By Monica Zangwill, MD

It’s not hard to find breast cancer survivors these days. A neighbor, a colleague, or your best friend perhaps—most of us know someone who has been treated for this disease, which is the most commonly diagnosed cancer in women. That so many women survive is a testament to current diagnostic and treatment methods that allow many women to jump on this disease quickly, conquer it, and continue to lead healthy and productive lives. Still, the dread of the word cancer and the fear of an unknowable future can knock a woman flat when first diagnosed.

Stephanie Gottesman, a 38-year-old mother of two young children, remembers the moment her doctor telephoned her. “I had just registered my daughter for kindergarten and it was dinnertime,” she recalls now three years later. “I get this call from the surgeon [who did the biopsy] and he says, ‘We’re very sorry, but we did find cancer.’ Well, I just fell apart.”

For Gottesman, and many others, her whole world changed in that instant. Her doctor explained that she likely had stage 0 breast cancer called ductal carcinoma in situ (DCIS), which is when there are cancer cells inside the breast ducts but no cancer is found in the surrounding fatty tissue or tissue lobules that make up the breast. Most often discovered by mammography and considered a precancerous condition by many, DCIS is rarely felt on breast examination, but it is quickly becoming one of the most frequently diagnosed types of breast cancers.

The American Cancer Society predicts more than 55,000 new cases of DCIS will be diagnosed in 2003 while there will be more than 211,000 diagnoses of all stages of breast cancer combined. Lobular carcinoma in situ (LCIS), which is also stage 0, refers to a sharp increase in the number, appearance, and abnormal behavior of cells contained in the milk-producing lobules of the breast (found within the lobes).

While LCIS (also called lobular neoplasia) is not considered cancer, its presence is considered a signal that breast cancer may develop later. According to the National Cancer Institute, a woman with LCIS has a 25% chance of developing some form of invasive cancer (either lobular, or more commonly, infiltrating ductal carcinoma). Women diagnosed with LCIS have a number of options that include close monitoring with regular clinical exams, screening, and mammography; taking a hormonal agent; or, in cases of strong history or anxiety, prophylactic bilateral mastectomy.

The other early-stage cancers are stage I and stage II. Ann Jennings was diagnosed with stage I breast cancer in March 1999.

“During a physical, my OB/GYN found a lump. He said it didn’t feel malignant but he still wanted to do an aspiration,” says the 37-year-old from Atlanta, Georgia. Jennings soon found herself having a biopsy that detected cancer. “I had never had a mammogram at that point, so I’m just glad my OB/GYN acted on the lump he found. I actually sent him flowers.”

In general, women with early-stage breast cancer have high survival rates, although the chance of the cancer coming back increases with the tumor size or number of involved lymph nodes.

The Initial Treatment: Facing the Operating Room
The goal of initial treatment, also called primary treatment, for DCIS and early-stage breast cancer is to surgically remove the cancer cells before they have time to grow larger and spread throughout the body. While at first this may sound simple, once women meet with their surgeons they quickly realize there may be several options open to them.

In most cases, the surgeon will also remove and examine some of the axillary nodes located in the armpit above the breast to determine if the cancer has moved beyond the breast. A procedure still being invesigated, called sentinel node biopsy (see CURE, Summer 2002), identifies the first node for removal.
Alice Mack, a 54-year-old mother of two, was treated for stage I breast cancer nine years ago. After the initial biopsy, her surgeon offered her the choice of a mastectomy, removal of the entire breast, or a breast-conserving surgery called a lumpectomy, which would remove only the tumor and surrounding tissue. Mack remembers, “It was really a hard decision to make.”

While a mastectomy removes the entire breast, it ensures the cancer is fully removed. But with a lumpectomy or other type of breast-conserving surgery (see sidebar), there may be a small risk that the surgeon will not get all the cancer and the patient will have to return to the operating room for a mastectomy.

To date, there is no definitive answer regarding which option is better in terms of survival because both procedures have a similar cure rate. The choice of surgery, depending upon a woman’s breast shape, tumor size, and whether there are indications of more than one site of cancer in the breast, also may affect her options for breast reconstruction and how she looks after surgery. After considering all these factors, Mack opted for a mastectomy, while Gottesman and Jennings chose lumpectomy.

In the Operating Room: Removing the Cancer
To make sure all the tumor is taken out, pathologists examine the removed breast tissue under the microscope after surgery. If no cancer cells are found in the healthy tissue surrounding the tumor, the surgeon has gotten a “clean” margin and removed the whole cancer.

However, sometimes this is hard to do in the operating room, says Hernan Vargas, MD, breast surgeon, Harbor-UCLA Medical Center, Torrance. He explains that in the operating room, removing the cancer is like trying to cut the filling out of a piece of ravioli. If the filling is the cancer and the pasta is the clean margin, the surgeon takes out the piece intact to see what’s inside, he says. “[But] you don’t know how close or far that margin is,” he says. So, during the operation, surgeons use ultrasound and X-ray techniques to help them locate the cancer.

After Gottesman’s lumpectomy, she was told that not all the cancer cells were removed. “The surgeon said she really needed to do a mastectomy,” Gottesman says, and so she returned to the hospital a few weeks later for another operation.

“There is certainly room for improvement [in surgical techniques],” says Dr. Vargas, considering cases like Gottesman’s. Since surgeons would like to target the cancer cells more directly and women who want breast-conserving surgery can’t always get it, Dr. Vargas and other physicians are looking for better ways to eliminate breast cancers.

In fact, Dr. Vargas and his colleagues recently completed a phase I trial using microwave radiation to destroy cancer cells with heat. The results were promising, with a high incidence of clean margins, and larger trials are currently under way.

Other investigators are looking at ways to get to the cancer cells by using methods such as ultrasound, lasers, or freezing the cancer cells. Dr. Vargas hopes these types of treatments that can directly target the cancer cells without cutting the skin will replace the need for breast surgery in the future.

Radiation Treatment For DCIS
For women with stage I or II cancer who choose breast-conserving surgery instead of mastectomy, there is strong evidence that radiation of the remaining breast tissue after surgery reduces the chance of recurrence. But the need for radiation treatment after breast-conserving surgery for DCIS is not as clear.
Melvin J. Silverstein, MD, breast surgeon, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, says if a patient with DCIS is at low risk for recurrence, she may be able to forgo radiation therapy. “The single most important [determining] factor is margin width,” he says. If the surgeon can remove the cancer cells and a wide area of healthy breast tissue surrounding them, thereby achieving a wide margin, the risk that the cancer will come back is lowered, he says.

Predicting the risk of recurrence also involves other important factors including the size of the tumor, how the cancer cells look under the microscope, and the age of the patient. Considering all of these factors, Dr. Silverstein recommends radiation treatment to patients at medium or high risk, but not necessarily to patients at low risk of recurrence.

Choosing postoperative therapy
For stage I and stage II cancers that are true invasive cancers and therefore have a higher chance of recurrence than DCIS, oncologists generally recommend adjuvant therapy after the initial surgical treatment. The goal of adjuvant therapy is to decrease the chance of relapse. Adjuvant therapy for early-stage breast cancer may include hormone therapy, radiation therapy to the lymph nodes or chest wall, and/or chemotherapy.

Figuring out who should receive adjuvant therapy can be complicated, says Eric Winer, MD, director, Breast Oncology Center, Dana-Farber Cancer Institute, Boston. In general, oncologists encourage adjuvant therapy for patients who have a risk of recurrence. To predict that risk, says Dr. Winer, oncologists look at several factors, including the size of the original tumor and whether or not the disease had spread to the lymph nodes. Whether the tumor cells had receptors for the female hormones estrogen or progesterone could also be considered a factor in choosing the type of treatment.

Once all the information is available, physicians and women need to discuss the options. “It really is an in-depth conversation with the patient to decide whether the side effects and risks of chemotherapy are worth its benefits,” Dr. Winer says. “Decisions need to be individualized.”

Doctors offer hormone therapy to women whose excised tumors had receptors for the hormone estrogen, in an attempt to block this hormone’s growth-promoting effects on breast cancer cells. The drug Nolvadex® (tamoxifen) blocks estrogen and decreases the likelihood of the cancer coming back. It has few side effects, although it can cause hot flashes, mood swings, and, on rare occasion, blood clots or uterine cancer. Other hormone-blocking drugs being studied for early-stage breast cancer are Fareston® (toremifene), Faslodex® (fulvestrant), and the class of medicines called aromatase inhibitors (see sidebar).

Oncologists are particularly excited about an aromatase inhibitor called Arimidex® (anastrozole). In a large, randomized study, Arimidex was found to be more effective than tamoxifen at preventing recurrence after surgery for postmenopausal patients with early-stage disease, and has received FDA approval for this indication.

Premenopausal women may have other options for hormone treatment. Since premenopausal women release female hormones from their ovaries, oncologists are studying the effectiveness of ovarian suppression. Particularly for women who had tumors with estrogen receptors, ovarian suppression is increasingly but cautiously being considered as an alternative to chemotherapy, says Dr. Winer. He notes there are large international studies currently under way that are examining the role of ovarian suppression, either by surgically removing the ovaries or by using drugs called luteinizing hormone-releasing hormone (LHRH) analogues, such as Lupron® (leuprolide) or Zoladex® (goserelin).

“Within the next five to eight years, we will have a much better understanding about how to use this [type of hormone] therapy,” Dr. Winer says.
Women who have a higher risk of relapse or whose tumors do not show female hormone receptors might receive chemotherapy. Chemotherapy might also be given in addition to hormonal therapy for women at high risk of relapse.
For women who had no breast cancer in their axillary lymph nodes (node-negative disease), the most commonly prescribed chemotherapy regimens include CMF (Cytoxan® [cyclophosphamide], methotrexate, and 5-FU [fluorouracil]; FAC (5-FU, Adriamycin® [doxorubicin], and Cytoxan); or AC (Adriamycin and Cytoxan). However, CMF has been used less often in recent years.

In women with a higher risk of disease recurrence, such as those who have positive axillary lymph nodes or other unfavorable features, the most commonly prescribed regimens include FAC, CEF (Cytoxan, Ellence® [epirubicin] and 5-FU), AC followed by Taxol® (paclitaxel), or TAC (Taxotere® [docetaxel], Adriamycin, and Cytoxan).

All of these drugs have side effects. Most of them cause temporary nausea, fatigue, hair loss, and a drop in white blood cells, which makes patients more susceptible to infection. Side effects can include infertility or possible cognitive dysfunction. And Adriamycin may cause heart damage, but these cases are rare. Dr. Winer says choosing a chemotherapy course requires a balance of risks and benefits.

After deciding on a course of chemotherapy, going through it can bring on renewed apprehension. Nine years later, Mack still remembers the physical impact of chemotherapy. She says she was queasy most of the time and very fatigued. But losing her hair was the most difficult psychologically. “That was very hard,” she says. “It was a crummy year.”

Physicians do know that undergoing chemotherapy is tough. However, there are still not a lot of alternatives, says Dr. Winer. “Although several years ago we all thought that we would have lots of new therapies and that chemo would be passé, unfortunately we still don’t have a tremendous number of new therapies,” he says. So he and other investigators are working hard to figure out how to give chemotherapy in an effective manner and in a way that minimizes side effects.

Every Woman is Different
Early-stage breast cancer is clearly survivable but in the midst of it all—the treatments, the decision-making, the emotional upheaval—fear and anxiety may dominate. Gottesman remembers, “Somebody once asked me, ‘When do you get over this?’ And I said, ‘Well, you don’t really get over it. It’s always looming overhead. But you know this is a battle you’ve conquered.’”