Ductal Carcinoma in Situ - Jim Waisman, M.D.
Jim Waisman is one of the most respected breast cancer oncologists in the world. For many years a leader in the research and academic aspects of breast cancer, Dr Waisman has been a Co-Director of Breastlink for the last five years. He has a unique ability to work alongside women in their fight for a cure and survival of breast cancer, and to become their friend and confidant in the process. He is a tireless campaigner of Optimal Care for women.
Introduction
In 1975, when I first started in medical oncology, we rarely saw patients with Ductal Carcinoma in Situ (DCIS). In a patient survey conducted by the American College of Surgeons in the early 1980s, only 3% of all breast cancer was DCIS. By 2004, however, 25% of breast cancer or about 60,000 American women per year were diagnosed with DCIS. What had happened? Is this, in fact, a new disease? In fact, it is not a new disease. Virtually all invasive breast cancer evolves from DCIS. The changes in incidence are due to one thing: the advent of high-quality routine screening mammography. It is this improvement in screening that has not only led to the increase in finding DCIS but has, along with better systemic therapy, led to a reduction in overall breast cancer mortality. In countries such as Great Britain which have adopted a major screening program over the past 20 years using mammography, breast cancer mortality has dropped by 50%. So although DCIS is not a “new” disease, our experience with it is relatively short-lived. Definitions of the nuances of the disease and decisions regarding breast treatment strategies are only now being determined. It is therefore not surprising that there should be significant controversies associated with it. It is my goal in this article to give you the most current understanding of the major topics of DCIS: surgery, radiation therapy, medical oncology and follow-up care. I will then conclude with the focus on future directions in care.
In medicine, the most challenging situations for a patient sometimes occur when there exists multiple options of care or patient choice: mastectomy vs. lumpectomy, lumpectomy alone, lumpectomy and radiation therapy, and the plan to have or not to have breast reconstruction. Our professional responsibility is to provide choice for women based on evidence-based, data-driven options of care.
This article will provide you the patient with a better understanding of ductal carcinoma in situ so that you may make decisions that are in your own best interest.
Take-home Message #1:
- Have a routine mammogram at a recognized center appropriately certified for mammographic screening
- Ductal carcinoma in situ is not a “new” disease but our understanding of it is new and management strategies are controversial.
- For you the patient, knowledge is power!
II DCIS: Pathology
Ductal carcinoma in situ (also called intraductal breast cancer) is defined as a group of neoplastic cells confined to the breast duct and limited by the basement membrane of the cells that line that duct. Once the cells have broken through the duct wall they are called “invasive breast cancer”. When the tumor invades by less than 1 mm, we call that microinvasive breast cancer. Although not the topic of this paper, it has a prognosis similar to DCIS. The five major types of DCIS include: cribriform, papillary, micropapillary, solid and comedo. Pathologists divide DCIS into two broad categories: comedo and noncomedo. These broad categories actually represent a continuum of lesions, with differences in genetic alterations particular to a given cell type. The most important prognostic determinants for recurrence are tumor size, histologic grade, margin status, nuclear grade (aggressiveness of cell division), and hormone receptor status. Margin status is defined as the distance between the DCIS and normal breast tissue. The wider the margin, the more likely that all of the DCIS has been removed. In an attempt to give better prognostication for the risk of recurrence, pathologists have come up with various classification schemes. A highly recognized and internationally used classification is the “Van Nuys Prognostic Index” or VNPI. This classification was developed by Dr Melvin Silverstein and colleagues in Van Nuys, California. This index uses tumor size, nuclear grade, patient age, margin status and the presence or absence of necrosis (death of cells) to define risk categories. This classification will be discussed in more detail later. Critics of the classification scheme have pointed to the difficulties in determining margins in any lesion. This is a major challenge for pathologists. DCIS is mostly nonpalpable and a vague area in the breast so margin definition is very hard to quantify. It is argued that because of the size of DCIS and the vagueness of the lesion, and because of the economic issues imposed on the pathologists in their routine evaluation of patients, only 5% of all margins can realistically be examined under the microscope. There is nonetheless significant consensus that margin status is the single most important factor in determining the risk of local recurrence.
Adequate treatment of DCIS requires a “management team”. Radiologists, surgeon and pathologist form a critical triumvirate. If there is a weakness at any level, treatment may be inadequate. In the minds of some, all the benefits of adding radiation therapy and tamoxifen to surgery are to overcome the limitations of surgical skill and experience, and the problems of pathologic evaluation to define the extent of DCIS and the true status of the margin. Thus, treatment that includes the entire breast by using radiation therapy and/or tamoxifen helps to “clear up” disease possibly left behind by surgery. The imprecise nature of the pathologic evaluation of DCIS leaves a degree of uncertainty as to the treatment of residual disease. This uncertainty can then be circumvented by this use of radiation and tamoxifen. The benefits are clear in that occult disease can be treated. However, this potential “over-treatment” of disease raises significant problems in terms of overall patient benefit.
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Take-home Message #2:
As a patient, a critical question to ask your management team is whether they have a “Triple Test Conference” whereby all cases are reviewed routinely by a team of radiologists, pathologists and surgeons to ensure consensus around treatment. Ideally that meeting of those three disciplines and preferably also including medical oncology, must reach total agreement as to the adequacy of treatment and the relative reliability of radiology, pathology and surgery to ensure adequate treatment. This is an essential quality check for a patient.
The grade of the malignant tissue (histology) and the cells (nucleus in particular) helps define the aggressiveness of DCIS and its potential for recurrence in the breast. This aggressiveness and, therefore, the risk of recurrence can be divided into high-grade, intermediate-grade and low-grade DCIS. Estrogen and progesterone receptors are more likely to be positive in well-differentiated DCIS. This leads to a better prognosis. Patients with high grade DCIS tend to have estrogen receptor negative tumors that are also often positive for the HER-2/neu growth factor: the HER-2/neu oncogene. This growth factor, along with estrogen receptor negativity and pathologically poorly differentiated DCIS, adds to the increased risk of local recurrence. There is evidence that lower-grade lesions may be at risk for a later recurrence. This means that ultimate outcomes regarding DCIS must lead to a follow-up period for as long as 20 years and perhaps longer. Most recent data suggests that it is not only DCIS but the interaction with the surrounding support tissue (blood vessels, lymph vessels and stroma) that has an interactive role, adding to the risk of local recurrence. The importance of this interaction at a molecular level and the new understanding as to the assessment of risk of recurrence are only now being fully appreciated.
Take-home Message #3:
Patients should understand their pathology report fully and be informed of its contents in as clear terms as possible. At the minimum the patient should know the tumor size, tumor grade and margin status, and should keep a copy of their pathology report. Patients should also note where their tissue is kept and stored as that tissue may prove to be important later when an improved understanding of the molecular biology will help give greater insights into the reasons for the risk of local recurrence and the progression to invasive breast cancer.
III Ductal Carcinoma In Situ: Surgery
It has been shown that for invasive breast cancer, more extensive surgery does not increase cure rate. The removal of muscle, extensive lymph nodes and skin does not help prevent systemic or metastatic disease – in the truest sense, the “horse is already out of the barn.” Once breast cancer is invasive and leaves the duct, it encounters blood vessels and lymph vessels that can carry the cancer cells systemically and thereby produce metastasis. The paradigm in which more extensive surgery fails to lead to an improved survival does not apply to DCIS. We know, in fact, that if a total mastectomy is done (the breast alone), the cure rate for any type of DCIS, no matter the grade or size, approaches 100%. The question is not whether we can cure DCIS with surgery. The question is how little surgery can we do to save the breast without a significant risk to the patient for local recurrence. We know that a local recurrence carries with it not only a risk to the patient's breast but also some risk of becoming an invasive cancer which can threaten the patient's life. Mastectomy is still the treatment of choice for large and extensive DCIS, particularly in smaller-breasted women where good cosmesis cannot be achieved with breast conservation. Because there is a significant potential for nipple involvement with DCIS, it is not standard to save the nipple, although newer nipple sparing techniques are being studied. Because DCIS does not pose risk to the skin, an incision around the nipple that hides the scar in a natural line around the areola (the darker tissue around the nipple) - a so-called “skin sparing” mastectomy - can be done. This removes the breast tissue through a circumareolar incision (an incision around the areola). Reconstruction with either an implant or a patient’s own tissue (usually from the abdomen or back) can then be used to create a breast mound. Surgeons skilled in oncoplastic surgical techniques (breast cancer surgery using plastic surgical principles) are available to maximize the cosmetic result after mastectomy.
Take-home Message #4:
Patients should ask their cancer surgeon and their plastic surgeon if they are skilled with the skin-sparing technique, and in the use of oncoplastic surgical principles.
The axillary lymph nodes (armpit) do not need to be evaluated unless ductal carcinoma is associated with a mass, or the size and the grade suggest a higher risk of occult invasive disease. The sentinel lymph node biopsy technique should be used when possible to minimize any morbidity. Several studies have shown that positive-appearing cells can be found in as many as 20% of patients who have their axillary lymph nodes removed by using overly sensitive stains (cytokeratin). This results in misleading findings that may result in overly aggressive treatment (chemotherapy) for a disease that can be entirely cured by surgery alone. Only standard (H&E) stains should be used to avoid confusion. In other words, if there is no invasive cancer found in the breast, it is highly unlikely that any lymph nodes will be positive for metastatic disease.
A key surgical principle is for the surgeon to coordinate with radiology and pathology to ensure for adequate margins. The studies by Silverstein et al. suggest that ideal margins in the patients who want to avoid radiation therapy should be greater than 10 mm. For those patients proceeding to radiation, a 2-3 mm margin would appear adequate. For patients so motivated, immediate breast reconstruction after mastectomy is ideally suited to DCIS. It is important to understand that the patient has time to consider treatment options. Second opinions with oncologic surgeons and plastic surgeons can safely be secured prior to definitive surgical treatment. It is not uncommon for a patient to take up to a month to secure the appropriate opinions before proceeding to treatment. In some cases, particularly among those with a strong family history and with proven genetic mutations (BRCA1 and BRCA2), it is reasonable for a patient to choose mastectomy for DCIS, and prophylactic mastectomy to protect against the increased risk of an opposite-sided breast cancer. This may seem radical, but in some patients the risk for breast cancer in the opposite breast may exceed 50%, and surgical planning, both oncologic and plastic, will maximize the best cosmetic results and minimize surgical and anesthetic risk. Respect for both the physical and psychological needs of the patient must be paramount at all times.
Take-home Message #5:
Prior to any surgery (when the dye is cast) it is appropriate for additional members of your management team (geneticist and psychotherapist) to be fully integrated so that their recommendations can be considered by the patient in making the best short-term and long-term decisions.
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IV Ductal Carcinoma In Situ: Radiation Therapy
We have mentioned that mastectomy is curative in almost 100% of patients with DCIS. We also have noted that DCIS tends to be in one area of the breast (unicentric) or limited to one duct system. Often, however, there are skipped areas (multifocal DCIS) where islands of cancer cells are separated by normal tissue. This makes the removal of larger lesions much more difficult. So in order to avoid a bigger and more deforming surgery, there is logic to using radiation therapy to treat the entire breast to ensure the treatment of hidden disease. There are now three clinical trials which show a benefit in the addition of radiation therapy to lumpectomy for DCIS. In these studies all patients in the radiation-treatment group received whole-breast radiation. In companion studies tamoxifen was added, and again a benefit was shown in adding an additional therapy (tamoxifen to radiation) to further reduce the risk of breast cancer recurrence. Tamoxifen was also shown to decrease the development of an opposite-sided breast cancer.
So now the controversy! Does every person with DCIS truly need radiation therapy and tamoxifen? Is an 85-year-old the same as a 45-year-old? Is a 3-mm low grade DCIS at the same risk as a 3-cm high DCIS? Do both of these patients need radiation therapy? I believe that there is a consensus that these patients are not at the same risk. I also believe that there is a consensus that margin status is an important variable in order to determine that risk. There is, however, no consensus as to how to best define the subgroups of patients at risk. I was personally privileged to be part of studies by Silverstein et al. from Van Nuys and then University of Southern California, where the VNPI index discussed earlier was proposed. Tumor size, grade, margin status, necrosis and age were used as the five discriminates of risk. A scoring system of 4-12 using these parameters was determined by statistical methodology. The higher the score (10-12), the higher the risk of recurrence. The risk was high enough that even with radiation therapy the recurrence was over 50%, and in this subgroup of patients mastectomy was the preferred treatment. On the other hand, in patients with low scores (4-6) the risks were so low (less than 5%) that radiation did not add benefit. In the middle group of patients with scores of 7-9 there was improvement in local recurrence rate with the addition of radiation therapy. None of the patients in the “VNPI/USC” study routinely received tamoxifen. In an attempt to resolve the controversy regarding management, a study was launched at Harvard in 1994 using the Van Nuys criteria and defining patients in similar subgroups to the Silverstein studies. The Harvard study, however, had to be stopped because the initial results revealed a statistically significant increased risk of local recurrence in the patients who were not treated with radiation. Why do these discrepancies in results exist? Is it differences in surgery? Is it differences in pathologic interpretation? The answers to these questions remain an unknown and are an ongoing controversy. Of note, in the United States about one-third of all patients with DCIS have mastectomy, one-third have lumpectomy and radiation therapy and one-third have excision alone.
Take-home Message #6:
As a patient you should fully explore your risk of recurrence based on your age, the size of your DCIS, and the ability to get clear margins, and understand fully the consequences of treatment with and without radiation therapy.
We know that radiation complications exist, although these have diminished with modern radiation techniques. Risks to the heart, bone, lungs are, although present, extremely rare. In the past, a boost (extra doses of radiation therapy to the tumor bed) was used. This boost technique is no longer necessary for DCIS. Women who chose to have radiation gave up the option of a “second chance”, when the breast can still be saved in spite of a local recurrence. Also, women who have radiation essentially give up the option of reconstruction with an implant. Radiation changes to the skin make implant reconstruction problematic with poor outcomes including pain and deformity.
Take-home Message #7:
Ideally, along with keeping your pathology report, you should know how to calculate your Van Nuys Prognostic Index (VNPI). Two examples will help. An 80-year-old woman with a 1-cm low grade DCIS with surgical margins greater than 1 cm has a score of 4/12. According to the Van Nuys/USC data, the risk of recurrence would be less than 5% over 10 years without a benefit from radiation therapy. On the other hand, in the second example, a 38-year-old with a 5 cm area of high-grade DCIS with the presence of DCIS at all surgical margins would have a score of 12/12, with a local recurrence rate way above 50% in spite of radiation. That patient would be best treated with mastectomy with or without breast reconstruction.
Take-home Message #8:
A full disclosure describing all the issues and all the consequences of any treatment need to be discussed between the patient and her entire management team: “Know yourself and understand your disease.”
V. Ductal Carcinoma In Situ: Medical Management and Follow-up
The only drug proven to be effective in decreasing the risk of local recurrence in DCIS is tamoxifen. The benefit is significant but is limited only to patients whose tumors are estrogen receptor positive.
Take-home Message #9:
Your DCIS tumor should be tested for estrogen and progesterone receptors. This was not recommended until recently, and in some institutions DCIS is not routinely tested for these receptors. It should be. As a patient, be certain that this test was performed.
There is no convincing data about the benefit of tamoxifen in patients treated with excision alone. A small study from the United Kingdom did in fact fail to show a benefit to decreasing recurrence rate from the addition of tamoxifen in patients treated with excision alone. Tamoxifen does have side-effects, including hot flashes, vaginal discharge and dryness and, rarely, blood clots and uterine cancer. The benefits of tamoxifen may be minimal in some patients. For example, a 65-year-old with a very small low-grade DCIS treated with widely clear surgical margins may not significantly benefit from the use of tamoxifen, and in this case the risks may actually outweigh those benefits. Again “one suit may not fit all”. The assessment and recommendations regarding the use of tamoxifen are best made by the medical oncologist on your team.
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Take-home Message #10:
Discuss the use of tamoxifen fully with your management team. In this case, the addition of the medical oncologist is critical if you are to make an informed choice.
So, for any given patient, the management team may include radiologist, surgeon, plastic surgeon, radiation therapist, medical oncologist, pathologist, geneticist and psychotherapist.
There are new research trials using aromatase inhibitors (drugs that decrease estrogen in postmenopausal women only). These trials compare aromatase inhibitors to tamoxifen. We do know that aromatase inhibitors show superior effectiveness to tamoxifen in patients with metastatic disease and in patients treated for early invasive breast cancer. Similarly, aromatase inhibitors may be superior to tamoxifen in patients with DCIS. The aromatase inhibitors do not carry with them the risks of more serious side-effects such as blood clots or uterine cancer, but are known to cause increased risk of bone loss (osteoporosis and osteopenia). They also can cause an unpleasant muscle ache and joint pain in 25% of women. The subgroup of patients with estrogen receptor positive and HER-2/neu positive DCIS, representing less than 10% of all patients, may in particular be helped by aromatase inhibitors. This is a subgroup of patients in whom the resistance to tamoxifen has been demonstrated.
VI What is Appropriate Follow-up for DCIS?
There are two parts to the follow-up of patients with DCIS. Broadly speaking, there is follow-up of the breast and then, as in other types of breast cancer, there is the follow-up of other health issues directly impacted by the breast cancer. Women with DCIS who save their breasts should see either their surgeon and/or their medical oncologist at least once, and preferably two times a year. Personally I recommend that a professional caregiver (internist, gynecologist or radiologist) see the patient on an alternate six-month basis,and the surgeon or medical oncologist see the patient on the alternating six months. This assures that a skilled physician sees the patient at least two times per year. The patient should have a mammography at least once a year,and in some high-risk patients twice a year,on the treated breast,and once a year on the opposite side. There are circumstances where a medical oncologist may need to see the patient routinely on an every six-month basis.
Breast MRI may add benefit in demonstrating the extent of disease in high-risk patients, particularly those with a history of high-grade DCIS. The use of MRI in low-grade ductal carcinoma in situ is less well established. However, the routine use of MRI or breast ultrasound should not be considered standard of care to follow patients with DCIS. There are no laboratory studies including tumor markers (CEA, CA 15-3, CA 27.29) that play a role in the surveillance of DCIS.
The second part of follow-up incorporates other members of the care team: primary care physician or an internist, gynecologist, gastroenterologist and nutritionist. By and large, the women with DCIS will be cured, and as they age they will be confronted by other health issues. Some of these issues relate directly to the breast cancer experience. The gynecologist plays a role in monitoring the ovaries and uterus which can be at increased risk for developing cancer due to the breast cancer history. Young women with DCIS should not preclude consideration of future pregnancy. I routinely tell women who plan a pregnancy to have a mammogram as close as possible to the time of conception. Mammography is contraindicated as a routine in the pregnant patient. Because of the changes of breastfeeding, I routinely ask women to wait for at least three months after completing their breastfeeding in order to allow for good mammographic follow-up. In this case, however, there may be an actual delay in annual mammography, so I encourage considering the pros and cons of breastfeeding and the possible delay in diagnosing breast cancer in any woman who has had DCIS.
In perimenopausal and postmenopausal women with DCIS, consideration can be given to the use of vaginal and systemic estrogen. This is a more challenging and controversial decision in women with invasive disease. Here again, the integration of the merits of tamoxifen vs. estrogen require a full risk/benefit disclosure between the patient, gynecologist and medical oncologist. The recommended avoidance of estrogen in “all women with breast cancer” may be overly broad when applied to DCIS. In particular, the patient with DCIS who has significant quality of life consequences from menopause, including hot flashes, issues regarding sexuality, etc., may be considered for either vaginal or systemic estrogen.
Osteoporosis is an added risk and should be monitored by bone density testing in postmenopausal women on an every one- to two-year basis. Treatment for osteoporosis has vastly improved over the years, and bone health needs to be fully reviewed by either the primary care physician, internist or gynecologist, or medical oncologist. A coordinated medical decision regarding treatment, including the use of medications (bisphosphonates), needs to be decided between the appropriate physicians in the management team and the patient.
Some women with DCIS have a higher risk of colon cancer, and all patients with breast cancer should have full colonoscopy after age 50 and at a minimum every five years thereafter. Certain patients with even a higher risk of colon cancer (family history or history of precancerous polyps) need to be examined even more frequently, such as every three years. The medical oncologist following a patient with DCIS has the responsibility to ensure that proper cancer surveillance is coordinated either directly by themselves or by the patient's primary care physician. Multiple studies show a benefit to maintaining an ideal body weight. There is a direct correlation between obesity and breast cancer risk, and several studies show an independent benefit to exercise in reducing breast cancer risk. Because it is a part of general health issues, weight control and exercise are primarily the purview of the primary care physician or internist. As a medical oncologist I assume an oversight role to support a prudent diet, weight control and an adequate amount of physical exercise.
VI Ductal Carcinoma In Situ: The Future
It is likely that our understanding of DCIS will move to the molecular level. Genetic alterations within the tumor will be defined by existing and future technologies, and will help us better categorize the disease. Older classification systems based on tissue and cellular morphology such as the VNPI will give way to more precise definitions. We will learn about the progression from benign to premalignant to malignant disease in both DCIS and in invasive breast cancer. Understanding these molecular and genetic changes will lead to a better understanding of the entire malignant transformation. This in turn will help us develop “targets” for the prevention and for the treatment of disease at its earliest stage. Tamoxifen is only the first of a series of drugs that can be used in a preventative strategy that targets the estrogen receptor. There are proposed trials using Herceptin and other agents to target the HER-2/neu oncogene. There are preliminary studies that suggest that we may be able to find proteins and other elements in the blood that determine the presence of DCIS. Screening programs that incorporate MRI and blood testing with standard mammography appear within sight. Screening tests using breast tissue and ductal fluid may allow us to find the disease before it even manifests itself as true cancer, further decreasing breast cancer incidence.
Take Home Message #11:
This article demonstrates that in the management of ductal carcinoma in situ the following disciplines have a role to play: radiology, surgery, radiation therapy, medical oncology, genetics, plastic surgery, pathology, primary care, nutrition, psychosocial, OB/GYN, gastroenterology and preventive medicine. The integration of these disciplines into a coordinated, efficient and cost-effective system with the singular attention to excellence is in the very best interest of patient wellbeing, and truly represents “optimal care.”
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