What are the short term side effects from chemotherapy? Clearly alopecia in most of the regimens used. Weight gain is very common. This always comes as a shock to patients. Fatigue is the overwhelming most common and problematic problem from adjuvant chemotherapy. Febrile neutropenia is quite rare. Neutropenia is quite common. It usually occurs with every course but febrile neutropenia is quite rare and hemorrhagic complications are even more rare.
Of more concern are the long term side effects from adjuvant chemotherapy particularly if you’re treating young women. It can cause premature menopause and then these women have usually not been thought to be eligible for hormone replacement therapy and are at risk for cardiovascular disease and osteoporosis.
If you look at women treated with adjuvant chemotherapy and compare them to women who have not had breast cancer and not been treated, their incidence of leukemia is actually fairly comparable. Now, there are some investigational arms who escalated doses of cytoxan where leukemia incidence appeared to be increased. But in the general adjuvant therapy we’ve given over the past few years, leukemia doesn’t appear to be increased, nor does cardiomyopathy.
Tamoxifen needs to be used at least more than two years and probably for five years and probably not for more than five years. At more than five years, there may actually be an ability for tumor cells to learn to use tamoxifen to grow and you have increased relapse of breast cancer with more than five years of tamoxifen. You also have an increased risk for other tumors, particularly uterine cancer. It clearly benefits people who are postmenopausal more than premenopausal and usually only those patients who are ER/PR positive will benefit the most. PR positive ER negative benefit also.
Tamoxifen, and you probably have heard so much about tamoxifen in the last few weeks you can’t stand it, probably benefits bone density and blood lipids. In the trial for prevention of breast cancer in normal women, they couldn’t really show that but with only four years followup I don’t think that’s so surprising and I think with longer followup they may be able to demonstrate that. But clearly in breast cancer patients we’ve known for a long time it reduces the risk of contralateral breast cancers by 50%. I think it reduces the risk of new breast cancers in the lumpectomy radiated breast and now we know that in women at risk for breast cancer who have not had breast cancer, tamoxifen reduces the risk of getting breast cancer.
What is the role of adjuvant radiation? I think the thinking about this has changed quite a bit in the past few months. I used to say that local radiation therapy only prevented relapse in the local area and didn’t do anything much for overall survival. There’s two very impressive articles in the New England Journal in October of last year and it showed that patients with any positive nodes receiving radiation therapy had a better survival when that was combined with chemotherapy versus chemotherapy alone. Most of the chemotherapy was with cytoxan methotrexate 5FU. Even in patients who had few nodes, one to three positive nodes, these are the patients who got radiation and chemotherapy versus chemotherapy alone, they seem to have a survival benefit.
In the past I had only applied radiation to patients with four or more positive nodes or large tumors or invasion of the chest wall or something like that. I am now radiating everyone with positive nodes. That may not be standard in all places.
What is the followup for patients who have had breast cancer and then adjuvant therapy or even just breast cancer? See a physician with a good history and physical every four months for the first two years and then every six months to complete five years and then yearly has been my practice and I think is fairly standard. I do a CBC and chemistry profile. You could argue that a CBC is not really necessary. The most important thing is clearly the physician breast exam, the yearly mammograms and other health care maintenance should be followed such as yearly pelvic exam, screening for blood in the stools and sigmoidoscopy after age 50.
Diagnosis and Treatment of Breast Cancer

In the node negative group, it’s a little more difficult to figure out but a conservative answer at this point in time, and this is changing kind of year by year, tumors more than a centimeter plus some other risk factor such as being ER/PR negative or having a high S phase, some people would say being HUR2 positive, even if they ER/PR positive, would make people treat them. Some people add in grading so if they’re poorly differentiated or moderately differentiated and have another one of these risk factors such as having a high S phase, they would give them systemic adjuvant therapy.

The choices for systemic adjuvant therapy, for estrogen receptor and progesterone receptor positive patients who are postmenopausal, hormone therapy can be as effective an adjuvant therapy as combination chemotherapy. For ER negative patients, combination chemotherapy is superior to hormone therapy and for all premenopausal women, regardless of their ER/PR status, combination chemotherapy is superior to hormone therapy. But hormone therapy may have a further additive benefit and those patients you may consider combined therapy. So chemotherapy is used for all premenopausal women and those postmenopausal women whose tumors are not much affected through hormonal manipulation.

Hormone therapy is useful for estrogen receptor positive postmenopausal women and my bent, and I think this is increasingly popular, is those women at low risk. So postmenopausal women, even if they’re ER positive with a number of positive nodes or other high risk factors, you may consider giving them chemotherapy then followed by hormone therapy. Premenopausal women who are ER positive would also be considered for chemotherapy then followed by tamoxifen. I don’t use tamoxifen and chemotherapy together and I don’t think most people do. It does increase your risk for clotting complications. If you sequence the therapy, it’s as effective and it avoids some of those clotting combinations. People clot on chemotherapy and they also have an increased risk for clotting on tamoxifen.

Adjuvant chemotherapy increases disease free survival more than overall survival. What that says is it just pushes back the time for relapse. In some patients it doesn’t actually cure them but in some patients it does absolutely cure them and you do add to quality life and you also do add to the bottom line a number of patients cured though not as many maybe as we’d like.

It’s clear you need more than one drug for adjuvant therapy and it’s increasingly clear that it’s much better to give good, high doses of chemotherapy over a short period of time than to string long doses over long periods of time and nobody should be getting adjuvant therapy for twelve months or more. Most adjuvant therapy is given over 12 weeks to 6 months, in that range.

This looks at patients given different doses of Cytoxan and Adriamycin 5-FU and this solid line, in terms of disease free survival and overall survival are those patients who are more aggressively dosed than patients who are given a lower dose. Dose does matter. Dose over time or dose intensity is a predictor for outcome.

These look at HUR2-nu expression and if you overexpress HUR2-nu, those patients who were HUR2 negative, they seem to fair pretty well whether they got high doses of chemotherapy or low doses of chemotherapy. But if you were going to get cured, you had to get high doses of chemotherapy if you overexpressed HUR2-nu. So I think HUR2-nu is a predictor for outcome. It also tells you how you have to treat patients. There’s also increasing information that hormone therapy is not useful for patients who overexpress HUR2-nu or their tumors overexpress HUR2-nu and that CMF probably isn’t very useful and that you need to use Adriamycin in good doses.

Tumor size does correlate with outcome. It’s not the strongest predictor of outcome but it certainly correlates and this just graphs tumor size against percent of disease free patients in five years. You can see as the tumor gets more than 5 cm, the chances to remain disease free gets less than 50%.
Nodes is the next way to stage and you either have negative nodes or positive nodes or N2 disease is nodes that have grown together or are matted. N3 disease is internal mammary nodes which, in fact, we don’t stage for very well but usually in patients who present with a real medial lesion, I will do a CAT scan to try and better assess those internal mammary nodes.
This correlates lymph nodes to disease free survival and lymph nodes are the biggest predictor of outcome in breast cancer. The predictive value increases with every positive node in a negative way. So if this is just the number of positive nodes against percent of disease free patients at five years, you can see that your chances to be disease free with ten or more positive nodes is less than 20%.
This is another way to look at that. If you have no positive nodes, your chance for relapse is about 20%, one to three about 60% and more than four positive nodes puts your chances to relapse in the 85% range. This, of course, has led us to target these patients with four or more positive nodes with more aggressive therapy such as high dose chemotherapy and autologous peripheral blood stem cell rescue or bone marrow rescue or get them into trials of more aggressive therapy.
If you have metastatic disease, then that makes you an M1. So it’s either you have metastatic disease or you don’t. Then you put these T and M classifications together. There’s only one way to be a Stage I breast cancer and that’s to have a tumor less than 2 cm, a T1 lesion, no nodes and no metastases. Anytime you have metastases, no matter what your T or your N, you’re a Stage IV.
Stage II can be all kinds of things and it’s easier to remember that Stage II is anything that’s not Stage I, III or IV. Stage III disease is anytime you have a T4 lesion, you’re going to be a Stage III. Let’s look at Stage III. Any T4 will put you in a Stage III. Any T3 with positive nodes is going to make you a Stage III. Any N2 disease will make you a Stage III and all the rest will be a Stage II. So the minute you have positive nodes, it makes you in Stage II or III. If it’s not N2 disease and it’s not a T4 lesion and it’s not a T3 lesion, you’ll be a Stage II.
If you go back and look at it, it makes a lot of sense. The only way you can be a T3 and still be a Stage II is not to have any positive nodes and that doesn’t happen very often. So all the T1 and N1 combinations make you a Stage II. Anytime you have nodes that aren’t N2 disease, you’ll end up being a Stage II usually.
This graph just shows you that this staging actually is pretty predictive and this is overall survival across years at 10 years. This black line at about 80% is Stage I disease. So no nodes tumor, 2 cm or less, this falls to about 50%. Anytime you have positive nodes, these are usually microscopically positive nodes, are a tumor that is greater than 2 cm. This line, Stage III disease, usually a big tumor or large matted nodes, puts you down to about 30-35% and you can see that there are no long term survivals in patients who have metastatic disease.
There are other prognostic features that we also consider. The one that’s most talked about, of course, is the estrogen and progesterone receptors. If you’re estrogen receptor positive and/or progesterone receptor positive you are less likely to relapse and have metastatic disease or if you do it takes a longer time. The S phase, the percent of cells that are in a dividing phase, usually determined by cell sorting, may have a predictive value and it’s becoming clear that the overexpression of the gene product from the epidermal growth factor gene or HUR2-nu is an independent predictor for outcome, independent of these other factors, and is probably in the future going to be increasingly used to predict risk of breast cancer.
Well, we use all these risk factors to decide who we think needs systemic therapy to try to eradicate microscopic disease and hopefully change that person from going on and relapsing from breast cancer to being cured of breast cancer. Clearly, when you saw a Stage II line that dropped right to 50%, all those patients are at high risk for relapse and they would be thought to need some sort of systemic adjuvant therapy to treat microscopic disease. So node positive patients, some sort of systemic adjuvant therapy.

I just wanted to mention ductal carcinoma in situ. This is a very controversial area in terms of management. The choices, I think, are mainly mastectomy with no axillary dissection. This is only in those cases where there is no invasive disease noted versus a lumpectomy and radiation versus a lumpectomy with no other therapy. There’s a randomized trial really looking at these three various options and the lumpectomy alone had an increased incidence of local recurrence. There are certainly places like Van Nuys, California and other places who are doing very careful pathology, requiring larger margins and with smaller tumors are able to do lumpectomy alone. I think you really have to recreate some of those pathologic techniques and surgical techniques to get those kind of results and so I would not probably apply a lumpectomy alone to all patients who have ductal carcinoma in situ.

Lobular carcinoma in situ I look at as just a marker for risk not much unlike family history or other risk factors and I think that diagnosis warrants closer surveillance. Only in those patients who have other high risk or have breasts that are really very difficult for surveillance, don’t mammogram well, are too dense for accurate mammography or ultrasound doesn’t work or whatever, they have lots of lumps and bumps, would I consider bilateral mastectomy.

Let’s talk a little bit about the approach to patients who have been diagnosed with invasive carcinoma, ductal carcinoma, medullary carcinoma, lobular carcinoma. Really the approach is the same. The two approaches to local control are either a modified radical mastectomy or a lumpectomy with radiation and an axillary sampling or dissection.

A caveat to that has been the sentinel node dissection. Usually a patient with a smaller tumor and a tumor that has been diagnosed by needle aspirate or biopsy but not been excised you can put dye or technetium or something into the tumor bed, trace it to the first axillary node, dissect that and in the appropriately selected patients, that should be 95% predictive as to what the axillary status is. So if it’s negative in the axillary nodes, it’s 95% that the rest of the nodes will be negative also and further dissection is not necessary. If it’s positive, there’s about a 3% chance that the rest of the next axillary nodes will be negative but it requires them to go and dissect the node if it’s positive.

This is a look at mastectomy versus lumpectomy radiation and axillary dissection. This is at eight year followup. The earliest publication with followup is now at 20 years. Similar studies have reproduced these exact results in Europe and it really shows that there’s no difference in overall survival in patients treated with these two different local options. The deal is that this is really an option for the woman in terms of how she wants to approach this and it shouldn’t make a difference in overall outcome.

There are a few reasons not to do a lumpectomy and radiation. If you’ve got a very large tumor in a small breast, you’re not going to get a very good cosmetic result and it probably isn’t the right thing to do. If there’s a multifocal tumor throughout the breast, doing lumpectomy is not really feasible. If the breast is very dense, a lot of other pathology in the breast, it may be that that won’t lend to good surveillance in the future of that radiated breast which will increase the fibrosis and density and perhaps mastectomy is the best thing to do. Very rarely there will be patients with such severe underlying heart disease or lung disease that you won’t think they can tolerate the radiation but that’s very rare.

If the patient does choose for mastectomy, it certainly should be discussed with the patient’s various reconstruction options. Most of this reconstruction is getting done at the time of initial surgery if the patient doesn’t appear to have advanced local disease.

Just to talk about staging a little bit because really everything we do is based on the predictive value of the staging and a few other predictive features. Staging is based on the tumor node and metastasis system. The tumor is divided between T1 through T4. A T1 lesion is less than 2 cm, T2 between 2 and 5 cm, T3 more than 5 cm and a T4 lesion is a lesion that extends into the muscle or into the skin. It also includes inflammatory breast cancer – breast cancer that presents as a red inflamed breast, has an erysipeloid kind of appearance and if you biopsy that, often their dermal lymphatics will show tumor cells within them.

Lifestyle is becoming increasingly recognized as having risk for breast cancer and smoking and alcohol intake has been related to an increased risk. Now there are a couple of studies that show vigorous exercise, particularly in the teenage years, may markedly decrease the risk for breast cancer.

As I noted there are four cloned genes that we know about that predispose to breast cancer. All of these conferring risk in an autosomally dominant way: BRAC-1, BRAC-2 – these are the breast and ovarian syndromes, ataxia telangiectasia. If the patients are homozygous, they don’t live to a very long life but if they’re heterozygous, they probably do have an increased risk for breast cancer and the importance of identifying these patients are that they are at great risk for risks of radiation and maybe increased surveillance by mammography is a bad thing to do for these patients. It’s a fairly rare thing. P-53 is the Li-Fraumeni syndrome. It’s related to increased incidence of sarcomas and breast cancers and other tumors.

Well, what is the standard screening for breast cancer? Certainly self exam, I think, should be incorporated although sometimes people argue whether studies show that this is useful. The clinical physical exam is of use and the main imaging technique for screening is mammogram. Breast self-exam in a couple of old prospective studies has shown that when used in a consistent way that it will lead to diagnosis of tumors that are more likely to be smaller in the Stage I category and with no positive nodes.

These are the American Cancer Society guidelines for early detection of breast cancer and the NIH has come more into line now with these guidelines. A few years ago they were not so aligned but from age 20-39, clinical breast exam by a physician or nurse every three years and a monthly breast self exam. Age 40 or older, and this is the difference, annual mammography, annual clinical breast exam and monthly breast self exam. Prior to this, the NIH had not recommended mammograms until age 50.

Now, these are for people at standard risk and patients who have a strong family history or look like they may be in a family at great risk, I usually start some sort of surveillance mammography about ten years prior to the onset of maybe the first degree relative that had breast cancer or something like that.

If there is an abnormality on the mammogram or a palpable lesion, what are the biopsy techniques? For mammographic lesions, stereotactic biopsies are very useful. It’s quite accurate in getting the needle right into the lesion on mammogram. Sometimes when you put these wires in for localization, you can be off by quite a bit. That’s why it’s so important to do the specimen mammogram after the excisional biopsy when the wires have been placed.

Fine needle aspirates, I think, are very useful. Particularly if you have a larger lesion you can localize it. To do a fine needle aspirate, you haven’t then been in there surgically and when you have the diagnosis you can concretely sit down and talk about all the surgical options. When people have a localized lesion, I think a fine needle aspirate is a nice way to go. If it’s not positive then you’re going to have to do an excisional biopsy but it often is positive or a needle directed biopsy.

Breast cancer is the most common diagnosed cancer in women. It’s not the most common cause of cancer death in women. That goes to lung cancer which occurs much less frequently than breast cancer but the morbidity is a great deal higher. These numbers have remained fairly stable over time. The mortality has also remained fairly stable although in some subgroups it has decreased. In women of higher socioeconomic status, more of those patients seem to be not having recurrent breast cancer or being cured, perhaps because of the effect of early detection through mammogram and education.
There are a number of risk factors that have been noted for breast cancer. The greatest risk factor is probably age and the peak incidence of breast cancer occurs between the fifth and sixth decade. If you’ve had a previous history of breast cancer in one breast, you’re certainly at increased risk to develop a second breast cancer either in the breast that’s had lumpectomy and radiation or in the other breast. Family history clearly puts you at some risk and depending on the number of members of the family that are positive and the closeness of the relationship dictates the risk. If you have a first degree relative that had bilateral premenopausal breast cancer, you probably have a lifetime risk of breast cancer that comes close to 50%.
Of course, now there are genes that we’ve identified that are inherited in an autosomal dominant way that confer lifetime risk in the 80% range and these are BRAC-1 and BRAC-2 genes. Other genes that are associated with breast cancers, P53, abnormality in the P53 gene and the ataxia telangiectasia gene that’s not been cloned.
Anything that prolongs cycling or the estrogenic cycling of the breast tissue probably is related to a slight increased risk of breast cancer. So never having a pregnancy or having a late age for first pregnancy, early menarche or late menopause all confer some increased risk for breast cancer. Prior radiation to the chest is clearly an increased risk for breast cancer particularly if it’s a lose dose radiation that occurs in the prepubertal years.