Beyond Genetics: Emerging Breakthroughs in Breast Cancer Battle

It has been 15 years since researchers discovered that mutations in the BRAC1 and BRAC2 genes predispose some women to certain breast and ovarian cancers and 10 years since trastuzumab (Herceptin) became a cornerstone of treatment for women with HER2-positive breast cancer.

Such discoveries paved the way for more scientifically advanced approaches to breast cancer; whereas, oncologists once selected a treatment based on clinical presentation and hoped for the best, these days they can often tailor treatment to a patient’s particular circumstances. This has transformed the diagnosis of breast cancer from a sentence of early death or disfigurement to a disease that, although serious, is often manageable with the appropriate treatment.

While researchers have supplied more answers, they have also generated more questions as their

attempts to fine-tune the diagnosis and treatment of breast cancers have uncovered new complexities about the nature of this disease, including the discovery of breast cancers that are resistant to multiple receptor-targeted treatments.

Triple-negative breast cancer: Biology, pathology, and therapy

Researchers were elated when HER2-positive breast cancer was first identified. The discovery allowed them to develop drugs that targeted and disabled the receptors in women whose tumors were HER2-positive. Down the line, however, they found that some tumors were resistant not only to HER2 but also to progesterone receptors (PRs) and estrogen receptors (ERs). These tumors are referred to as triple-negative breast cancer because they are HER2-negative, PR-negative, and ER-negative.

About 15% of women with breast cancer in the United States have triple-negative tumors, according to Dan Silver, MD, of the Dana-Farber Cancer Institute at Harvard Medical School, who is studying the biological underpinnings of this condition. Triple-negative breast cancer primarily occurs in younger women, 70% of whom have BRAC1 genetic mutation, and it is more prevalent in black women than in white women. Dr. Silver says that, unfortunately, patients with triple-negative breast cancer have a poor prognosis.

Although triple-negative breast tumors tend to be less aggressive than ones that test positive for one of the 3 growth receptors, they present their own challenges. If the cancer does not have a growth hormone receptor to target in an effort to disrupt tumor-cell growth, what course of treatment should be pursued?

Some researchers have begun to focus their efforts on turning these ‘negatives’ into a positive for such patients, reexamining older chemotherapies and hunting for new drugs that target other receptors known to contribute to tumor growth in triple-negative breast cancer. Most clinical discoveries are still in the preliminary stages of investigation and are not quite ready for prime time, but they do offer a glimpse into the future of treatment for patients who have triple-negative breast disease.

Identifying cell lines and molecular markers in triple-negative breast cancer tumors

Dr. Silver and several of his colleagues believe that cell lines exist that could be used to identify women with triple-negative disease. Consensus on what these cell lines are and how to detect them remains elusive. “Oncologists are still rather in the dark in terms of sporadic triple-negative disease,” said Dr. Silver. “But we know most of them fall into the BRAC1 subtype.” Dr. Silver says it would be ideal if researchers found a way for physicians to determine the tumor’s specific cell line in patients with triple-negative cancer before they select a course of treatment.

Cisplatin may be one treatment option for women with triple-negative disease, regardless of whether they have the BRAC1 gene mutation. One clinical trial examined tumor response to neoadjuvant cisplatin in 23 women with stage II/III triple-negative breast cancer. The study found that 14 had either a “complete” or “significant” response to cisplatin therapy. A smaller trial involving 10 women with a BRAC1 mutation found that 9 showed complete pathologic response to cisplatin therapy.

Dr. Silver said that if these early observations are borne out, “it appears that a subset of sporadic triple-negative breast cancer will share the susceptibility to cisplatinum shown by the BRCA1-related breast cancers.” He said these early clinical observations are consistent with findings from preliminary laboratory models that show BRCA1 and triple-negative tumors demonstrate mitomycin C and poly (ADP-ribose) polymerase (PARP)—inhibitor sensitivity (PARP is a key enzyme in DNA repair). Dr. Silver cautioned “don’t try this at home,” emphasizing the preliminary nature of these findings. “These data are from pre-clinical models and are very small; there are many ways in which they could be wrong or misleading. These considerations, and others like them, should be used to think creatively about future clinical trials but not used in current clinical practice.”

Andrea Richardson, MD, of Brigham and Women’s Hospital, largely agreed with Dr. Silver on the need to identify molecular classifications of triple-negative breast cancer. She said that with BRAC1 gene expression as a clue, subsets of triple-negative breast cancer tumors might be revealed. Dr. Richardson also said that abnormalities in the tumor protein 53 (p53) gene might constitute a clue. “There is heterogeneity within the triple-negative molecular subtype for a number of genes and features of triple-negative breast cancer tumors,” she said, indicating groups of epithelial gene clusters that seem to show a distinct set of features in triple-negative breast cancer.

Dr. Richardson said relying on gene expression that identifies the 3 subtypes of breast cancer constitutes one way to classify the disease, but other subtypes exist that may allow more specific tailoring of treatment. She noted that oncologists have yet to reach a consensus on the nature of these subtypes: “The clinical significance of various subtypes within triple-negative tumors is a hotly debated issue and under active investigation.”

The desire to develop more effective treatments specific to an individual patient’s disease is what drives the search for biological markers that will allow physicians to differentiate between subtypes of triple-negative breast cancers. Martine J. Piccart-Gebhart, MD, Jules Bordet Institute, suggested that until these identifiers are found, practicing oncologists must find new ways to work with existing cancer-fighting tools. “While there are clearly emerging molecular targets for the treatment of triple-negative breast cancer which deserve our enthusiasm,” said Dr. Piccart-Gebhart, “the reality of today’s clinical practice is we mostly rely on chemotherapy.”

Dr. Piccart-Gebhart said that in her practice, a treatment she calls “metronomic therapy” has proven effective in patients with ER-negative breast cancer. This treatment involves prolonged administration of relatively low doses of a selected chemotherapy agent at close intervals rather than a large initial dose. She mentioned a small study on adjuvant chemotherapy in people with triple-negative breast cancer that used weekly doxorubicin, daily oral cyclophosphamide, and weekly paclitaxel (Taxol) plus carboplatin, but said that there was “no evidence to favor a particular chemotherapy at this time.”

All these oncology colleagues shared the view that if progress toward a treatment is to be made, researchers at various clinical trial sites need to be more forthcoming in offering their findings for comparison and contrast.

Hormones and insulin expression may guide future breast cancer treatments

Researchers have solidly established that the hormone estrogen contributes to cancer growth. Therapies like tamoxifen (Novaldex) block receptors of estrogen in ER-positive women and therefore inhibit the body’s ability to use the hormone. Tamoxifen is undergoing increasing scrutiny to determine whether it might also inhibit tumor angiogenesis (new blood vessel formation) by blocking the vascular endothelial growth factor (VEGF) receptor pathway.

Maura Dickler, MD, of Memorial Sloan-Kettering Cancer Center said that although therapies such as tamoxifen have proven effective in blocking VEGF in the clinical setting, particularly as a first-line treatment for ER-positive women, “recurrence remains a problem, as eventually the body becomes resistant to endocrine therapy.” Does this mean that angiogenesis plays a role in endocrine resistance? Some researchers say yes. One study that included 96 women found that those who were ER-positive and had high VEGF levels also had the lowest chance for recovery. Pilot studies in the very early stages indicate that anti-VEGF drugs may delay or prevent the onset of endocrine resistance in women with certain types of breast cancers.

A small phase II study is underway that combines bevacizumab (Avastin), a VEGF inhibitor, with letrozole (Femara), an aromatase inhibitor (AI). Whereas tamoxifen blocks a tumor’s ability to use estrogen, AIs reduce the amount of estrogen throughout the body. After 17 months of treatment, a clinically significant number of patients had PFS. “This was interesting,” Dr. Dickler said, “because many of the women had already been on AIs.” She concluded that VEGF mediates estrogen-induced angiogenesis and that an increase in VEGF encourages angiogenesis, contributing to endocrine-therapy resistance. Similar phase II and phase III trials are underway, as well.

In addition to studying VEGF inhibitors, oncologists are trying to determine whether inhibiting insulin-like growth factor receptors (IGF1R) can also combat tumor growth. According to Lyndsay Harris, MD, Yale School of Medicine, IGF1R is a “good target because it is ubiquitously expressed in all cancers, even if the signaling is not active.” Dr. Harris explained that IGF1R is present in all breast cancer cells, to some degree. “There’s no such thing as an IGF1R-negative breast cancer,” she said, “so it’s not a matter of whether [IGF1R] is present, but a matter of whether it is active and where it sits on the cell surface.”

Clinical trials are looking at drugs that target IGF1R in combination with trastuzumab. Early results indicate that inhibiting IGF1R raises the rate of apoptosis from 10% to 20% in trastuzumab-resistant tumors. Approximately 25 drug compounds that target IGF1R receptors are in development and currently under evaluation as potential cancer treatments, either in doublet or triplet therapies.

Can preliminary response guide the choice and course of sustainable treatment and predict long-term survival?

The ability to identify the status of a tumor as ER-, PR-, or HER2-positive has dramatically changed the way in which clinicians choose an initial treatment for their patients with breast cancer. Even if a tumor is found to be positive for one of these 3 receptors, this is not predictive of whether a patient will respond to a particular regimen. It is important that oncologists follow other clinical findings vigilantly when considering whether a treatment is working effectively, ideally in the neoadjuvant setting.

“Partial clinical response and clinical response are powerful early surrogates of long-term survival, but there is no baseline measure to accurately define response,” said Lajos Pusztai, MD, DPhil, of M. D. Anderson Cancer Center. “There’s just no such thing.”

According to Dr. Pusztai, a patient’s initial response to 2 cycles of chemotherapy, combined with knowledge of her hormone-receptor status, can help the oncologist determine whether the best possible therapy has been selected for the patient and what the next step should be. Tumor size at diagnosis and following neoadjuvant therapy, the extent of lymph node involvement, and cancer burden all hint at the patient’s prognosis for long-term survival. “Pathologic clinical response is a strong predictor of survival for an individual, but do not confuse this with a survival rate in a clinical trial treatment arm,” Dr. Pusztai said, adding that “it’s important to remember that residual invasive cancer burden is a powerful predictor of long-term prognosis in an individual, but not [in] a group.”

Gunter von Minckwitz, MD, University of Frankfurt, uses ‘early clinical assessment’ as his measuring stick until conclusive molecular markers are available to guide treatment choice. After administering 2 or 3 cycles of neoadjuvant chemotherapy, Dr. von Minckwitz says his clinic performs ultrasonography or a mammogram to see whether the tumor has shrunk more than 50% from when it was first detected. “Then,” he said, “we might switch chemotherapy if needed.”

New Ways, New Drugs, and New Targets on the Horizon in Breast Cancer

Goserelin: Increasing the Dose to Decrease Dosing Frequency

Quality-of-life for people with breast cancer can be affected in many ways. One way to enhance it is through making therapy more convenient. Researchers are increasingly trying to find other ways to deliver an efficacious dose of chemotherapy to patients while making their lives easier. For example, goserelin (Zoladex), a gonadotropin-releasing hormone used to block the production of estradiol, is often used with tamoxifen to treat premenopausal women with early estrogen receptor (ER)-positive breast cancer. Typically, a 3.6-mg dose of goserelin is implanted subcutaneously in the patient’s body once a month for as long as her doctor deems necessary.

Iwata and colleagues conducted a multicenter, open-label trial of 170 Japanese women with breast cancer to determine whether administering goserelin as a 10.8-mg dose would require less frequent administration yet deliver the same levels of the drug each month. Preliminary findings suggest that it did, but data on disease-free survival are not yet available.

Sorafenib (Nexavar) combined with anastozole may offset aromatase inhibitor (AI) resistance. Sorafenib, an angiogenesis/tyrosine kinase inhibitor that stops cells from dividing, is used to treat inoperable kidney and liver cancers. The drug is now under consideration as a possible enhancement to anastrozole (an AI) in patients with ER-positive and progesterone receptor (PR)-positive metastatic breast cancer (MBC). Subramaniam and colleagues hope that the combination will offset AI resistance, which is common in patients with MBC. According to preliminary results from this still-accruing clinical trial, adding sorafenib to anastrozole is thought to restore the patient’s sensitivity to AIs by creating an alternate pathway of delivery to tumor cells. In total, 27 patients have been enrolled in the study. Of these, 5 achieved a stable disease state for more than 6 months, 2 had partial response greater than 6 months, 10 had disease progression; others were not response-evaluable. Researchers believe the findings from this small study offer strong evidence that adding sorafenib to anastrozole in patients with ER/PR-positive and AI-resistant MBC is beneficial.

Nab-paclitaxel (Abraxane) may offer substantial advantages in breast cancer treatment. The need to find alternative ways to deliver anticancer agents to tumor cells—either to replace exhausted pathways or to help patients resistant after long-term use of a particular chemotherapy agent—has led breast cancer researchers to look at cutting-edge technologies. Nab-paclitaxel is a product of this search. Paclitaxel (Taxol) must be dissolved in a castor oil solution before administration and requires ~3-hour intravenous administration. Nab-paclitaxel, however, binds paclitaxel to the protein albumin, eliminating the castor oil step and bypassing a long list of potential complications associated with its intravenous administration. Patients enrolled in a phase III study of nab-paclitaxel also demonstrated nearly double the overall response rate and had significantly longer time to tumor progression compared with patients receiving traditional paclitaxel.

Results from a smaller ongoing study of nab-paclitaxel and bevacizumab (Avastin) plus gemcitabine (Gemzar) in patients with previously untreated HER2-negative MBC is currently underway. Gluck and associates have enrolled 22 patients in their study so far; 64% are ER-positive and 36% are PR-positive. Preliminary results show that 75% of patients have demonstrated partial response to the combination therapy. Investigators say findings indicate that, in the future, this triplet regimen may become an important first-line option for patients with MBC.

Updates on New Uses for Established Drugs and New Therapies on the Horizon

Capecitabine: New Combinations, New Ways of Administration

Breast cancer patients who develop metastatic disease likely have already undergone chemotherapy with agents such as anthracyclines or taxanes. After a period, patients may develop resistance to these and other drugs or perhaps they did not respond to them in the first place. Controlling metastatic breast cancer (MBC) in these patients presents a particular challenge for oncologists. At this point, the antimetabolite capecitabine (Xeloda) is often used in an attempt to prolong the lives of people with MBC. Researchers continue to explore additional uses for capecitabine in breast cancer treatment, however, such as combining it with new chemotherapeutic agents or using it in novel ways.

Ixabepilone (Ixempra) is a promising treatment for MBC patients who have stopped responding to treatment or are resistant to other therapies. Approved by the FDA late last year, it is the first epothilone—a bacteria-derived substance that disrupts cell division—approved to treat locally advanced breast cancer and MBC.

Two randomized phase III trials involving patients with MBC evaluated whether combination therapy with ixabepilone plus capecitabine was more effective than capecitabine alone. Hortobagyi et al enrolled patients resistant to anthracyclines (eg, daunorubicin, doxorubicin, and epirubicin), and the other study included patients who had been pretreated for MBC extensively, primarily with taxanes. According to investigators, adding ixabepilone to a regimen of capecitabine improved PFS, although the change in overall survival in both arms was slight.

In addition to chemotherapy’s adverse effects, keeping appointments for intravenous administration adds another burden that detracts from patients’ quality-of-life. A third capecitabine-related study examined the bioequivalence between different delivery schedules for the drug. Levy et al enrolled ~40 patients and allocated them evenly to 2 groups. One group was given the standard schedule for capecitabine treatment: 1250 mg/m² twice a day for 14 consecutive days every 3 weeks. The other group received 1000 mg/m² of capecitabine, twice a day, 5 days per week. After 3 cycles, the regimens for the 2 groups were switched, and all patients received 6 cycles in total. The study concluded that both schedules were safe, efficacious, and bioequivalent in the patients. This finding offers the potential to improve patients’ quality-of-life by freeing them from a grueling chemotherapy schedule.

Docetaxel: New Drug Combinations Show Promise in Early and Metastatic Breast Cancers

The mitotic inhibitor docetaxel (Taxotere) is traditionally used as adjuvant therapy in treating certain types of breast and other cancers, and new indications are always being sought out. Researchers recently studied whether docetaxel, alone or in combination with other therapies, would be effective in treating patients with early stage or metastatic breast cancers.

One phase II study involved patients whose tumors had been detected early and were removed, whose cancer had not spread to the axillary nodes, and who had not undergone adjuvant chemotherapy or radiation. Garcia Bueno and colleagues sought to discover the efficacy of a regimen often used in patients whose cancer has already spread to the axillary lymph nodes: docetaxel followed by doxorubicin plus cyclophosphamide. Of the 58 patients in the trial, 2 experienced disease progression within a median follow-up of just over 1 year. In total, 20% of patients suffered neutropenia after doxorubicin and cyclophosphamide were added to the regimen. Researchers concluded that, overall, the regimen was “feasible and well-tolerated as an adjuvant therapy for early stage breast cancer without axillary involvement.”

Another study examined the effect of the antimetabolite gemcitabine (Gemzar) plus docetaxel versus docetaxel alone in patients with advanced breast cancer. El-Shenshawy and associates enrolled 70 patients who had locally advanced, recurrent, or metastatic breast cancer; 51 had undergone prior treatment with anthracycline. The overall response rate in the group that received the gemcitabine plus docetaxel therapy was ~60%; 11.4 patients demonstrated complete response. In comparison, the overall response rate in the docetaxel-only group was just over 34%, with 5.6 patients achieving complete response. Patients in the combination gemcitabine plus docetaxel group also had longer time-to-progression and a greater overall survival rate.

Severe thrombocytopenia was seen in 11.4% of the combination therapy group. In light of the “encouraging synergistic activity” observed with the gemcitabine plus docetaxel combination, researchers concluded that the toxicity rate was “tolerable.”

Patients with early stage breast cancer, regardless of HER2 status, have long benefited from docetaxel in terms of disease-free survival and overall survival. Encouraged by these findings, Yardley et al are looking at combining bevacizumab (Avastin) with 3 adjuvant docetaxel regimens plus trastuzumab (Herceptin) in HER2-positive patients. An early phase IIB trial, which plans to enroll 225 patients by completion, is analyzing the following: doxorubicin plus cyclophosphamide followed by docetaxel; docetaxel plus doxorubicin plus cyclophosphamide; and docetaxel plus carboplatin plus trastuzumab for HER2-positive enrollees. All 3 patient groups are also receiving bevacizumab 15 mg/kg q3w on day 1 for 52 weeks total. Preliminary data indicate that adding bevacizumab to these docetaxel-based adjuvant therapies has an acceptable safety profile and no unexpected toxicities; however, 3 early chronic heart failure events occurred in the patients who received anthracyclines.

Lapatinib May Disrupt Tumor Growth, Increase PFS, and Enhance Quality of Life

People with HER2-positive metastatic breast cancer (MBC) whose disease continues to progress despite trastuzumab (Herceptin) maintenance therapy pose a challenge to oncologists. The well-known monoclonal antibody is often used in patients with MBC because of its ability to bind to the HER2 receptor and kill HER2-positive cancer cells.

In a phase III randomized open-label study, Burstein and colleges are looking at whether adding lapa-

tinib (Tykerb), a combination EGFR inhibitor/tyrosine kinase inhibitor, to trastuzumab might help these patients. Patients received lapatinib alone or in combination with trastuzumab; those who experienced disease progression on the monotherapy regimen were allowed to cross over to the combination group.

Based on patients’ self-assessment questionnaires on quality-of-life measures (including physical, functional, emotional, and social/family wellbeing), patients who received lapatinib alone or in combination with trastuzumab improved significantly from baseline. As indicated by the patients’ quality-of-life assessments and rate of prolonged PFS, researchers believe adding lapatinib to trastuzumab produced a “meaningful clinical benefit” in these patients.

Similarly, a separate phase III randomized double-blind global study of women with MBC examined whether lapatinib increased the effectiveness of paclitaxel (Taxol), a mitotic inhibitor, compared with paclitaxel alone. Results from this large multinational study are still being evaluated, but thus far show “clinical activity” in a subset of HER2-positive patients. Researchers said they made an incidental, yet potentially important, discovery: “The large proportion of patients from China and Thailand suggest that Asian countries have the potential to grow into major players in global clinical studies.”

Lapatinib may one day join the list of other tyrosine kinase inhibitors that facilitate anti-vascular activity in breast cancer, killing off cancer cells by cutting off their blood supply. To test this theory, Weisenthal and colleagues used a new profiling assay system that measures tumor cell death and endothelial cell death in floating cell microclusters. After analyzing 25 fresh biopsies of human cancer tumors, researchers concluded that lapatinib induced greater tumor-cell death in breast cancers compared with other types of cancerous tumors. Used alone, lapatinib did not accelerate endothelial cell death in breast cancers any more than in other types of cancers. When combined with bevacizumab (Avastin), however, it seemed to enhance the ability of bevacizumab to do so.

Based on these early laboratory findings, researchers concluded that lapatinib demonstrated better antivascular activity than the tyrosine kinase inhibitor sorafenib (Nexavar). They suggested that the combination of lapatinib plus bevacizumab “may be the first clinically exploitable anitivascular drug combination,” and that it would be “clinically advantageous, even in HER2-negative tumors.”