Clinical advancements in treating breast cancer

Breast cancer is the second leading cause of cancer-related deaths in women, second only to lung cancer, and the most common malignancy diagnosed in women. The American Cancer Society (ACS) estimates approximately 215,990 women will be diagnosed with breast cancer in 2004. It is estimated that 40,110 women will die from breast cancer in the United States this year alone.

Currently, the incidence of breast cancer is 100 cases per 100,000 women. Overall, a woman's lifetime risk for developing breast cancer is one out of eight. Although the etiology of breast cancer is unclear, all women are at risk. Female gender and age appear to be the most common risk factors associated with breast cancer development. Seventy-seven percent of all female breast cancer cases occur in women over 50 years of age. Additional risk factors include family history, exposure to female reproductive hormones, dietary factors, and environmental factors. According to the Surveillance, Epidemiology, and End Results (SEER) Program, Caucasian, Hawaiian, and African-American women have the highest incidence of invasive breast cancer in the United States, while Korean, American Indian, and Vietnamese women have the lowest. Although the cause is unclear, African-American women have the highest death rate associated with breast cancer and are more likely to be diagnosed at a later stage.

Screening techniques

Numerous clinical trials have shown that earlier diagnosis of breast cancer results in improved overall survival rates. Currently, three screening techniques are employed in the United States: breast self-examination, clinical breast examination, and mammography. While many healthcare professionals recommend the use of self-examination as a screening tool, limited scientific evidence is available to support its use as a screening modality. Although the utility of self-examination has been questioned scientifically, an estimated 80% of women who are diagnosed with breast cancer have identified the mass themselves. ACS recommends women do a breast self-examination monthly, beginning at the age of 20 and continuing throughout life.

The value of mammography and clinical breast examination in women over 50 is well established. Screening trials demonstrate a 30% reduction in overall mortality after seven years. As a result, ACS, the National Cancer Institute (NCI), and the United States Preventive Services Task Force (USPSTF) recommend mammography every one to two years for women 50 years of age or older and an annual clinical breast examination. Screening guidelines for women between the ages of 40 and 49 are more controversial. Limited data regarding the clinical benefit of screening in this population have resulted in a lack of consensus when screening guidelines have been developed. All three groups currently recommend that women begin annual or biannual mammography at 40 years of age. Women in this age range should have a clinical breast exam on an annual basis. As a result of the screening controversies, breast cancer screening for women ages 40 to 49 should be based on the individual's risk factors and family history.

A detailed discussion of the risks and benefits of screening techniques should be held between the healthcare professional and individual. Women aged 20 to 39 should have a clinical breast exam every three years. Women should be educated to perform breast self-examinations on a monthly basis during the week after their menstrual cycle ends.

The utility of magnetic resonance imaging (MRI) in screening for breast cancer has recently been evaluated by a group of physicians from the Netherlands. In a study of 1,909 women at high risk for the development of breast cancer, participants were screened utilizing clinical breast examination every six months and mammography and MRI once annually. Women included in the study were deemed at high risk if they had a greater than or equal to 15% cumulative lifetime risk of breast cancer. Of the women included in the trial, 358 had allelic mutations. With a median follow-up of 2.9 years, 51 tumors (44 invasive cancers, six ductal carcinomas in situ, one lymphoma, and one lobular carcinoma in situ) were detected. The proportion of invasive tumors detected that were 10 mm or less in diameter was significantly greater with the MRI when compared with mammography (p=0.04).

Although these data provide valuable information regarding the use of MRI in breast cancer screening, additional clinical trial evaluation is necessary to validate its use. Additional screening techniques under investigation include ductal lavage, ultrasound, optical tomography, PET scanning, and digital mammograms.

Presentation, diagnosis, and staging

Breast cancer commonly presents as a painless, nonmobile, irregular mass located in a single breast. Less than 10% of women present with pain in the breast, skin dimpling, or nipple discharge. A presentation of skin edema, redness, and warmth may be indicative of more advanced disease. Over the past decade, diagnostic techniques for breast cancer have made limited advancements. The initial workup for a suspicious breast lesion is a physical examination and a clinical breast exam. Additional diagnostic techniques may include a three-dimensional (stereotactic) mammogram or ultrasound based on the location and size of the questionable mass. Due to the variability in mammography interpretation and limited utility for masses less than 5 mm in size, newer techniques for evaluating mammograms, including the use of computer-guided analysis and digital mammography, are being evaluated in clinical trials.

After the precise location of a mass has been determined, a biopsy is required. Based upon the high false-negative result rate associated with fine-needle aspiration, clinicians recommend either a core biopsy or excisional biopsy to assess a suspicious lesion. A core biopsy is performed using an 8- to 14-gauge needle, which is inserted into the mass while excising a small piece of tissue. Excisional biopsy is considered the standard of care for breast mass biopsy. Although associated with pain and possible unwanted cosmetic effects, excisional biopsies enable a clinician to determine whether a tumor is invasive to adjacent structures or in situ as well as obtain an appropriate specimen for histologic evaluation. Tumors that can't be palpated on clinical breast examination require guidance techniques such as ultrasound or stereotactic mammography.

Following the pathologist examination of the biopsied breast tissue, a determination of whether cancer is present is made. In addition to being used for histologic confirmation of breast cancer, tissue will be evaluated for cell differentiation patterns, histologic and nuclear grade, ploidy, proliferative rate, estrogen and progesterone receptor status, HER2/neu amplification or overexpression, and tumor suppressor gene mutations. These tests will further guide clinicians in determining which options are most appropriate for treating individual breast cancer cases.

Breast cancer staging is based on the TNM (tumor, node, metastasis) Staging System. Staging may be used to determine overall prognosis as well as guide treatment decisions. Stage 0 disease is characterized as "in situ" carcinoma, referring to abnormal cells lining the gland (lobular carcinoma in situ) or ducts (ductal carcinoma in situ). Stage I breast cancer is early disease with mass size less than 2 cm in diameter with no local extension. A wide spectrum of disease characteristics comprises Stage II disease. Tumors may be less than 2 cm in diameter yet involve local lymph nodes, 2-5 cm in diameter regardless of lymph node involvement, or greater than 5 cm in diameter in size with no lymph node extension. Stage III breast cancer is considered locally advanced disease where tumor size is greater than 5 cm in diameter and lymph nodes are involved. Metastatic disease is defined as Stage IV. The most common sites for metastatic involvement are the bone, liver, lung, and brain.

Rationale for chemotherapeutic-biologic regimens

Chemotherapeutic and biologic agents exert antitumor effects through various mechanisms of action. The use of certain agents with complementary and synergistic mechanisms of action, while possessing differing toxicity profiles, allows for an improvement in efficacy parameters without an increase in toxicities. Clinical and experimental data are continually being presented and published with regard to advances in the management of breast cancer. Keeping up with all the updated information is a daunting task for any clinician. As a result, the remainder of this article will provide highlights of data presented at the 26th Annual San Antonio Breast Cancer Symposium and the 40th Annual Meeting of the American Society of Clinical Oncology held in New Orleans.

Chemotherapy combination regimens

Epirubicin-containing regimens: When compared with doxorubicin, epirubicin (Ellence) has a lower incidence of myelotoxicity and cardiotoxicity. The two agents have similar spectrums of activity although dosing regimens differ. An evaluation of the weekly administration of cisplatin-epirubicin-paclitaxel (PET regimen) versus every-three-week administration of epirubicin-paclitaxel (ET regimen) was evaluated in previously untreated metastatic breast cancer patients. A cohort of 132 patients was randomized to receive either 12 weekly cycles of PET (cisplatin 30 mg/m², epirubicin 50 mg/m², paclitaxel 120 mg/m² with filgrastim support) or six cycles of ET (epirubicin 90 mg/m², paclitaxel 175 mg/m²). At present, 120 patients are evaluable for efficacy and toxicity. Comparing the clinical results of PET versus ET, complete response rates were 20% and 12%, respectively, while partial response rates were 60% and 38%, respectively. The median time to treatment failure was 13.2 months and 14 months for the PET and ET arms, respectively. Overall, the difference between the two regimens appears to be toxicity-based-the PET regimen had significantly more anemia and nonhematological toxicity associated with it than does the ET regimen.

As with other chemotherapy regimens and agents, epirubicin used in a dose-dense fashion has been widely investigated. The difference between conventional and dose-dense regimens is how often chemotherapy is given. Most conventional regimens are given every three to four weeks, while dose-dense regimens are given every week or two weeks. Due to the differences in dosing frequency, side effects often differ. In a phase III clinical trial evaluating the use of standard versus accelerated (dose-dense) FEC (5-FU, epirubicin, and cyclophosphamide) regimen in early breast cancer, the accelerated regimen provided improvement in survival when compared with conventional FEC dosing (18% reduction in risk of death). Of particular significance was the improvement in survival noted in women below the age of 50 years. The Hazards Ratio associated with the accelerated arm was 0.51 (95% CI 0.27-0.94) for the younger subset of women compared with 0.71 (95% CI 0.40-1.25) for women over 50 (p=0.049).

5-fluoropyrimidine analog-containing regimens: As a single agent, capecitabine (Xeloda) has demonstrated good clinical activity, tolerability, and efficacy in the treatment of breast cancer. Due to its oral administration, capecitabine provides a reasonable alternative to intravenous chemotherapy regimens for the palliative treatment of breast cancer in women who do not desire or are not appropriate candidates for intravenous chemotherapy. To evaluate the efficacy and toxicity of single-agent capecitabine in elderly women with metastatic breast cancer, 63 patients were included in a phase II clinical trial. Patients received capecitabine 1,250 mg/m² by mouth twice daily on days one through 14 of a 21-day cycle. The regimen was repeated a total of six cycles or until disease progression or undesired toxicities occurred. The overall response rate was 26.9% (partial responses) and 42.9% of patients had stable disease. At the time of analysis, the median time to progression was 3.5 months.

The combination of vinorelbine and capecitabine followed by docetaxel (Taxotere) was evaluated in women with advanced breast cancer by Ghosn and associates. This sequential approach was designed to enable the administration of these three active drugs while minimizing adverse effects. Forty-two patients received vinorelbine 25 mg/m² on days one and nine in combination with capecitabine 825 mg/m² twice daily by mouth on days one through 14. The regimen was repeated every three weeks for a total of four cycles. Women with an objective response went on to receive docetaxel 25 mg/m² administered for 12 consecutive weeks. Overall, the regimen was well tolerated, with an incidence of 14% for grade 3/4 neutropenia and 8% for febrile neutropenia. The response rate was 80%, including one complete response, three stable disease, and three disease progression.

Nucleoside analog-containing regimens: After entering tumor cells, gemcitabine (Gemzar) is phosphorylated by deoxycytidine kinase to form diphosphates and triphosphates. Both the di- and triphosphate forms are physiologically active against tumor DNA. Six phase II trials have confirmed the safety and antitumor effects of single-agent gemcitabine. Gemcitabine in combination with paclitaxel was approved for the treatment of metastatic breast cancer in May. In a randomized trial comparing the combination of gemcitabine (1,250 mg/m² given intravenously on days one and eight) and paclitaxel (175 mg/m² given on day one of a 21-day cycle) with paclitaxel alone, the combination regimen resulted in a statistically significant improvement in time to disease progression (5.2 months versus 2 months, p<0.0001) and overall response rate (40.6% versus 22.1%, p<0.0001) as compared with the single agent. Although not statistically significant, a trend toward improved survival was noted with the combination regimen.

As first-line therapy for advanced breast cancer patients, the combination of mitoxantrone (Novantrone) and gemcitabine has been proven safe and effective. In a phase II clinical trial evaluating the use of this regimen as second- or third-line therapy, patients received mitoxantrone 10 mg/m² on day one and gemcitabine 1,000 mg/m² on days one and eight. The objective response was 24%, although no patients had a complete remission. The combination was well tolerated; the most common adverse effects were leukopenia (39%), neutropenia (41%), and anemia (13%).

Taxane-containing regimens: The utility of paclitaxel in treating breast cancer is well established. Clinical trials indicate paclitaxel has efficacy in both adjuvant therapy for early and locally advanced breast cancer as well as in the metastatic setting. Paclitaxel exerts its cytotoxic effects by promoting the assembly of microtubules and stabilizing their formation by inhibiting proliferation. As a result, the microtubule bundle is nonfunctional. The optimal dose and administration schedule for paclitaxel continue to be investigated. Newer regimens include weekly and biweekly administration as well as administration times ranging from one to 24 hours in duration. Also, the sequence of administration of paclitaxel in combination with other chemotherapy agents plays a significant role in the efficacy and toxicity of the combination. Due to the increased incidence of hypersensitivity reactions associated with paclitaxel administration, all patients should receive premedications consisting of steroids, H₂ blocker, and H₁ blocker.

Novel combination regimens containing paclitaxel are continually evolving. The efficacy of paclitaxel in combination with trastuzumab (Herceptin) given every three weeks in women with HER2 overexpression has been validated in a large pivotal trial, which led to its approval by the Food & Drug Administration. Alternative dosing regimens are being examined. In a phase II trial involving 77 patients who received previous anthracycline treatment and were HER2 overexpressors, the combination of weekly paclitaxel (90 mg/m²) and trastuzumab (4 mg/kg loading dose on week one and 2 mg/kg weekly thereafter) was evaluated. Following a median duration of 24 weeks of treatment, an objective response rate of 69% was achieved, including 19% complete remissions. The most common adverse events associated with this treatment combination included anemia (34%), leukopenia (30%), fever (9%), and thrombocytopenia (5%). Of note, 15% of patients developed a grade 2 or greater peripheral neuropathy.

In a phase III randomized, multicenter trial involving 188 patients, the addition of carboplatin to the combination of paclitaxel and trastuzumab in women with HER2 overexpressing metastatic breast cancer was evaluated. Women received either the triple therapy of paclitaxel, trastuzumab, and carboplatin AUC=6 or paclitaxel and trastuzumab as double therapy. In both arms, chemotherapy was administered every three weeks, while trastuzumab was administered weekly until progression. The overall response rate and time to progression were significantly improved in the triple arm compared with the double (52% versus 36%, p=0.04; 11.9 months versus 6.8 months, p=0.02). Although not statistically significant, there was a trend toward improved overall survival in favor of the triple combination (42.1 months versus 33.3 months, p=0.27). Grade 3/4 neutropenia and thrombocytopenia were modestly increased in the triple arm although there was no difference in the incidence of neutropenic fever.

The PET regimen given IV on a weekly schedule is being evaluated in women with large operable breast cancers. To date, 47 of a planned 50 women have been enrolled in this prospective analysis. PET is administered with filgrastim support on days three through five of each treatment week. Of the 47 patients enrolled, 40 are evaluable for efficacy and toxicity. A 50% complete remission rate and 48% partial remission rate have been recorded, giving a 98% overall response rate. At 33-month median follow-up, only four relapses and one death had occurred. Following completion of the PET regimen, 24 of 40 women were able to undergo breast-sparing surgical procedures. Toxicities were minimal, with grade 3/4 neutropenia and anemia occurring in 27% and 5% of patients, respectively.

The role of dose-dense chemotherapy in the adjuvant setting of breast cancer is undisputed. Numerous clinical trials have confirmed improvements in overall survival for dose-dense regimens when compared with conventional dosing schedules. Interestingly, the agents utilized in the dose-dense fashion appear to be as different as breast cancer itself. In a phase III randomized trial comparing the use of dose-dense therapy in older women with lymph node-positive breast cancer with conventional dosing schemes, the combination of epirubicin and paclitaxel given in a dose-dense fashion followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) was shown to have a favorable safety profile. Efficacy data are being evaluated.

In a phase II trial evaluating the use of dose-dense therapy as primary systemic treatment in women with locally advanced breast cancer, a series of 34 patients were treated with three doses of doxorubicin 60 mg/m² given IV every three weeks followed by dose-dense paclitaxel 175 mg/m² given IV every two weeks in combination with cyclophosphamide 600 mg/m². Following completion of chemotherapy, patients proceeded to surgical resection and radiation therapy, as appropriate. Clinical complete remissions were obtained in 71% of women, while a pathologic complete remission at the time of surgical resection was noted in 38%. This regimen was well tolerated, with one case of grade 4 granulocytopenia without febrile neutropenia observed. With a median follow-up of three years, no recurrences have occurred in patients who experienced a pathologic complete remission.

Another trial enrolled 1,250 patients to compare the administration of six cycles of FEC (Arm B [5-fluorouracil 600 mg/m², epirubicin 90 mg/m², cyclophosphamide 600 mg/m²]) to four cycles of FEC followed by dose-dense paclitaxel 100 mg/m² given weekly for a duration of eight weeks (Arm B). Toxicity results indicate Arm A developed a statistically significant greater number of febrile neutropenia episodes than did Arm B (10% and 6.4%, respectively; p=0.044). Grade 3 neuropathy developed in 4.4% of patients in Arm B while receiving paclitaxel.

Docetaxel is a semisynthetic taxane which is similar in structure, mechanism of action, and spectrum of activity to paclitaxel. Differences in efficacy data may be the result of docetaxel's higher affinity for microtubules than paclitaxel as well as a lesser degree of cellular efflux, which results in higher intracellular concentrations of docetaxel. Due to the increased incidence of edema associated with docetaxel administration, all patients should receive premedication with dexamethasone to reduce the incidence and severity of fluid retention.

The effectiveness of docetaxel in the primary treatment of women with large or locally advanced breast cancer has been evaluated in two phase III clinical trials. In the Aberdeen trial, patients received a combination of CVAP (cyclophosphamide 1,000 mg/m², doxorubicin 50 mg/m², vincristine 1.5 mg/m², and prednisone 40 mg by mouth for five days) for a total of four cycles. Responders were randomized to either continue CVAP therapy for an additional four cycles or docetaxel 100 mg/m². Of the 162 women enrolled in the initial study, 66% had a clinical response and went on to the randomized component of the trial. The overall response rate (85% versus 64%, p=0.03), complete remission rate (31% versus 15%, p=0.06), and overall survival at 65 months follow-up (93% versus 78%, p=0.04) favored the docetaxel arm.

The PACS 01 study involved a total of 1,999 women with node-positive breast cancer. This comparison involved the FEC regimen (5-fluorouracil 500 mg/m², epirubicin 100 mg/m², cyclophosphamide 500 mg/m²) for a total of six cycles (Arm A) versus FEC for three cycles followed by docetaxel 100 mg/m² for three cycles (Arm B). Treatment was completed in 95% and 93.4% of Arms A and B, respectively. In Arms A and B, hematologic toxicity was the most common adverse effect, 14% and 9%, respectively, while dose reductions were necessary in 1.8% and 2.3% of cycles, respectively. Additionally, grade 3/4 toxicities include the following for Arms A and B, respectively: neutropenia (9.5% and 7%), febrile neutropenia (1.6% and 2.5%), mucositis (0.9% and 1.2%), and nail disorders (0.3% and 3%). Efficacy data are being evaluated. These two trials confirm the use of docetaxel in the management of large or locally advanced breast cancer is feasible without unexpected toxicities.

The combination of epirubicin and docetaxel (ED regimen, 75 mg/m² and 75 mg/m²) was compared with epirubicin and cyclophosphamide (EC regimen, 90 mg/m² and 600 mg/m²). Each regimen was administered every three weeks for a total of six cycles. At the close of accrual, 224 patients were randomly assigned to the treatment arms. Of those, 154 are evaluable for efficacy. The overall response rate for EC/ED was 47% and 56%, respectively. At present, there is a trend, although not statistically significant, toward improved survival in the ED arm. The most common grade 3/4 toxicities for EC/ED included leukopenia (41.5% and 54.3%), thrombocytopenia (2.9% and 1.3%), febrile neutropenia (5% and 5%), nausea and vomiting (2% and 2.7%), and alopecia (23.6% and 20.8%).

Paclitaxel and docetaxel are widely used taxanes for the treatment of breast cancer patients. In randomized trials, reported response rates for paclitaxel given over a three-hour infusion range from 16% to 29% and for docetaxel from 30% to 48%. Until recently, no direct comparison of these two agents had been completed. In a randomized trial involving 449 women with metastatic breast cancer, paclitaxel 175 mg/m² given IV as a three-hour infusion was compared with docetaxel 100 mg/m² given as a one-hour infusion. Both agents were administered every three weeks. The results of the trial are provided in Table 1. Although both agents are safe and effective in the treatment of breast cancer, this study provides evidence of the differing response rates and toxicity profile. A quality-of-life analysis is ongoing as a follow-up trial.

As with paclitaxel, novel combination regimens are being investigated with docetaxel. The use of neoadjuvant docetaxel and carboplatin with filgrastim support is being evaluated in women with locally advanced breast cancer. A total of 22 patients have been enrolled to date, with 16 evaluable for efficacy and toxicity. Patients received docetaxel 90 mg/m² and carboplatin AUC=6 on day one, followed by filgrastim 480 mcg given subcutaneously on days two through 10. After four cycles, patients underwent appropriate surgical resection and radiotherapy as indicated. The response rate was 100%, 31% complete response and 69% partial response. Overall, the regimen was well tolerated with minimal adverse effects reported. The most common adverse effects included myalgias, diarrhea, and fatigue/asthenia. There was only one episode of grade 3 myelosuppression with infection.

The development of the TAC (docetaxel, doxorubicin, and cyclophosphamide) regimen has led to significant improvements in response rates regardless of hormone receptor status. In a phase II trial of TAC in locally advanced breast cancer patients, 33 patients received docetaxel 75 mg/m², cyclophosphamide 500 mg/m², and doxorubicin 50 mg/m² on day one of an every-three-week cycle. Filgrastim support was administered on days five to 11 in an effort to modulate the incidence of neutropenia experienced. A 27% complete remission rate and 63.6% partial remission rate were observed. Of the responders, 18% had complete pathological responses while 24.2% had partial pathological responses. All patients developed grade 3 alopecia, and four patients developed grade 3 asthenia. No grade 4 toxicities were observed.

American Pharmaceutical Partners filed a New Drug Application with the FDA for Abraxane, a nanoparticle albumin bound (nab) formulation of paclitaxel. Also known as ABI-007, Abraxane differs from Taxol in that it is a Cremophor-free paclitaxel formulation in which the drug is delivered as nano micelles using a polymeric carrier. In a phase III clinical trial that included 454 patients with metastatic breast cancer, patients were randomly assigned to receive either Abraxane 260 mg/m² given IV over 30 minutes without premedications every three weeks or Taxol 175 mg/m² given IV over a three-hour infusion with premedications every three weeks. Patients received a total of six cycles. The Abraxane treatment arm had significantly higher response rates and longer time to tumor progression as compared with Taxol (24% versus 11.1%, p<0.001; 21 weeks and 15.4 weeks, p=0.014).

Hypersensitivity reactions did not occur in the Abraxane arm despite the absence of premedications. Grade 4 neutropenia occurred less frequently in the Abraxane arm (7% versus 19%, p<0.001) with a higher median absolute neutrophil count (1,350 versus 900, p<0.001). The incidence of grade 3 sensory neuropathy was 10% for Abraxane compared with 2% for Taxol (p<0.001) with no episodes of grade 4 neuropathy. The improved antitumor activity of Abraxane may be secondary to selective tumor vessel permeability, albumin-receptor mediated transport, and cellular uptake, which results in increased biodistribution and greater tumor accumulation. Alternative dosing regimens including 100 to 125 mg/m² given IV on a weekly basis for metastatic breast cancer are currently under investigation.

The novel taxane BAY 59-8862 is being developed for patients with metastatic breast cancer that has exhibited taxane resistance to previous treatment regimens. Another agent, Xyotax, is a polyglutamate polymer that is linked to the chemotherapeutic agent paclitaxel. Preliminary clinical trials indicate Xyotax is significantly more water-soluble than Taxol and is more selective to tumor tissue as compared with normal tissues. Trials are ongoing.

Vinca alkaloid-containing regimens: Compared with other vinca alkaloids, vinorelbine inhibits mitosis with a higher therapeutic index and lower incidence of neurotoxicity. As a single agent, vinorelbine has shown a response rate of 30% to 40% in women with metastatic breast cancer. With the proven efficacy associated with the use of vinorelbine alone, investigators are examining the clinical efficacy of novel combinations, including the addition of taxanes and biologic response modifiers. In a dose-dense study as neoadjuvant treatment in women with breast cancer, the combination of docetaxel and vinorelbine is currently under investigation. Vinorelbine (45 mg/m²) and docetaxel (60 mg/m²) were given IV every two weeks for a total of six cycles. To date, more than 300 cycles have been administered to the enrolled 60 women. Grade 3/4 toxicities include neutropenic fever (18%), epiphora, mucositis, and neurosensory side effects. Fifty-one patients are evaluable for clinical response, with 54% being complete responses and 41% partial responses.

Sixty-eight patients with HER2 overexpressing metastatic breast cancer were evaluated for response to a combination of vinorelbine and trastuzumab for a total of six four-week cycles. Patients were treated with weekly IV administration of vinorelbine (30 mg/m²) and trastuzumab 4 mg/kg loading dose at week one and 2 mg/kg weekly thereafter. Altogether, the combination was well tolerated, with the incidence of trastuzumab hypersensitivity of 0.3% and grade 3/4 neutropenia of 46.8%. Interestingly, only one episode of febrile neutropenia occurred. Forty patients have achieved an objective clinical response, with 13.8% being complete responses and 47.7% partial responses.

Biologic combination regimens

EGFR TK-containing regimens: The identification of epidermal growth factor receptor has provided an additional mechanism for targeting malignant cells. The function of tyrosine kinases is to regulate cell growth, differentiation, and death. The epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitors reversibly bind to the ATP-binding site, which inhibits the autophosphorylation of EGFR-TK. This blockade results in cell cycle arrest and inhibition of angiogenesis.

The addition of gefitinib (Iressa) to the combination of paclitaxel and carboplatin for the treatment of advanced breast cancer was evaluated in 68 women. Patients received paclitaxel 175 mg/m² administered as a three-hour infusion and carboplatin AUC=6 every 21 days for a total of six cycles. Gefitinib, 250 mg/day given by mouth, was continued until either disease progression, unacceptable toxicity, or voluntary withdrawal occurred. To date, 39 patients are evaluable for efficacy and toxicity evaluation. The complete response rate was 9%; the partial response rate was 37%. Nineteen patients have progressed, and seven have expired. The regimen was well tolerated, with the most common adverse events being neutropenia (16%), anemia (10.5%), diarrhea (7.5%), thrombocytopenia (6%), peripheral neuropathy (6%), and allergic reaction (6%). Following the completion of this study, gefitinib will be evaluated in a randomized fashion to evaluate its utility in maintenance therapy for advanced breast cancer.

The combination of gefitinib and docetaxel was evaluated in a phase II clinical trial as first-line treatment in patients with advanced breast cancer. Fourteen patients received gefitinib 250 mg/day by mouth and docetaxel 75 mg/m² given IV on day one of an every-three-week schedule. As no unacceptable toxicities developed at this dose level, 14 additional patients received a dose escalation of docetaxel to 100 mg/m² while receiving an equivalent gefitinib dose. Patients could continue to receive gefitinib therapy after completion of the six prescribed chemotherapy cycles if no evidence of disease progression or unacceptable side effects was noted. Currently, 28 patients have been enrolled and are evaluable for toxicity. The most common adverse effect was neutropenia, 21% grade 3 and 36% grade 4. Additional adverse effects included anemia, diarrhea, and skin rash. The response rate was 64% with two complete remissions and seven partial remissions among the initial docetaxel dosing group. The median duration of response and time to progression were 5.5 and 7.6 months, respectively. This study confirms the safety of gefitinib when used in combination with docetaxel. GW572016, an oral EGFR-TK inhibitor, has demonstrated preliminary efficacy in metastatic breast cancer patients at a dose of 1,500 mg by mouth daily.

Farnesyltransferase inhibitor-containing regimens: Although mutational upregulation of ras oncogenes occurs infrequently in breast cancer, numerous farnesyltransferase inhibitors are being evaluated in patients with metastatic breast cancer. The cytotoxic effects noted with farnesyltransferase inhibitors may be secondary to preferential cycling to the inactivated ras-GDP, although the exact mechanisms of action are under investigation. The feasibility of the combination of AC (doxorubicin plus cyclophosphamide) and tipifarnib (Zarnestra) was evaluated in a phase I dose-finding clinical trial of women with metastatic breast cancer. Eligible women received tipifarnib at various dosing levels in combination with doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²) given every two or three weeks. Initially, the trial design called for every-three-week administration of AC. Following the publication of dose-dense data supporting improved efficacy, the trial was amended to administer AC on an every-two-week schedule. Results are presented in Table 2. Subsequent clinical trials will evaluate the dosing regimen of tipifarnib 200 mg twice daily.

HER2 antagonist-containing regimens: Trastuzumab is the first humanized antibody approved for the treatment of HER2/neu overexpressing breast cancer. In normal breast tissue, HER2 encodes for cellular proteins which regulate normal cell division and multiplication. The binding of trastuzumab to HER2-binding sites is believed to interrupt or alter growth signals, thereby retarding tumor growth. Research indicates approximately 25% of breast cancers overexpress HER2.

A comparison of docetaxel alone versus docetaxel in combination with trastuzumab as first-line therapy for women with metastatic HER2-positive breast cancer was completed. A total of 188 patients were randomly assigned to either treatment arm. Docetaxel 100 mg/m² was given IV once every three weeks for a total of six cycles. A 4 mg/kg IV loading dose of trastuzumab was administered on day one, followed by weekly doses of 2 mg/kg until disease progression. Patients who progressed on the docetaxel-alone arm were allowed to cross over to the trastuzumab-containing arm upon evidence of disease progression.

The overall response rate for the combination arm was 61% compared with 36% in the docetaxel-alone arm (p=0.001). The overall survival rate for the combination arm was significantly better when compared with the docetaxel-alone arm despite the crossover of 44% of patients upon disease progression (p=0.0002). The median survival, time to progression, and median duration of response were also improved in the combination arm when compared with the single agent (27.7 months versus 18.3 months; 10.6 months versus 6.1 months, p=0.0001; 8.3 months versus 4.2 months, respectively). Adverse effects were similar between the treatment arms, with the exception of leukopenia and neutropenia, which occurred more frequently in the combination arm. Febrile neutropenia occurred in 23% of the combination arm and 17% of the docetaxel-alone arm.

Proteasome inhibitor-containing regimens: Two phase II trials have evaluated the use of bortezomib (Velcade) in the treatment of metastatic breast cancer. The primary objective of the trials was to determine the objective tumor response. Twelve patients who had received minimal treatment for metastatic disease were included in each trial. Patients received biweekly bortezomib 1.5 mg/m² on days one, four, eight, and 11 in a 21-day cycle. Patients were evaluated every three weeks for efficacy and toxicity. Overall, bortezomib was well tolerated, with the most common toxicities being thrombocytopenia, grade 2/3 pulmonary toxicity, fatigue, rash, and nausea. No patients in either trial exhibited a clinical response. The median time to progression was 25 and 47 days, respectively. As a result of the lack of clinical efficacy, both study authors recommend the evaluation of bortezomib continue only in combination with cytotoxic chemotherapy or other biological agents.

VEGF inhibitor-containing regimens: The role of bevacizumab (Avastin) in combination with docetaxel for the neoadjuvant treatment of women with advanced breast cancer was evaluated in a phase II clinical trial. To date, 33 of the planned 60 patients have been enrolled. Women were randomly assigned to receive either docetaxel for a total of two eight-week cycles of 35 mg/m² weekly for six doses with a two-week break in combination with bevacizumab 10 mg/kg administered IV every other week or docetaxel alone. Although data have not matured to allow for an evaluation of efficacy, toxicity data are available for 26 patients. The most common toxicities was grade 4 neutropenia (15%), grade 3 anorexia (11.5%), stomatitis (11.5%), gastrointestinal bleeding (3.8%), neuropathy (3.8%), and wound-healing delay (3.8%). Contrary to previously published phase II trials, no hypertension, proteinuria, or thrombosis was observed.

Bevacizumab (10 mg/kg given IV on days one and 15) in combination with docetaxel (30 mg/m² IV on days one, eight, and 15) was given on a 28-day cycle for a total of six cycles. Although only preliminary data from 16 patients are available, a significant incidence of adverse effects has been observed. Notably, 19% of patients have experienced grade 4 toxicities, including pulmonary embolism and infection. Grade 3 toxicities include leukopenia (19%), fatigue (19%), mucositis (13%), headache (13%), hypertension (6%), dyspnea (6%), pleural effusion (6%), and tearing (6%). Partial responses have been obtained in 54% of patients, while 31% maintain stable disease, and 14% have been removed from the trial due to excessive toxicity.

Biologic response modifier combinations

A logical progression following the discovery of newer targeted biologic agents is to combine productss with differing mechanisms of action. The combination of EGFR-TK and VEGF inhibitors was evaluated in women with metastatic breast cancer. To date, 13 women have been enrolled in a trial evaluating the combination of erlotinib (Tarceva) 150 mg/day by mouth and bevacizumab 15 mg/kg IV every three weeks. Response is evaluable in 75% of patients at this time. One patient has a confirmed partial response, while two have stable disease and five have progressive disease. Grade 4 pulmonary embolus (n=1) and neutropenia (n=1) were experienced. Grade 3 toxicities included rash, diarrhea, hypertension, and nausea/vomiting.

To determine the appropriate dosing combination of erlotinib and trastuzumab, a phase I dose-finding trial was completed. Sixteen patients included in the trial were HER2 overexpressors with metastatic breast cancer. Trastuzumab was dosed at 4 mg/kg on day one and 2 mg/kg weekly thereafter beginning on day eight, for a total of 58 four-week courses. Erlotinib was dosed at 50, 100, and 150 mg in an escalating fashion. The most common toxicities were grade 1/2 diarrhea (11 patients) and rash (10 patients). Due to the favorable toxicity profile of the combination, subsequent phase II trials will be completed with full-dose erlotinib (150 mg) and trastuzumab.

Conclusion

Breast cancer and its treatment result in significant morbidity and mortality. This year, an estimated 215,990 women will be diagnosed with breast cancer in the United States alone, and 40,110 will succumb to the disease. These statistics provide evidence for the continued investigation into newer, more effective treatment modalities. A knowledge of the mechanisms of action and toxicity profiles is necessary to decrease cross-resistance and overlapping toxicities. Pharmacists are the most accessible healthcare professional. Women undergoing chemotherapy for breast cancer will often seek your expertise and advice when experiencing side effects. Up-to-date knowledge of novel combinations, efficacy data, and toxicity profiles is necessary.

References are available upon request.

TEST QUESTIONS

Write your answers on the answer form appearing on page 47 (photocopies of the answer form are acceptable) or on a separate sheet of paper. Mark the most appropriate answer.

1. Which of the following statements is true regarding breast cancer?

a. Breast cancer is the leading cause of cancer-related death in women.

b. The incidence of breast cancer has increased incrementally over recent decades.

c. A woman's lifetime risk for developing breast cancer is one in eight.

d. Seventy-seven percent of all female breast cancer cases occur in women below the age of 50.

2. All of the following are high-risk factors associated with the development of breast cancer except:

a. Age ? 65 years

b. One primary relative with breast cancer at < 50 years

c. History of breast cancer

d. Atypical breast hyperplasia

3. Mammography every one to two years in conjunction with an annual clinical breast examination is recommended for the following age group:

a. Older than 50 years c. 30-39 years of age

b. 40-49 years of age d. Below the age of 30

4. Which of the following statements regarding screening techniques for breast cancer is true?

a. Breast self-examinations should be performed the week prior to a woman's menstrual cycle.

b. Ultrasound and ductal lavage are commonly used for screening.

c. MRI use requires validation.

d. Mammography screening trials demonstrate a 50% reduction in mortality over seven years.

5. Most early breast cancer lesions are described as producing:

a. Skin edema

b. Redness

c. Warmth

d. No pain

6. Which of the following statements regarding breast mass biopsy is true?

a. Core biopsy is considered the standard of care.

b. Excisional biopsy uses an 8- to 14-gauge needle.

c. Core biopsy enables examination of adjacent structures.

d. Fine-needle aspiration has a high false-negative rate.

7. Which of the following statements regarding chemotherapeutic combination regimen development is correct?

a. Regimens with complementary mechanisms of action are preferred.

b. Regimens with overlapping toxicities are recommended.

c. Regimens with cross-resistant agents are preferred.

d. None of the above

8. The dosing schedule for epirubicin in the PET regimen is:

a. 30 mg/m2

b. 50 mg/m2

c. 100 mg/m2

d. 120 mg/m2

9. Which of the following statements regarding the comparison of PET versus ET in the treatment of previously untreated breast cancer patients is true?

a. Complete remission rates were improved with ET.

b. The median time to treatment failure was statistically different.

c. Anemia occurred more often with the ET regimen.

d. The difference between the regimens is toxicity.

10. As a single agent, capecitabine has demonstrated all of the following except:

a. Improved overall survival

b. Clinical activity

c. Tolerable toxicity profile

d. Efficacy

11. The chemotherapeutic classification of gemcitabine is best described as:

a. EGFR-TK inhibitor

b. Microtubule stabilization

c. VEGF inhibitor

d. Nucleoside analog

12. Which of the following statements regarding paclitaxel is true?

a. The sequence of paclitaxel and other chemotherapeutic agents plays a significant role in the efficacy.

b. The optimal dose is 120 mg/m2 in breast cancer regimens.

c. Paclitaxel requires no premedications.

d. Paclitaxel should be administered no more frequently than every three weeks.

13. Differences between paclitaxel and docetaxel include all of the following except:

a. Microtubule affinity

b. Side-effect profile

c. Mechanism of action

d. Cellular efflux

14. In the direct comparison of paclitaxel and docetaxel, which of the results were observed?

a. The difference in overall survival favored docetaxel.

b. Patients receiving paclitaxel had an improved overall response rate.

c. Docetaxel patients experienced a lower incidence of neutropenia.

d. Time to progression was not statistically different.

15. Abraxane is best described as:

a. A Cremophor-based paclitaxel

b. An oral taxane

c. A nab paclitaxel

d. A polyglutamate polymer paclitaxel

16. Compared with other vinca alkaloids, vinorelbine:

a. Has a higher incidence of neurotoxicity

b. Exhibits a higher therapeutic index

c. Has limited activity in breast cancer

d. Is dosed 120 mg/m2

17. Gefitinib, combined with paclitaxel and carboplatin, has resulted in all of the following clinical trial results except:

a. Complete response rate of 9%

b. Partial response rate of 9%

c. Neutropenia of 16%

d. Peripheral neuropathy of 6%

18. The dose of tipifarnib to be further investigated in clinical trials is:

a. 100 mg b.i.d.

b. 300 mg b.i.d.

c. 200 mg b.i.d.

d. None of the above

19. Trastuzumab works by all of the following mechanisms except:

a. Interrupting growth signals

b. Inhibiting EGFR-TK

c. Retarding tumor growth

d. Binding to HER2-binding sites

20. All of the following are side effects associated with bevacizumab administration except:

a. Hypertension

b. Thromboembolic disorders

c. Neutropenia

d. Anemia