New Treatments for Early Breast Cancer

The complications of radiation are exceptionally rare, pneumonitis can occur, that happens in about 1 in 1000 women, rib fracture can occur years after the treatment is completed from osteoporosis, soft tissue necrosis is extremely rare and second malignancies are only really an issue in a very very young patient. This is what radiation pneumonitis looks like. This is a CAT scan of a patient who was treated to the left supraclavicular region, you can see the lung is clear here, but there is considerable scarring and fibrosis of this part of the radiated lung. No positive women, the vast majority of the time get chemotherapy with or without tamoxifen depending on their estrogen or progesterone receptor status. This is not a definitive slide, this is just to give you some thought processes so that when a woman walks in your office with a 2 cm mass, you can kind of understand what the sequence of events will be. If the tumor is less than 1 cm, most of the time they get no adjuvant treatment. If the tumor is less than 1 cm, greater than 5 mm they have to look at good versus poor prognostic factors and then they decide chemotherapy no treatment versus tamoxifen and this can be very complex and a very difficult issue. If the tumor is greater than 1 cm the vast majority of the time they get some sort of chemotherapy with or without tamoxifen. The most common regimens used now are Adriamycin and Cytoxan, Taxol is being increasingly used, sometimes CMF is still used. Follow-up after breast cancer may increasingly fall in the hands of the gynecologist, patient’s often seek the gynecologist for their primary care. We recommend ipsilateral mammogram every six months for two years, a contralateral mammogram just like you would normally do every year, a physical examination of the breast every four to six months, usually every four months for the first year.

It has been my experience that women rarely go back to self breast exam after a diagnosis of malignancy for a whole variety of reasons, so it’s really important for the physician to take the time to do a careful breast exam. Routine imaging and blood work is not needed, it’s still routinely done, however, there are multiple studies showing that chest x-rays, CT scans routinely CBCs and SMAC probably do not ultimately impact on a woman’s survival should her breast cancer recur. Recurrences are detected about a third by self exam, about a third by mammography, but about a third are detected just by the physician’s exam, so it’s especially important for you to examine the breast of a breast cancer survivor.

I would love it if in five years I wouldn’t have to stand up here anymore. We are always looking for the golden eggs that will allow us to prevent breast cancer once and for all. So I thought I would spend the last minute talking about some of the studies that have been done which are leading us in that direction. The NSABP 1 tried to prevent breast cancer in high risk women and they chose tamoxifen which was well defined for early breast cancer versus placebo. This was a huge study, received a lot of national attention, and basically these are the results. If you look at all tumors comparing tamoxifen in the light versus placebo in the orange, tamoxifen decreased the risk of all tumors by half. Most important, it decreased the rate of invasive tumors by about half. If you look at the thousands and thousands of women treated, this resulted in very few actual cancers being prevented, but the statistics were still highly significant. The problem was we were debating did tamoxifen really prevent cancer or did it just treat the early ones because most of the breast cancers that were prevented were estrogen and progesterone receptor positive. Tamoxifen unfortunately increases the risk of endometrial cancer and thromboembolic events, so it probably not the holy grail that we had planned. At about the same time, raloxifene was used for postmenopausal women to prevent osteoporosis, and it’s thought to avoid the estrogenic stimulation of the uterus and low and behold, when they looked at the woman independently who were treated with raloxifene versus a placebo for their osteoporosis, the women that got the raloxifene had a decreased risk of breast cancer. So ongoing trial from NSABP is called the star trial, it is currently accruing women 22,000 postmenopausal women will be accrued and the arms are tamoxifen versus raloxifene and we await the results of that trial.
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Early Breast Cancer. New treatment

There are several contraindications to breast preservation so you can judge when a woman walks in your office, may she be a candidate for breast preservation or not. If you have a large tumor, usually greater than 5 cm, most of the time they cannot be preserved. There are some considerations for neo-adjuvant chemotherapy but the vast majority of women would be best served by a mastectomy. If you have two palpable lesions in separate quadrants of the breast, usually they are not a candidate for breast preservation because too much of the breast tissue needs to be removed for a cosmetically acceptable result and most of the time, that breast could not be controlled with radiation therapy afterwards. If the patient is in the first two trimesters of pregnancy, she is best served by a modified radical mastectomy because radiation therapy should not be given when a patient is pregnant. If she is in the last trimester and radiation therapy can be delayed until the baby has been delivered, then breast preservation may be considered. If the woman has had prior breast radiation either for breast cancer or for lung cancer on that breast, she can’t have that breast preserved. If she had breast cancer on the other side and was preserved with radiation, there is nothing wrong with treating the other breast with radiation therapy. There are sometimes social or medical conditions precluding radiation, the patient can’t get to the treatments six days a week, they are bedridden, they are in a nursing home, those are patient’s who would best be served by a mastectomy.

This is a mammogram of a woman that should not have breast preservations. I think the calcifications that you see are pretty obvious from the back of the room and these all indicate very extensive infiltrating and intraductal carcinoma, and this patient would be best served by a mastectomy. There are some relative contraindications to breast preservation. If a patient has a history of collagen vascular disease, especially lupus, their skin can have an extreme reaction to the radiation therapy, sometimes to the point of necrosis requiring reconstruction, so that patient needs a very careful discussion about risks benefits of radiation therapy before you proceed. If there are multiple tumors in the same quadrant of the breast, you have to kind of judge how much of that quadrant is involved by tumor, how big the tumors are, how far apart they are and if you feel that the tumors are too large to be adequately excised, then that patient would be best served by a mastectomy. There is some older thinking about patient’s that shouldn’t be preserved that are kind of old wives tale. First of all, if you have positive axillary lymph nodes, there is no reason that patient cannot have breast preservation. If the tumor is underneath the nipple, there is no reason that patient cannot have breast preservation. If there is a strong family history, there is no evidence, at least at this point that a young woman with a strong family history cannot be treated with breast preservation. There is no long term data suggesting that their local control is poorer even in a BRCA 1 or 2 family.

This is a classic mammogram of a patient who is an excellent candidate for breast preservation. She has a small mass in the upper portion of her breast, very well defined, the rest of the breast is relatively fatty with no other lesions noted. The lesion is excised with needle localization and you can see the spiculations of the mass with a margin of normal breast tissue around it. This patient would then receive radiation therapy, as a radiation oncologist, I have to tell you a little bit about that, you treat the entire breast, you may or may not treat the regional nodes. Radiation treatment therapy is now for the most part done with CT based treatment planning, these are just localization marks on the patient. You can see that the biopsy cavity is here and the surgeon outlined it in clips. We can then make very detailed plans and these little blue lines show that the radiation is going only within these lines and the rest of the body is not even being treated, especially the heart. This is what a patient looks like on the last day of treatment. There is skin reaction and you can imagine that’s where the port would be in a little bit of a square. That skin reaction peaks usually toward the last week or so of radiation therapy and then heals within the first month after treatment.

Early Breast Cancer. Treatments

The real debate is, do all women need radiation therapy? Even though I am a radiation oncologist, sometimes I say probably this patient’s won’t benefit. There is a certain morbidity to radiation, it’s very expensive, one must question whether small low grade tumors, especially if you are considering adding tamoxifen need to have radiation therapy for improved local control. This is the kind of ductal carcinoma in situ I am talking about. I had to circle in red because you can barely see it. It’s a 3 mm low grade ductal carcinoma in situ, excised with 2 cm of normal margin. Does that patient really need radiation therapy? Some physicians in California, tried to develop a retrospective prognostic index, what they did is they looked at their thousands of patient’s they had treated for the last 20 years in a nonrandomized way and they decided that tumor size nuclear grade, the presence of necrosis and the margin width could kind of be juggled into a grid to help you decide which patient’s may or may not benefit from radiation therapy. So they developed a score, and you may see these scores on your pathology reports because they are becoming increasingly used to help you determine the clinical significance of the ductal carcinoma in situ. The size is given a score of 1, 2, 3, based on how many mm it is, the margin is given a score of 1, 2, 3, based on if it’s a little bit of a margin, or a great big margin and the grade is 1, 2, 3, so the lower the score, the better, the higher the score, the worst. Then they basically add up your scores and they help you decide a treatment option. If you have a score of 3 or 4, they show that excision alone will allow about a 90% long term local control in the breast without radiation, a 5, 6, or 7 indicates that radiation therapy gives the best chance in addition to excision with local control, and if you have an 8 or 9, no on would disagree that a simple mastectomy is appropriate.

This is a histograph of an infiltrating ductal carcinoma and you can see that this is much different than ductal carcinoma in situ. Now we have the stroma of the breast infiltrated by these strands of very malignant cells still forming small ducts.

Infiltrating ductal carcinoma is treated much like ductal carcinoma in situ with a few exceptions. You again start with bilateral mastectomy, biopsy, most of the time a post mastectomy mammogram, postbiopsy mammogram is indicated. A patient is then treated by either a modified radical mastectomy which includes dissection and chest wall radiation therapy is becoming increasingly used for premenopausal women based on the risk factors at the time of mastectomy. The vast majority of patient’s are treated with breast preservation in which the axillary nodes are removed either by sentinel node biopsy and/or level 1 and 2 dissection and excision of the tumor is done with negative margins and then the breast is radiated. You think breast preservation is new, this is from 1947. This was Jeffrey Keats who first tried to preserve breasts by putting radium needles into the breast and the regional lymphatics. As painful as that looks, it was highly successful and his results were reported to be the same as Sir Halstead who was the ruling guru of radical mastectomy of the day. His work stopped not because it was ineffective but because the war prevented the continued use of radium needles and it wasn’t until many years later that others took up the concept of breast preservation. Breast preservation has now been well established in over randomized trials comparing modified radical mastectomy to excision and radiation therapy. This is just a brief slide of the different series, the yellow is the modified radical mastectomy and the red is breast preservation. This is a graft of local recurrence. Local recurrence with breast preservation is about three to 19% at 10 years. Most important, there is no difference in survival, whether a woman has her breast removed or is allowed to keep her breast.

Early Breast Cancer. New Treatments

Ductal carcinoma in situ is obviously enough abnormal cells in the ducts. This is a little different than lobular carcinoma in situ in the way that it presents and in it’s management. The incidence of ductal carcinoma in situ is dramatically rising, about 10 years ago, it was about 2% of cancers that were diagnosed in women and many of those were palpable. Because of screening mammography, picking up these little tiny microcalcifications, the incidence of DCIS has risen to about 20 to 30% of all cancers and will probably continue to rise. The classic presentation are little tiny abnormal microcalcifications on a mammogram. There are five subtypes of ductal carcinoma in situ with some thinking that the comedo subtype, comedo meaning necrosis is the most aggressive. Lymph nodes are never involved with ductal carcinoma in situ because the tumor cells are still confined to the basement membrane so they cannot go through the basement membrane, they don’t have access to the regional lymphatics, so axillary lymph node dissection does not need to be performed. This is a picture of ductal carcinoma in situ, this is actually a cribriform type because it has these holes in it with a little bit of necrosis in the center, and you can see that the cells are still very well confined within this duct. The management of ductal carcinoma in situ is different than lobular carcinoma in situ. The patient needs a bilateral mammogram, a biopsy, and then because most of the time you find these little microcalcifications and remove them, you need to do a post biopsy mammogram to make sure they are gone. You don’t want residual microcalcifications left in the breast. If a ductal carcinoma is wide spread, meaning that either the microcalcifications are all over the breast or the area that is removed is large and there is ductal carcinoma in situ throughout the breast, then the best treatment choice is a simple mastectomy with or without reconstruction and one might consider discussion of tamoxifen. If ductal carcinoma in situ is in one quadrant of the breast, the patient still has an option of simple mastectomy, that is a personal choice, the patient may have a lumpectomy and we’ll talk about lumpectomy alone in a minute.

The most common treatment is lumpectomy or removal of the ductal carcinoma in situ with negative margins followed by radiation therapy and then again, one might have a discussion about tamoxifen. Lumpectomy and radiation therapy was first used for invasive disease and it wasn’t later until we started using it for ductal carcinoma in situ. The control in the breast is about 80 to 92%, depending on patient selection and the carefulness of the physician in determining who is a candidate for breast preservation. Survival for ductal carcinoma in situ is 96 to 100%, this is a highly curable disease. Follow-up of these patient’s is about 10 years and the benefits of tamoxifen will be discussed in a moment. This is just a graft to show four series of patient’s this is a local control with excision plus radiation therapy and then this is the ultimate survival, so you can see that survival is excellent when a lumpectomy and radiation therapy are used. In the NSABP 24 trial, women were randomized to either receive placebo versus tamoxifen. All the women got a lumpectomy and radiation therapy up front, half got the tamoxifen and half got the placebo. Tamoxifen which is shown in red decreased the risk of invasive recurrence. The yellow bar indicates placebo and the red indicates tamoxifen. If you looked at all the recurrent cancers, both in situ and invasive, tamoxifen decreased the rate of all cancers. The ones you worry about are the invasive ones because those are potentially life threatening and it decreased the risk of invasive cancers in about half of the patient’s. So tamoxifen for the diagnosis of ductal carcinoma in situ is at least warranted in a discussion.

Treatments for Early Breast Cancer

I am going to briefly go through the general management of three types of breast cancer because they are all unique in how to be managed. The first is lobular carcinoma in situ, then ductal carcinoma in situ and then invasive cancer. Lobular carcinoma in situ is classically defined as abnormal cells in the lobules and someone argued that this is really not a cancer at all. We would consider this to be sort of a risky breast. It makes up about one-third of all in situ lesions, it classically is more common in premenopausal women, it is an incidental finding, the mammogram is normal, and lobular carcinoma in situ is found when a biopsy is done for another reason, 40 to 80% of LCIS is multicentric, meaning if you biopsied the rest of the breast, you would find LCIS in about 40 to 80% of women, and 20 to 70% of patient’s it’s bilateral. In the old days they used to do a mirror biopsy, about 70% of the time they would find LCIS in the other breast and this is very important when you are considering appropriate management, 10 to 40% of women if followed long enough will eventually develop an infiltrating ductal carcinoma, not an infiltrating lobular carcinoma. The actual risk of developing an infiltrating cancer is about 1% per year. This is a classic histological photograph of a lobular carcinoma in situ and you can see that the lobule remains very well defined. The membrane is intact but it’s full of these atypical cells. Treatment options for lobular carcinoma in situ are basically two. After a bilateral mammogram which is usually done, and something else is found and a biopsy is performed, you find the diagnosis of lobular carcinoma in situ. If that is your only histologic finding, the patient has two choices, one is observation, nothing more needs to be done, with or without discussion about tamoxifen as we will discuss in the chemo prevention trial.

Bilateral mastectomy, not unilateral but bilateral mastectomy used to be a very common procedure for LCIS because it treats both breasts, but this is an extreme procedure for a noninvasive, non life threatening condition of the breast, so bilateral mastectomy is usually reserved for women with either very high levels of anxiety or a very strong family risk.

New Treatments for Early Breast Cancer

This is just to review the anatomy of the breast, of course there is the nipple, and then multiple, multiple ducts which strand into the nipple, so the highest concentration of ducts is right behind the nipple and then deeper to the breasts are the lobules. The number of lymph nodes at this point in time continues to determine the prognosis of the tumor. So a patient with one positive axillary node does not have the same prognosis as a patient with 10 positive axillary nodes. Internal mammary nodes can sometimes be clinically affected but usually only with medial tumors in which a patient already has documented positive axillary nodes. Supraclavicular nodes indicate distant disease and by definition are metastatic disease in the staging system. Metastases most commonly occurs to the bone, brain, liver and lung. History is important in a patient who may have a breast cancer, especially their family history, what age the family member was at their diagnosis, was it bilateral, was there any history of ovarian, uterine or colon cancer which may either indicate a BRCA one or two family or a Lynch syndrome family. Did they have radiation, especially if you’re from Chicago because many, many women were radiated for acne or thymic problems and those women later had thyroid cancers and we’re now seeing those women develop a breast cancer, or lymphoma as a child and then as a radiation oncologist we need to know, does the patient have a history of collagen vascular disease because that may not allow them to receive radiation therapy. We need to know if the patient had breast implants, where they are, are they subpectoral, we need to know the date of their last period, and never forget a pregnancy test because women can be pregnant when they have breast cancer. Many women come using estrogen replacement therapy, it’s a reminder to stop it at the time of the diagnosis, you need to know if there is nipple discharge, either unilateral, bilateral, if it’s bloody or guaiac positive, and then if they have any symptoms of distant disease, most commonly bone pain.

Physical exam should be a careful one and you can gain a lot of information by just the classic careful physical exam, you can tell the tumor size, if it’s fixed to the skin or the chest wall, if you’re considering breast preservation you look at the ratio of the breast to the tumor size, is the breast a huge breast with a tiny tumor or is this a medium sized tumor in a small breast which may prevent breast preservation. You want to find out if there are palpable tumors in other parts of the breast or in the other breast, and of course you would check for regional node enlargement. You want to make sure there is not locally advanced disease like skin ulcerations, satellite nodules, peau de orange which is that sort of dimply texture of the skin from dermal lymphatic invasion, inflammatory skin changes which are commonly misdiagnosed in young woman, you think it’s a mastitis when it turns out to be an inflammatory carcinoma or lymphedema of the arm. Diagnostic workup is important to include bilateral mammograms. Unless the woman has had a mammogram of the contralateral breast within the last several months, both breasts should be evaluated. Ultrasound, especially the new 3-D ultrasound is becoming increasingly important to characterize tumors, something can be solid on the mammogram but a simple cyst on ultrasound. Chest x-ray is a standard diagnostic evaluation. CBC, liver functions and alkaline phosphatase are routinely performed. We don’t need to get a bone scan or a CT scan of the liver for early disease, unless there is pain or elevation of the alkaline phosphatase. Staging system is based primarily on surgical staging and it just is broken down by tumor size. I just want to show you that in the staging system, ductal carcinoma and lobular carcinoma in situ are both as TIS which is a stage 0 tumor. The nodal disease is based on whether they are movable fixed, and where they are, and notice that supraclavicular nodes are considered distant disease.