradiol.

Another difference apart from their different mechanisms is the populations of patients that can take each drug. While tamoxifen works in both pre-menopausal and post-menopausal patients, AIs are usually used in post-menopausal patients since once the ovaries stop working, then the main source of estrogen in the body is from peripheral fat stores. This process of androgen conversion to estrogens in the fat cells can therefore can be inhibited with an AI. In pre-menopausal women, the ovaries are the most active source of estrogen; hence if the ovaries are still functioning, AIs are useless in affecting overall estrogen production and signaling. Therefore, if a pre-menopausal patient cannot take tamoxifen or wants to take an AI for other reasons, they must have chemical ovarian suppression or have their ovaries removed surgically for this approach to work. Ovarian suppression is accomplished via a monthly injection of Zoladex or Lupron.

Recurrence/Metastasis

To where can inflammatory breast cancer metastasize?

Inflammatory breast cancer (IBC) can spread to virtually anywhere in the body, but there are some locations that may be more likely. Bone is a common location for metastasis, and in IBC bone metastasis acts more aggressively than other breast cancer bone metastases. Other common sites are lung, liver, skin and distant lymph nodes. If you have health concerns regarding other anatomical locations that are persistent and not explained by your known health issues, IBC recurrence should be ruled out.

What are the signs of inflammatory breast cancer recurrence that I should be aware of?

Some symptoms of metastatic IBC may include: