Lately, it’s hard to keep pace with breast cancer advances. Innovative drugs—targeted agents, monoclonal antibodies, kinase inhibitors, cancer vaccines, hormone modulators and novel versions of old chemotherapies&mdash;are emerging so rapidly that patients, and even some doctors, may not be fully aware of new treatment options. For patients facing critical decisions, it’s worth knowing what’s out there and what’s headed to market.

For the women in the U.S. with metastatic breast cancer, some promising treatments include Halaven (eribulin), a newly approved synthetic substance that incapacitates dividing cells, and poly (ADP-ribose) polymerase (PARP) inhibitors, a group of drugs that block repair of single-strand DNA breaks.

While these drugs are being tested in a variety of tumor types, in the case of PARP inhibitors, some of the immediate benefit—and buzz&mdash;applies to their apparent activity in some women with metastatic, triple-negative breast cancer (TNBC).

Stephanie Robin of Boca Raton, Florida, is an energetic mother and fundraiser who has been living with breast cancer since she was diagnosed in 2004 at age 36.

After undergoing bilateral mastectomy with reconstruction and months of chemotherapy, her cancer came back in multiple lung spots in 2007. She received additional treatment cycles to no avail. A genetic counselor, who had determined that Robin harbors a BRCA mutation, encouraged her to enroll in a clinical trial with a PARP inhibitor.

The study explores how PARP inhibitors work in women with advanced breast cancer who have an underlying BRCA deficiency, says Mark Robson, MD, an oncologist and director of the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center in New York City. He’s taken care of Robin since November 2007, when she began taking the investigational PARP inhibitor, olaparib.

People who inherit mutations in the BRCA gene are prone to malignancies because that protein, when present, repairs double-strand DNA breaks. In normal cells, PARP handles single-stranded DNA nicks. The theory is this: together, these non-overlapping repair systems protect cells with damaged genetic material from dividing. If either mechanism is out-of-whack, chromosomal damage can be propagated and progressive, leading to malignancy.  If both enzymes are knocked out, the DNA-damaged cells can’t replicate, and they die—exactly what you’d want to happen to cancerous cells. But normal cells would not be affected since they have normal BRCA function.

“There are two general ways we might use the PARP inhibitors,” Robson suggests. First, they can enhance the effects of other agents. “A lot of drugs cause double-strand DNA breaks,” he explains. PARP inhibitors increase the burden of those breaks by neutralizing the ability of chemotherapy-exposed cells to repair genetic damage. This chemo-sensitizing effect may apply to many tumors; it might also be effective regardless of BRCA status.

The second mechanism applies to patients, such as Robin, who carry BRCA mutations, he says. “For this reason, PARP inhibitors are unlikely to work as single agents except in BRCA-deficient cases,” he says.

Robin is continuing treatment and says she feels fine. She flies to New York City periodically for CT scans and other evaluations for the experimental protocol. Still, she’s aware that many patients on the study, which is restricted to women with BRCA mutations, haven’t fared so well.

Kathy Miller, MD, a breast cancer specialist at Indiana University School of Medicine, has considered this question from an oncologist’s  perspective.  “What the experience has already made clear is that, while many of these drugs will be profoundly successful, they’ll probably be beneficial to just a small subset of patients,” she says.

In TNBC, typically tough to treat, the tumor cells lack estrogen receptors, progesterone receptors and HER2 overexpression, rendering them insensitive to hormonal treatments and drugs targeting HER2, such as Herceptin (trastuzumab).

TNBC cases account for approximately 15 percent of breast cancers and up to 20 percent for black women and younger, premenopausal women. As things stand, patients with metastatic TNBC have few treatment options apart from chemotherapy.

It’s for this reason that some trials of PARP inhibitors and the chemotherapy drug Halaven, reported at this past June’s meeting of the American Society of Clinical Oncology (ASCO), drew so much attention.

During the meeting, researchers reported on the intravenous PARP inhibitor iniparib and the results of a randomized trial of 116 patients with metastatic TNBC.  In the study, women received a commonly used chemotherapy combination regimen, gemcitabine and carboplatin, either alone or in combination with iniparib.

The clear results have since been updated to show that, for women with metastatic TNBC, the addition of iniparib bumped the response rate from 21 to 62 percent and lengthened overall survival from 7.7 months to 12.2 months on average.

The original iniparib trial looked very promising, Miller says. It generated lots of interest in PARP inhibitors, especially for women with triple-negative disease. But she cautions that it was a small study, and other trials so far have not yielded such positive results.

Everybody's been so fixated on the triple-negative breast cancer, but the benefits may be broader.

Some researchers have suggested that PARP inhibitors, because they impede a DNA repair pro- cess, might enhance the risks of secondary cancers from treatment. “We haven’t seen that,” Miller says. “But that theoretical risk might matter more as we use these drugs in the adjuvant setting as opposed to in patients with advanced disease.”

Patients with HER2-positive, metastatic breast cancer have some reason for hope that there may be another treatment with low toxicity because of a drug being studied called T-DM1.

While the data on T-DM1 are preliminary, results of a phase 2 trial released in October at the European Society for Medical Oncology generated enthusiasm among researchers there. At a six-month follow-up, the T-DM1 arm of the study had an overall response rate of 48 percent comparedto 41 percent in the trastuzumab (Herceptin) and docetaxel (Taxotere) arm of the trial. In addition, three of 67 women treated with T-DM1 had complete responses, compared to one of 70 given trastuzumab and docetaxel.

For those women with advanced, refractory breast cancer, the other up-and-coming agent that gained attention with a major ASCO presentation is Halaven. This intravenous drug, derived from the natural marine sponge product halichondrin B, works by crippling microtubules, which are essential to the intracellular scaffolding required for chromosome separation during division.

What’s interesting, says Christopher Twelves, MD, professor at the Leeds Institute of Molecular Medicine and St. James’s Institute of Oncology in the U.K., is that other cancer drugs, such as Taxol (paclitaxel), also bind to tubulin but in a different way. “In the laboratory, cancer cells that are not sensitive to Taxol can still be sensitive to eribulin [Halaven],” he says.

These drugs require us to think differently of breast cancer—as a group of related but very different diseases that happen to occur in the breast.

Twelves presented the clinical findings from a phase 3 open-label study of 762 patients with heavily pretreated, metastatic breast cancer.

In that EMBRACE trial, median overall survival was 13.1 months for patients who received eribulin and 10.6 months for those who didn’t. The drug extends life, on average, by 2.5 months.

Some critics are puzzled by the hype, but Twelves is enthusiastic about the findings thus far.

“Eribulin [Halaven] is more effective compared to other ‘real life’ choices for chemotherapy in terms of likelihood of shrinking the cancer, delaying its progression and also prolonging survival,” he says, adding that it’s the first drug to significantly prolong survival in women with such heavily pretreated disease.

In addition, he says, side effects, such as tiredness and a fall in blood counts, are generally no more troublesome than with other agents.

Miller, in Indiana, is cautiously optimistic about the PARP inhibitors and the growing understanding of breast cancer biology.

“These drugs require us to think differently of breast cancer—as a group of related but very different diseases that happen to occur in the breast.”

According to Miller, distinct breast tumors may need to be treated, diagnosed and even prevented differently.  In this context, it’s understandable that some patients, physicians and researchers are encouraged by large studies that demonstrate small benefits. Survival statistics don’t tell the whole story. For a small but significant fraction of patients, such as Robin, who is particularly sensitive to PARP inhibitors, and perhaps other outliers who respond to drugs for reasons unknown, the difference could be a matter of years.

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Features

Understanding breast cancer biology provides some new targets.

New Drugs, New Direction

The field of breast cancer has been a model for innovation and discovery. The earliest randomized trials were launched in the 1950s to study whether the first generation of chemotherapy could improve curability after surgery. Then the very “out-of-the-box” idea of less radical surgery was tested.

Decades later, the field remains a hotbed of studies to elucidate biomarkers and genetic changes that are the drivers of cancer—and new targets for therapy. We have made contemporary advances that are producing an immediate impact in the diagnosis and treatment of breast cancer. 

 will tell you, in our usual CUREstyle, about the basic and clinical science behind the new developments and why they make a difference.

In this supplement, you will learn how less invasive sentinel lymph node surgery is proving to be just as effective, with fewer side effects, as more invasive surgery. The latest surprise—that even a positive sentinel node might not necessarily require further node surgery&mdash;is still being discussed and interpreted.

The “less is better” concept now also involves radiation therapy, where only part of the breast or a shorter time of radiation therapy—even just one day at the time of surgery&mdash;may be an option in selected cases.

Improving cosmetic outcomes after breast surgery is the goal of a new fusion discipline called “oncoplastics,” where the skills of breast and plastic surgery are combined in one doctor. And nipple-sparing surgery offers women the chance to keep all their skin for reconstruction.

We are moving toward personalized medicine, with gene patterns of breast tumors guiding us as to the value of chemotherapy, and it appears that we can treat fewer patients with chemotherapy as we identify those who don’t stand to benefit and will do quite well with hormonal therapy alone.

The most challenging arena in breast cancer is still the management of patients with advanced metastatic breast cancer, where progress has been the slowest. Still, we are seeing stepwise improvements in survival with new chemotherapy and biological drugs. In this supplement you will learn about the elegant science behind PARP inhibitors and about a drug derived from a marine sponge  that has just been approved by the FDA.

The speed of research and change in practice are picking up. We invite you to read our choices about the advances that are having the biggest impact.

 issues, you will read other important stories that will continue to deliver hope to all those with the most common cancer in women—one that is becoming more curable and treatable every year.

Professor of Medicine, University of Southern &shy;California

Co-Leader, Women’s Cancer Program at the USC/Norris Comprehensive Cancer Center

Editor's Page

New directions in surgery, treatment and reconstruction are changing breast cancer.

Good news for women with breast cancer who have only one or two positive lymph nodes: a new study suggests they may be able to skip more invasive surgery that carries a risk of chronic pain, swelling and limited range of motion in the shoulder.

During the 2010 meeting of the American Society of Clinical Oncology (ASCO) in June, researchers produced the strongest data yet suggesting that women with one or two positive lymph nodes who kept their axillary nodes fared just as well as those who had multiple nodes removed in axillary node dissection.

“This is viewed as a practice-changing study,” says Marilyn Leitch, MD, a breast cancer surgeon at the University of Texas Southwestern Medical Center in Dallas and one of the study’s authors. “It is a major shift to take this leap,” Leitch says.

Doctors and patients alike are wary of leaving axillary nodes behind without assurances they are free of cancer. That’s because, when breast cancer spreads, malignant cells use the body’s lymphatic system as their own personal highway.

The first stops are the grape-shaped lymph nodes, which sit in bunches in the armpit and in other patches throughout the body. The lymph nodes are part of the body’s immune system, trapping bacteria, stray cancer cells and other harmful invaders. Each node connects to a system of channels that carries lymphatic fluid in the same way arteries and veins transport blood.

Much about a woman’s diagnosis depends on an assessment of the lymph nodes. After a cancer diagnosis, doctors use a dye or radioactive tracer to identify and remove the node or nodes in which the cancer is most likely to head first—the sentinel node&mdash;for testing to determine if cancer cells are present.

If the sentinel node shows no signs of cancer, it’s likely that the cancer has not yet spread. This means patients are spared a full node dissection. If just one or two nodes contain cancer cells, the meaning is less clear.

To be cautious, surgeons usually will go ahead and remove more than a dozen other nearby nodes, called the axillary nodes, on the chance that they, too, have collected cancer cells. But over the past decade, experts have questioned whether the removal of axillary nodes is really necessary when the sentinel node (or nodes if two are involved) is positive. New data now provide the strongest support yet for the idea of leaving axillary nodes untouched when only one or two sentinel nodes test positive.

In addition to the study released at ASCO, other data released this summer offers reassurance to what is now a standard approach of leaving the axillary nodes when the sentinel nodes do not show any traces of cancer. While data up to now have supported the practice of leaving the axillary nodes, the newest study is the most definitive so far, says Thomas Julian, MD, of the Allegheny General Hospital in Pittsburgh and the study’s co-author. “This nails the lid on the box,” he says. “When sentinel nodes are negative, you don’t need to take any more axillary nodes out.”

Taking out lymph nodes would not be such a dilemma if the surgery did not have the potential for serious consequences. The side effects aren’t life threatening but can profoundly affect a woman’s quality of life. With lymph nodes gone, the normal circulation of lymphatic fluid gets disrupted. This can lead to lymphedema, a condition that can result in persistent pain, swelling, numbness, tingling and a restricted range of motion in the shoulder (see "

In the future, fewer women may need to face that risk, according to the data released at ASCO. The research involved 891 women with one or two positive nodes who were randomly assigned to either sentinel and axillary node removal or sentinel node removal alone. All patients received whole-breast radiation. After five years, the survival rates for both groups were similar: 91.9 percent for those who underwent axillary node removal and 92.5 percent for those who did not. The likelihood of breast cancer recurrence in the breast at five years was also similar at 3.7 percent for those who had axillary node removal and 2.1 percent for sentinel node removal only.

Given these numbers, Leitch says, women with only one or two positive nodes should be told that skipping axillary removal is a realistic choice. “I think it’s a discussion that a surgeon has to have,” she says. “I think many people are convinced, myself included, that this is reasonable.”

et some surgeons still remain hesitant. “It’s a complicated issue,” says David Krag, MD, a surgeon at the University of Vermont College of Medicine. Krag points out that the study started in 1999 with a goal of enrolling 1,900 women—the number determined to have the statistical power needed to detect even small, but real differences in survival. The data presented this summer involved only about half that number, which weakens the confidence that the results are accurate, he says. “I think we’re still left with the question,” he says. The women in the study will continue to be followed for up to 10 years, important because local recurrences can occur up to five or 10 years later. It may be too early to make conclusions about this trial.

Data presented at the meeting on node-negative women found that, after an average of eight years, a full axillary dissection did not affect survival, but it did greatly increase the side effects in the affected arm.

 What is no longer in question, Krag says, is what to do for the three-quarters of women who do not have sentinel lymph node involvement. Data presented at the meeting on node-negative women found that, after an average of eight years, a full axillary dissection did not affect survival, but it did greatly increase the side effects in the affected arm. When it comes to women with clean sentinel nodes, he says, “the case is closed.” 

Sentinel node biopsy reduces complications of breast surgery.

When Less is Best in Breast Surgery

One of the primary goals of sentinel node biopsy is to reduce the need for axillary dissection to minimize a woman’s chance of getting lymphedema, a chronic buildup of fluid that occurs as a result of the body’s impaired ability to drain lymph fluid from tissue. Lymphedema, which can be managed but not cured, can leave a woman’s arm significantly enlarged, greatly affecting her quality of life.

According to statistics compiled by the American Cancer Society, the percentage of women who get lymphedema as a result of full node dissection and radiation ranges widely, from 6 to 48 percent. While studies concur that sentinel node biopsy reduces the risk of lymphedema, the rates vary depending on a number of factors, such as whether the woman received radiation. But it doesn’t eliminate the risk, says Wendy O’Rear, PT, a certified complete decongestive therapist at Presbyterian Hospital in Dallas.

The huge variation in statistics also reflects that whether someone gets lymphedema depends on a number of factors, including location of the tumor, body mass index, age, physical condition and other medical conditions that can contribute to unbalanced fluid levels in the body.

O’Rear treats women with lymphedema using complete decongestive therapy, which clears lymphatic pathways of fluid and decompress fluid-filled areas to allow the limb to return to normal or near-normal size. Patients then may use special compression garments to prevent the arm from re-swelling while learning exercises to help the arm eliminate fluid.

“Who gets lymphedema varies, and it’s multifactoral,” says O’Rear. “I have had women who had sentinel node surgery who swelled immediately, and then I have another patient who had surgery 38 years ago when they took all the nodes and followed it with radiation—and she just got lymphedema.”

Typically, O’Rear says, she sees fewer women with immediate problems if there were fewer than 10 nodes removed and there was no radiation. She emphasizes that it’s important for women to understand that the fluid in the tissue contains protein, which is inflammatory and produces scar tissue. When lymphedema is not controlled, it will increase in severity, she says. O’Rear emphasizes that women need to be vigilant for the rest of their lives and follow the guidelines from the National Lymphedema Network (

“We have had women tell us that someone told them that after five years they could begin getting blood pressure taken on the affected arm, and that isn’t true,” O’Rear says. In fact, she says, as women age and their tissue becomes more firm, particularly if they have had radiation, they can lose lymph function faster.

Content

One of the primary goals of sentinel node biopsy is to reduce the need for axillary dissection to minimize a woman’s chance of getting lymphedema, a chronic buildup of fluid that occurs as a result of the body’s impaired ability to drain lymph fluid from tissue.

Limiting Lymphedema

Surgery combined with radiation is standard treatment for local control of early-stage breast cancer. Studies show that a lumpectomy followed by whole-breast radiation offers women just as low a risk of local recurrence as a mastectomy. The exception may be in women over age 70 who have small, estrogen-positive tumors, since studies show equivalent survival rates for these women using hormonal therapy alone. 

Radiation also may improve survival in some cases of higher risk tumors, so some physicians are recommending radiation after mastectomy.

While the need to optimize radiation in local control is accepted, a number of trials are exploring new ways to deliver radiation in a shorter time as well as ways to help radiation pack more of a punch. For instance, boost radiation, an additional, focused course of treatment, has been shown in clinical trials to improve local control of breast cancer, says Terry Mamounas, MD, medical director of Aultman Cancer Center. 

Boost radiation typically is administered in the area where the tumor was removed for an additional week after six weeks of whole-breast radiation.

Another innovation is radiosensitization, where a substance, such as a drug, is used to make the tumor more vulnerable to radiation therapy.

“Boost is something we now routinely use,” Mamounas says. The trade-off, he adds, may be a little more fibrosis, scarring and hardening of the breast tissue in a small percentage of patients.

Preclinical research has indicated that use of the targeted breast cancer therapy Herceptin (trastuzumab) appears to make tumor cells that overproduce the HER2 oncogene more sensitive to radiation.

This theory is now being tested in a phase 3 clinical trial in patients with HER2-positive ductal carcinoma in situ.

Combining radiation and Herceptin has already been found to be safe in patients with invasive HER2-positive breast cancer, says Mamounas. Other drugs, such as Xeloda (capecitabine) and investigational biological drugs called PARP inhibitors, are being studied in this setting.

Other innovations in radiation therapy are aimed at improving convenience for the patient. One such approach is accelerated, whole-breast radiation, in which the course of treatment is streamlined from six weeks to three or four, with slightly higher doses administered. (Larger doses given in fewer appointments is known as hypofractionated radiation therapy.)

“There have been a number of studies that have proved for some patients that it’s as appropriate and effective, and shortens the course of therapy,” says Bruce Haffty, MD, medical director of The Cancer Institute of New Jersey. Research continues in this area, but guidelines for treating patients in this manner are being established.

Scientists are also evaluating partial-breast radiation that focuses on the area where the patient’s lumpectomy occurred.

While clinical trials are still enrolling women to look at the effectiveness of partial-breast radiation, a study released in a 2010 issue of 

 offered the results of a meta-analysis (a pooled analysis of numerous smaller clinical trials) comparing partial-breast radiation with whole-breast radiation that found no statistically significant difference between partial- and whole-breast radiation associated with death or distant recurrence. However, there was a stastically significant association between partial-breast radiation and increaed risk of local and axillary recurrence.

The study’s authors concluded that, while partial-breast radiation does not seem to jeopardize survival and may be used as an alternative to hole-breast radiation, the issue of locoregional recurrence needs to be further addressed.

Women considering possible radiation delivery options should talk with their surgeon and radiation oncologist about what’s known, what kind of factors are used to select appropriate candidates and whether any of the trial approaches result in  long-term or late effects.

The study also examined the effectiveness of another partial-breast radiation technique that involves implanting radioactive seeds in the lumpectomy cavity known as brachytherapy, or internal radiation. Strict guidelines as to who might be a candidate for partial-breast radiation outside of clinical trials have been established by the American Society for Radiation Oncology (ASTRO, see "

Guiding the Use of Partial-Breast Radiation

In the latest delivery option now being researched, women would wake up from surgery having completed their radiation treatment. A clinical trial presented at the 2010 meeting of the American Society of Clinical Oncology offered results for TARGIT, short for Targeted Intraoperative Radiation Therapy. In TARGIT, physicians give a single dose of radiation to the cavity where the tumor was removed from women undergoing lumpectomy for early-stage breast cancer while they are still in the operating room with the incision open.

The results of the 10-year clinical trial found that the single-dose intraoperative radiation treatment was both safe and effective and would save time and money for patients, who would wake from surgery having finished radiation, according to a press release from the University of California, San Francisco, the lead U.S. cancer center in the study.

While a number of breast cancer experts expressed excitement about TARGIT, an equal number cited issues with the study, including the cost and availability of the specialized radiation equipment in the operating room, the reduced  radiation received by the women undergoing TARGIT and the lack of long-tem follow-up.

Anthony Zietman, MD, professor of radiation oncology at Harvard Medical School and chair of ASTRO calls it “intriguing but still unproven.”

“Intraoperative only radiates the lining of the cavity where the cancer was,” he says. “What if there is cancer elsewhere in the breast?”

What everyone agrees on is that TARGIT will remain experimental until these questions are answered. As with other forms of partial-breast radiation, some centers are beginning to offer TARGIT for select patients based on age, tumor size, location, negative nodes and other factors. Apart from this, the standard of care in radiation remains whole-breast radiation except for women over aged 70 who have very favorable, early-stage disease.

Radiation techniques have been refined and shortened for women who qualify.

New Era for Radiation

The controversy over the use of accelerated partial-breast radiation (APBI) is reflected in the recommendations from the professional organizations that oversee radiation oncology and surgery.

The American Society for Radiation Oncology (ASTRO) issued its first-ever consensus statement in 2009 to provide guidance regarding the use of APBI outside of a clinical trial and to serve as a framework to promote additional clinical investigations into the optimal role of APBI in the treatment of breast cancer. The guidelines, which were written for clinicians, indicate that “conservative patient-selection criteria” be followed. Specifically, the guidelines offer a long list of criteria but exclude women with ductal carcinoma in situ (DCIS) and those who show multicentricity or multiple locations of tumor.

Those suitable, according to the guidelines, include women over the age of 60 with tumors smaller than 2 centimeters, pathologically negative nodes and positive estrogen-receptor status.

The American Society of Breast Surgeons has indicated that APBI can be used for women aged 45 and older who have either invasive or DCIS disease, tumors 3 centimeters or less with negative margins and a negative sentinel lymph node.

Both organizations recommend patients discuss the risk and benefit of the treatment with their radiation oncologist. The guidelines will certainly evolve as more data comes in.

Two innovative studies are showing that molecular profiling is not only changing the way we treat breast cancer but also how we can test new drugs faster. The I-SPY 2 and TAILORx studies are using the molecular and genetic make-up of a patient's breast tumor, a process called molecular profiling, to help figure out what drives an individual tumor, the likelihood of it returning and if it will respond to certain treatments, among other insights.

Researchers measure certain proteins and genetic factors, together called biomarkers, to better understand a tumor. Biomarkers can provide prognostic or predictive information, and sometimes both. Prognostic biomarkers provide information about the natural progression of the disease, such as the risk of recurrence or metastases, whereas predictive biomarkers offer insight into how a tumor would respond to a certain treatment.

The most well-known biomarkers in breast cancer are the estrogen receptor and HER2 protein, which dictate the type of treatment a patient receives, such as hormonal therapy or Herceptin (trastuzumab).

In addition to HER2 and hormone receptor status, physicians are increasingly looking to other gene profiles, including those tested by the Oncotype DX and Mammaprint assays, which are being used in the TAILORx and I-SPY 2 studies, respectively.

Oncotype DX, used mostly in the U.S., looks at 21 genes to help predict the risk of recurrence for early-stage, estrogen receptor-positive breast cancer, as well as if chemotherapy will help reduce that risk. Mammaprint, a 70-gene profile, looks at the risk of recurrence in node-negative breast cancer. However, because this assay requires fresh tissue, physicians must plan for the test before surgery, which has limited its use in the U.S. “Right now, we’re only using these assays to make a go or no-go decision regarding whether to recommend chemo,” says Joseph Sparano, MD, professor of medicine and women’s health at Albert Einstein Cancer Center-Montefiore Medical Center, but future research may hold the answer to many other treatment questions. “We  hope to have an assay in five to 10 years that can identify which patients can be cured by just surgery and don’t need any additional therapy.”

The I-SPY 2 and TAILORx studies are first steps toward that reality by making use of the two assays to help determine treatment in a subset of breast cancer patients, and also by changing how clinical trials are designed, which may help all cancer patients.

I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2) is unique because it’s testing several therapies—up to five experimental treatments&mdash;at a time. Twenty percent of patients are randomly selected to receive the standard of care, treatment they would receive outside a clinical trial. The other patients get standard care plus an experimental drug based on their tumor’s genetic profile.

Jane Perlmutter, PhD, lead advocate on the trial, says they will test eight to 12 drugs during the trial  by beginning with five initial investigational drugs including veliparib (a PARP inhibitor) and neratinib (HER2 inhibitor) with more being added as the trial progresses.

“It’s not only finding cures, it’s finding out which drugs aren’t going to help, and those things go hand and hand.”

Its adaptive study design also means researchers will be able to learn more, faster, Perlmutter says. The standard protocol in treating locally advanced breast cancer is to remove the tumor surgically and then follow up with systemic therapy to kill any remaining cancer. It may take years to know whether the treatment worked, as recurrence can take up to 10 or 15 years to become apparent. 

I-SPY 2 researchers, on the other hand, can identify benefit in months by giving patients drugs before surgery and then taking scans and biopsy samples throughout the trial. The biopsy samples are tested with Mammaprint and other assays to look for tumor biomarkers, such as those that indicate recurrence and those that predict a better response to specific drugs. 

The thinking is that a change in the size of the tumor or a biomarker during the weeks of therapy will show researchers if the drug is working against the tumor. If it's not working, they change drugs. After the course of therapy, the patient undergoes surgery to remove any remaining cancer. 

When a drug "graduates" with positive marks, information about the biomarker profile and the patients who responded to the drug—and those who didn't—may be enough evidence to test it further. If it doesn't look like the drug works at all, it's dropped and replaced with another one. 

"While we will not be able to get a definitive answer that will allow drugs to be used outside of trials, we'll have a lot of evidence on certain kinds of drugs and biomarkers," Perlmutter says. That evidence can be a springboard for future trials that produce real results. "It's not only finding cures, it's finding out which drugs aren't going to help, and those things go hand and hand."

Researchers hope that I-SPY 2 signifies a less expensive, quicker and more productive way to test cancer drugs. It could also encourage collaboration among research institutions and pharmaceutical companies—as shown by the number of different drugs being tested in one trial.

"Our hope is that this trial not only introduces new treatments for breast cancer patients but will really push the envelope in how clinical trials are conducted—including the use of biomarkers—so we can start making faster progress toward personalized medicine," says Perlmutter.

Researchers hope that another trial, TAILORx (Trial Assigning Individualized Options for Treatment), will answer the question of whether chemotherapy is needed for thousands of women diagnosed with breast cancer each year.

Although Oncotype DX can help determine risk of recurrence and response to chemotherapy, not every breast cancer patient needs it. It’s only useful in certain women who have estrogen receptor-positive breast cancer with little or no lymph node involvement. And, it’s typically only used when it’s not known through clinical or pathological features whether chemotherapy is warranted after the initial surgery and endocrine therapy.

If the trial shows some benefit [from chemotherapy], it will be very modest, and the next challenge would be to identify which patients in that group are really benefiting.

TAILORx is expected to release data in about five years and may answer that question by randomizing those with an intermediate score to receive chemotherapy or not, in addition to hormonal therapy. If the trial shows chemotherapy doesn’t offer any benefit to women who have a mid-range recurrence score, it could save as many as 20,000 women each year from unnecessary treatment, says Sparano, lead investigator of TAILORx.

“If the trial shows some benefit [from chemotherapy], it will be very modest, and the next challenge would be to identify which patients in that group are really benefiting,” he says.

Research already hints at that, namely expression of a gene called topoisomerase 2 (TOP2A). A study published in 

 in 2009 by Sparano and colleagues has suggested that patients with elevated TOP2A expression had double the risk of recurrence and would probably benefit from chemotherapy. “But we haven’t validated it,” Sparano cautions, “so it’s not something we can use right now.”

The second objective of TAILORx will help future molecular profiling studies. Every patient enrolled in TAILORx had tumor and blood specimens banked for future studies. This allows researchers to test other molecular profiles in the future without having to repeat a lengthy and expensive randomized trial.

In addition, another trial, MINDACT, is taking a different approach by comparing whether clinical features or molecular features more accurately predict benefit from chemotherapy. It is expected to complete enrollment in the next year.

These tests aren’t necessary for everyone. “They’re only useful in circumstances when there is uncertainty about what therapeutic decision to make,” says Sparano.

Currently, Oncotype DX and Mammaprint only focus on determining if a subset of breast cancer patients would benefit from chemotherapy. But the promise of molecular profiling could be realized for many more patients very soon.

“In the future we’ll see assays that may predict what patients benefit from Herceptin, endocrine therapy and, as other new therapies come out, who benefits from those therapies,” Sparano says.

Knowing the cellular basics drives treatment decisions.

Getting to the Core

At 59, Andrea Ziltzer’s mother was diagnosed with breast cancer. A year later, she died. Of course, there are no words to describe the agony of losing a mother, but in Ziltzer’s case, it also forced her to make several decisions regarding her own health.

The Westchester, New York, mother of two didn’t know whether her mother carried either of the two genetic mutations for breast cancer, BRCA1 or BRCA2, but she decided to be tested. She learned at age 45 that she carried the BRCA2 mutation.

Then she made another decision: to have a  preemptive prophylactic mastectomy. “Getting tested was a much harder decision to make than deciding whether to get a mastectomy,” Ziltzer says. “I was much more scared of cancer than any operation.”

After extensive research, Ziltzer picked a one-step, nipple-sparing mastectomy in which the breast tissue is removed and replaced with an implant. In traditional reconstruction, the nipple and areolar are removed and recreated.

The nipple-sparing surgery is still uncommon and lacks consensus among breast surgeons, but it is becoming increasingly popular among health consumers as they look for less invasive options.

The main concern of opponents revolves around the fact that the nipple complex is rich in breast ducts from which most breast cancers arise. What health professionals agree on is that the pool of candidates for nipple-sparing surgery is small and falls into three major groups:

 who are considering a mastectomy as a preventive measure.

 that are not located in danger zones near the nipple.

 have biopsied the breast tissue and determined that the locations of tumors do not pose risks for the nipple-sparing procedure.

Typically, the nipple and areola are removed along with the breast tissue for reconstruction because traditionalists worry about them harboring cancer cells. One study showed tumor cells in about 20 percent of mastectomy specimens done for breast cancer, but no tumor cells were found in cases of prophylactic removal. But in recent years, researchers have revisited the danger of cancer cells lurking in the nipples or nearby tissue—and whether the risk is low enough to leave them.

The results have been mixed. One study by the Cleveland Clinic found very low rates of recurrence in 149 nipple-sparing mastectomies it performed between 2001 and 2007. Another by the Memorial Sloan-Kettering Cancer Center had similar results, with doctors concluding that the procedure could lead to excellent results with the right candidates.

This has revolutionized reconstructive surgery.

The two- to three-hour operation, with the official name of “total nipple areolar sparing with direct-to-implant reconstruction,” is a process where implants are immediately inserted after the mastectomy, according to C. Andrew Salzberg, MD, a pioneer of the surgery and chief of plastic surgery at Dobbs Ferry Hospital in New York.

“This has revolutionized reconstructive surgery,” says Salzberg, who has done 800 procedures in the past nine years. “And it has made the decision of having a mastectomy much easier for some patients because they will know they’ll look just as good—or better&mdash;almost immediately.”

However, some physicians fret that the study groups have not been large or controlled enough to give the procedure a green light.

Sally Knox, MD, a breast surgeon at Baylor University Medical Center in Dallas, says she hasn’t adopted the procedure primarily because she hasn’t seen the need.

“We are doing areola sparing, and we can save the pigment, and the plastic surgeons build a nipple that looks great,” she says. “Why save the tip of the nipple where all the ducts converge if you are getting a good cosmetic result?”

Knox says that no sensation is saved in the nipple-sparing procedure, which means the only difference is that the woman is saving the nipple and has all her own skin for the possibility of an improved cosmetic appearance.

“Some surgeons will love it, and others won’t,” she adds. “The ladies should talk over the benefit and risk with their surgeons.”

Ziltzer says the initial recovery “was not a piece of cake.” But as the healing began, “it was absolutely manageable.” And even though the immediate post-surgery look is “really unattractive,” Ziltzer says it’s a process.

Eventually, she felt she looked better than before the mastectomy.

Surgeons disagree on whether nipple-sparing surgery has benefits.

Under Reconstruction

> There is still no consensus among doctors about nipple-sparing procedures.

> Nipple sparing is more accepted as prophylactic surgery for women at very high risk for developing breast cancer, or in cases where the tumor is small, away from the nipple and has other favorable features including negative nodes.

> The risk of recurrence and the long-term preservation of cosmetic results and sensation are not known.

> If you are interested in this option, be a good health consumer. Research your options and discuss them with your plastic surgeon and oncologist.

> An estimated 5 percent of women who get mastectomies choose the nipple-sparing option.

> Nipple-sparing mastectomy is typically covered by insurance, and it costs about the same as traditional reconstructive surgery.

> Online sources about nipple-sparing operations include Facing Our Risk of Cancer Empowered (

) and The Breast Preservation Foundation (

Things to know before deciding on a nipple-sparing mastectomy.  

Details of Nipple Sparing

The Internet offers numerous websites where you can find information, videos and even people to talk about all aspects of breast cancer. Be sure you research with care and gather information from reputable organizations, including those listed below. Those with the 

 indicate they have Spanish-language materials available.

 A voluntary organization that offers a variety of services to patients and their families. The ACS also supports research, provides printed materials and conducts educational programs. 

 (Formerly Y-ME National Breast Cancer Organization, Inc.) 

 Network of Strength serves women with breast cancer and their families through its national hotline (available 24 hours a day), open-door groups, early detection workshops and support programs. 

 A nonprofit website dedicated to providing the most reliable and complete information available. 

 The Dr. Susan Love Research Foundation works to eradicate breast cancer and improve the quality of women’s health through innovative research, education and advocacy. The foundation is recruiting for the Army of Women who will take part in research for all aspects of breast cancer.

FORCE: Facing Our Risk of Cancer Empowered

 FORCE provides support, information and resources for women with hereditary breast or ovarian cancer and for those at high risk of the disease.

Inflammatory Breast Cancer Research Foundation

 The foundation provides education, background, opportunities to be involved in clinical research and links to clinical trial information.

 LBBC provides educational materials, a calendar of events, a quarterly newsletter, a young survivors network and a toll-free helpline.

 Sisters Network seeks to increase local and national attention about the impact that breast cancer has in the African-American community. All chapters are run by breast cancer survivors and receive volunteer assistance.

Connects young Jewish women recently diagnosed with breast cancer with volunteers.

 A toll-free breast cancer helpline is answered by trained volunteers whose lives have been personally touched by breast cancer. Breast health and breast cancer materials are available. 

 The foundation’s mission is to raise awareness of triple- negative breast cancer and to support scientists and researchers in their efforts to determine the definitive causes so that effective detection, diagnosis, prevention and treatment can be pursued and achieved.

 YSC is the only international network of breast cancer survivors and supporters dedicated to the issues of women under 40 who are diagnosed with breast cancer. 

Resources

Women with triple-negative breast cancer, a cancer that does not respond to hormonal therapy or HER2-targeted drugs, are treated with chemotherapy and tend to have a high recurrence rate. Lately, many high-profile clinical studies have focused on this patient group, including one announced in October at the American Society of Clinical Oncology Breast Cancer Symposium.

Researchers revealed that a large percentage of women with triple-negative breast cancer have one of the BRCA mutations, which carry a high risk of breast and ovarian cancers.

Unfortunately, many triple-negative breast cancer patients aren’t being tested for a mutation. The study calculated that about 43 percent of the women who tested positive in the study for a BRCA mutation would not have been tested for the mutation under current guidelines, which only suggest BRCA testing for women with a family history of breast cancer or a diagnosis of triple-negative breast cancer who are under age 45.

But there’s also good news. The same researchers at M.D. Anderson Cancer Center in Houston also noted that the 77-woman study shows that patients who have BRCA mutation-associated breast cancer may have a lower risk of recurrence than patients without the mutation even though they have a much higher risk of a diagnosis of breast cancer. Of the patients with a BRCA mutation, recurrence-free survival at five years was 86.2 percent compared with 51.7 percent in patients without the mutation. Five-year overall survival was 73.3 percent versus 52.8 percent.

As the first study to consider BRCA mutation status in triple-negative breast cancer patients, its results further suggest the need for genetic testing in this patient population.

For years, the National Comprehensive Cancer Network, a non-profit alliance of 21 leading cancer centers, has released guidelines to help steer doctors in directing the best treatments for various types of cancer. In September, the organization released its first 

NCCN Guidelines for Patients: Breast Cancer

, written in understandable language for patients to learn more about breast cancer and its treatments.

The guidelines, which were funded by a $160,000 grant from Susan G. Komen for the Cure, are available at 

 with plans to also distribute hard copies of the guidelines. In addition, the NCCN also released patient guidelines for lung cancer. Patient guidelines for melanoma, colon cancer, prostate cancer and non-Hodgkin lymphoma are in the planning stages.

The National Breast Cancer Coalition has set a goal to end breast cancer in less than a decade in its Deadline to End Breast Cancer campaign. It compares curing breast cancer to President John F. Kennedy’s pledge to walk on the moon and the development of a polio vaccine—both completed in under a decade.

“Hope will not end breast cancer. We need a plan … We need a deadline,” states NBCC president Fran Visco in a video statement from the NBCC, “not the goal of a new drug or a new way to find cancer. The goal needs to be the end of breast cancer.”

News and perspectives from the breast cancer community.

Winter Supplement 2010 | CURE