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From OncoLog, January 2010, Vol. 55, No. 1

Graphic: Compass Compass, a quarterly supplement to OncoLog, discusses cancer types for which no standard treatment exists or more than one standard treatment is available. Our goal is to help readers better understand the nuances of management for such diseases and the variables that MD Anderson specialists consider when counseling patients about treatment alternatives.

Ductal Carcinoma In Situ
Choosing Treatment for a Common Group of Early, Confined Breast Cancers

Overview

By definition, ductal carcinoma in situ (DCIS) is a cancer arising from and pathologically confirmed to be confined to the terminal duct lobular units of the breast. It is therefore considered a noninvasive breast cancer. Each year in the United States, about 64,000 women are diagnosed with DCIS, representing 30% of women diagnosed with breast cancer.

Three decades ago, DCIS was found in patients relatively rarely, typically co-existing with invasive cancers in mastectomy specimens. In the even rarer instance in which a patient presented with clinically evident DCIS—a palpable mass or nipple discharge—she was treated with mastectomy.

Today, it is still unusual for DCIS to present symptomatically; approximately 90% of these cancers are discovered as microcalcifications on mammograms. Not coincidentally, the incidence of DCIS has risen dramatically since screening mammography became common. Indeed, finding small, early, and treatable breast cancers is the goal of such screening. “We consider it a bonanza when we find a very tiny breast cancer,” said Wei Yang, M.D., an associate professor in the Department of Diagnostic Radiology at The University of Texas MD Anderson Cancer Center. “When breast cancers are larger or symptomatic at diagnosis, the treatment options are different.”

DCIS is not an immediately life-threatening cancer, and by definition it is not an invasive cancer. Experts have even begun to question whether it should be called a carcinoma. Nonetheless, DCIS is almost always treated as if it is an invasive carcinoma: standard treatments include mastectomy or breast-conserving lumpectomy with or without radiation therapy—treatments derived from studies not of DCIS but of invasive cancers.

When DCIS is treated according to current standards, the 10-year overall survival rate is nearly 100%. DCIS is, however, associated with an increased risk of invasive breast cancer. According to Banu Arun, M.D., an associate professor in the Department of Breast Medical Oncology, when a woman is diagnosed with DCIS, her risk of developing invasive breast cancer in either breast increases two to four times.

In addition, DCIS does recur, and some recurrences progress to invasive cancer. Recurrence rates vary according to the aggressiveness of the initial treatment: women treated with lumpectomy have higher recurrence rates than those treated with mastectomy, and women treated with lumpectomy alone have higher recurrence rates than those who receive lumpectomy with radiation.

When DCIS recurs and remains noninvasive, survival rates are the same as for women who have an initial DCIS occurrence, and DCIS that becomes invasive confers a similar mortality risk as other initial occurrences of invasive cancers. This is because most recurrences are discovered early with proper surveillance.

Just as only some DCIS lesions will progress to invasive cancer, some will remain clinically irrelevant—an estimated 14%-50% would become invasive if left untreated, according to Henry Kuerer, M.D., Ph.D., a professor in the Department of Surgical Oncology. Hence, it is reasonable to postulate that current standards result in overtreatment for some women with DCIS. Currently, all women with DCIS undergo surgical excision of the tumor or the whole breast, followed by radiation therapy for some women.

Is it possible that some DCIS could be left alone or treated with a chemopreventive agent (one that prevents or delays invasive progression) instead of surgery? Given that the goal of cancer screening is to identify early treatable cancers, it is difficult to propose doing nothing when such cancers are found and difficult to mount clinical trials in which women would forego a known curative treatment.

The answer to the question, then, lies in learning more about the biology of DCIS and identifying biologic markers that are predictive of its behavior: will it progress to an invasive cancer, or will it lie indolent for many years as an in situ lesion, or will it perhaps remain forever harmless?

Like invasive breast cancer, DCIS is not one entity but a heterogeneous group of at least four subtypes, and intratumoral heterogeneity (mixed histologies within a lesion) may be observed. Thus, the clinical behavior of DCIS varies. Furthermore, because known DCIS has always been treated, little is actually known about its natural history. Dr. Kuerer believes that the ability to predict which DCIS will progress to invasive cancer is paramount to developing individualized therapies, and current research initiatives are likely to have a significant impact on treatment paradigms for this disease.

Toward Tomorrow

Even though DCIS is now diagnosed in 64,000 women a year, little is known about the natural history of the disease. The few clinical trials in DCIS are old and do not account for all the patient risk groups that can be meaningfully stratified with the sophisticated tools available today.

One of the bigger questions about DCIS is which ones will progress to invasive cancer. Treating all DCIS has resulted in a low disease-related mortality rate, yet surely some of those women have been overtreated, said Henry Kuerer, M.D., Ph.D., a professor in the Department of Surgical Oncology at MD Anderson. “We currently have what I consider a national epidemic of women requesting bilateral mastectomies—a 4- to 5-fold increase in recent years—when they are diagnosed with breast cancer, including many with DCIS,” Dr. Kuerer said, speaking to the fear that is associated with a cancer diagnosis. “We need to know more about DCIS so we can better counsel and reassure patients about their actual risks.”

Toward that end, several research initiatives targeting DCIS will be part of a new MD Anderson collaborative called the DCIS Discovery Enterprise. The mission will be to prevent invasive disease while also reducing unnecessary surgery or radiation.

Among the research initiatives in the Enterprise:

  • Genetic expression profiling and study of molecular characteristics that distinguish lesions at high risk of invasive progression from clinically irrelevant lesions. Previous studies have shown that different subtypes of DCIS may follow different progression pathways. A better understanding of these pathways and their genetic and molecular markers will enable clinicians to select targeted treatments or active surveillance.

  • Investigation of neoadjuvant (preoperative) treatments that may achieve disease regression, stabilization, or elimination as detected by modern imaging. Studied agents will include tamoxifen and aromatase inhibitors for ER-positive tumors. Studies of agents for ER-negative DCIS will include a phase II trial of lapatinib for HER-2-positive or epidermal growth factor receptor (EGFR)-positive tumors. Other non-endocrine agents that warrant study include COX-2 inhibitors, retinoids, and tyrosine kinase inhibitors such as trastuzumab. According to Dr. Kuerer, a recent study at MD Anderson showed that one intravenous dose of trastuzumab can induce a strong immune response in patients with DCIS. “This opens the door for a potential preventative agent for invasive breast cancer, he said. “And as DCIS is a local phenomenon, image-guided local therapy using trastuzumab may prove even more effective than systemic intravenous delivery.” Vaccines will also be investigated.

  • Creation of a multi-institutional DCIS renewable bio-repository that will be linked through information technology with translational science and clinical outcome data. This tissue- and case information-sharing cooperative, believed to be the first of its kind, will advance and facilitate the studies of tumor characteristics and risk profiling.

In the future, women diagnosed with DCIS will have more treatment options. Some may be told their lesions require no treatment at all. Still others may undergo less invasive and life-changing treatments than they do today. And, investigators hope, those patients who do require more invasive or life-changing treatments will be confident that such measures saved them from a deadly disease.

Treatment Approaches
Evaluation

When a DCIS lesion is discovered, the next task belongs to the diagnostic radiologist. “Additional imaging is crucial to help the treating physician delineate the extent of disease, optimize treatment, and ultimately reduce the risk of a local recurrence,” Dr. Yang said. “Additional imaging is used to determine whether other possible disease foci are present in either breast, to precisely map their size and location three-dimensionally, and to determine their proximity to the nipple-areolar complex and their distance from overlying skin in order to ensure the best surgical outcome.” The size and location of disease foci dictate the area or areas to be biopsied and also have implications for treatment choices. Currently, mammography of both breasts is the imaging method of choice for women diagnosed with DCIS, particularly those who present with mammographic calcifications.

Once the biopsy targets are identified, a close collaboration between the radiologist and breast pathologist begins. During image-guided biopsies, clips may be placed to accurately mark the lesion for subsequent excision. Digital radiographs of removed specimens are annotated to confirm that targeted calcifications have been removed and to provide correlation with the pathologist’s findings.

Constance Albarracin, M.D., an associate professor in the Department of Pathology, said radiologic/pathologic concordance of findings is critical. The pathologist’s goal is to determine histologic makeup and whether the carcinoma is truly in situ or contains any invasive component. Estrogen receptor (ER) status is also noted.

At MD Anderson, intraoperative analysis is provided to the surgeon by both the pathologist and the radiologist. Removed tissues—both en bloc and sliced specimens—are examined by the pathologist and also imaged intraoperatively to determine whether an adequate tumor-free margin has been achieved. Intraoperative collaboration between the surgeon, pathologist, and radiologist has been shown to reduce the rate of second surgeries from 50% to below 20%, and it is where Dr. Albarracin feels she has the greatest personal impact on patients’ lives. “It’s not always possible to avoid a second surgery—sometimes we find things on permanent sections, after surgery, that could not be detected during surgery,” she said. “But when we can advise the surgeon that a larger margin is needed during the operation, we spare the patient and her family or caregiver the time, expense, and worry of another operation.”

After surgery, permanent pathologic analysis of removed specimens is performed, and again, concordance between radiologic and pathologic findings is essential.

Mastectomy vs. lumpectomy

Few absolute medical considerations indicate mastectomy over breast-conserving lumpectomy. But the decision may be influenced by numerous factors, many related to risk or personal preferences:

• Tumor size and location

According to standard guidelines, lumpectomy is usually not advisable when a tumor-free surgical margin is not possible. Adequate margins are considered an important predictor of recurrence risk. Although recommendations about acceptable margins vary, most studies have shown significantly fewer recurrences when the margins are negative.

Lesions that are large in proportion to breast size may leave a significant defect. For DCIS that encompasses more than a quarter of the breast, mastectomy with or without immediate breast reconstruction may be the better choice for cosmetic reasons. Lumpectomy or removal of just a portion of the breast is not feasible in women who have cancer in multiple regions of the breast.

• Need for radiation

Radiation therapy is not required after mastectomy for DCIS, but whole breast irradiation after lumpectomy for DCIS has been shown in numerous studies to reduce recurrence rates by as much as 50%. (Currently, partial breast radiation given only to the breast region where the cancer is located and given over a much shorter 5-day period is being tested in clinical trials as an alternative to whole breast radiation.) However, according to Dr. Kuerer, women who have small, unifocal, low-grade tumors that can be excised with wide margins (at least 10 mm) have a low risk of recurrence and may reasonably forego radiation.

For other patients, the likelihood that radiation would be needed after lumpectomy must be considered before the choice of surgery is made. If radiation is likely to be needed, then women who are unable to undergo radiation therapy for any reason would not be candidates for lumpectomy. This includes women who have had previous radiation to the chest, women who are pregnant during the time radiation would be given, or women who have severe scleroderma or another confirmed severe active connective tissue disorder that may render tissues more sensitive to radiation.

Further, some women are unable or unwilling to undergo daily radiation treatments for several weeks. If reconstruction will be necessary, it will be best accomplished with autologous tissue, and therefore women for whom implant reconstruction is preferable might opt for mastectomy rather than lumpectomy.

• Recurrence risk factors

Although neither tumor histology nor size represents an absolute indication for mastectomy, higher recurrence rates are associated with tumors that are large, high grade, ER negative, or HER-2/neu positive and those that have comedo-necrosis. No specific architectural pattern or histology has been proven predictive of whether recurrence is more likely to be DCIS or an invasive breast cancer

Patient age is not a decisive recurrence risk factor but is considered. Young age (< 40 years) has been associated with a higher risk of recurrence in at least two large studies; the findings do not mean that younger women are not candidates for breast-conserving surgery but may suggest that younger women would derive greater benefit from radiation, according to the American College of Radiology.

There is no conclusive evidence that family history predicts for recurrence. However, women who have undergone genetic testing and are found to carry a BRCA mutation are at a significantly higher risk of invasive breast cancers, and many such women who develop DCIS are now opting for bilateral mastectomies.

• Patient perceptions and preferences

Finally, Dr. Kuerer pointed out that the choice of treatment is a very personal one, and numerous psychological factors may contribute—among them, fears about radiation treatment, the desire for minimal disruption of body image, and fear of recurrence—and which of those emerges as the most important varies among individuals. Some patients choose breast conservation because they view it as the least disruptive and invasive option. For others, the choice of mastectomy is based on their perception of risk—they believe that mastectomy provides the best chance of “getting rid of all of it.” However, the perception of risk is something that requires physician-patient counseling: it is important for patients to understand what their risk actually is. “To say that a treatment lowers risk by 50% is not altogether meaningful if that risk was only 2% in the first place,” Dr. Kuerer said. “We need to determine which patients are actually at risk of invasive progression—it may be very few—and which might need no therapy—it may be as high as 30%–40%. This is where our research efforts must focus.”

Sentinel Node Biopsy

As DCIS is, by definition, confined, sentinel node biopsy is rarely necessary. However, postoperative pathologic analysis sometimes reveals an invasive component. In patients whose DCIS has an invasive component, lymph node status is very important. “Theoretically, in pure DCIS, no lymph node involvement would be expected,” Dr. Albarracin explained, “but in reality there will be lymph node involvement in a very small percentage of patients.” She believes this is more likely when a DCIS is large or high grade.

Mastectomy renders sentinel node mapping in a subsequent operation impossible if invasive cancer is also identified; in such cases, postoperative staging of the lymph nodes would require axillary dissection, a procedure associated with significant morbidity. Thus, at MD Anderson, sentinel node mapping is recommended during initial surgery in patients who have mastectomy.

Pathologic analysis of sentinel nodes is carried out intraoperatively on frozen sections. “If metastatic invasion is verifiable at that time, axillary dissection is carried out. However, if pathologic results are uncertain, we wait for the more reliable postoperative permanent section analysis before proceeding to axillary dissection,” Dr. Albarracin said. Frozen sections can contain artifacts, such as ice crystals, owing to the high water and fat content in the specimen. Permanent specimens are sliced more thinly and analyzed with immunohistochemical staining, which makes it possible to see single cells and arrive at a more definitive judgment.

Adjuvant therapy options

Since DCIS is, by definition, a localized disease, systemic chemotherapy is not part of the treatment. “However, even if the patient’s disease is treated adequately by surgery and/or radiation, her risk of future breast cancer is higher,” Dr. Arun said. “For some patients, this suggests a role for adjuvant therapy, which is not a treatment but rather a risk-reduction measure.”

Therefore, the possibility of adjuvant therapy with tamoxifen should be discussed with patients whose DCIS has positive ER status. Studies have shown a significant small absolute reduction of recurrence risk within the treated breast associated with tamoxifen as an adjuvant chemopreventive agent for ER-positive DCIS. Tamoxifen can also decrease occurrences of contralateral invasive and noninvasive breast cancer.

Despite such findings, Dr. Arun said that only about half of women with DCIS who are eligible to consider tamoxifen actually opt to take it. “This is likely because their risk is relatively small, and the drug does have side effects,” Dr. Arun said.

In addition, there are no agents available for the prevention of ER-negative breast cancers. “Therefore, we are studying other agents to address ER-negative cancers and to identify chemopreventive agents with lower toxicity profiles,” Dr. Arun said. Agents under investigation include COX-2 inhibitors, retinoids, tyrosine kinase inhibitors, and statins.

Contributing Faculty
The University of Texas MD Anderson Cancer Center

Photo: Dr. Constance Albarracin

Constance Albarracin, M.D.
Associate Professor, Pathology

Photo: Dr. Banu K. Arun

Banu K. Arun, M.D.
Associate Professor, Breast Medical Oncology

Photo: Dr. Henry M. Kuerer

Henry M. Kuerer, M.D., Ph.D.
Professor, Surgical Oncology

 

Photo: Dr. Wei Yang

Wei Yang, M.D.
Associate Professor, Diagnostic Radiology

 

For more information on this topic or for questions about MD Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

Other articles in OncoLog, January 2010 issue:

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