|Julia Draznin Maltzman, MD|
|The Abramson Cancer Center of the University of Pennsylvania|
This article discusses the highlights of an NOCR (Network for Oncology Communication and Research) sponsored meeting where highlights from the San Antonio Breast Cancer symposium 2003 were presented. Leaders in the field of breast cancer from numerous academic institutions convened to discuss some of the most important abstracts presented at the annual San Antonio conference. Topics discussed included issues surrounding the diagnosis, prognosis and prevention of breast cancer, adjuvant and neo-adjuvant treatment as well as therapies for metastatic disease.
Since it is not possible to cover every abstract discussed, OncoLink has emphasized a few that have provoked much discussion and controversy in the breast cancer community. For more information about topics and articles discussed, please email Julia Draznin at firstname.lastname@example.org or log onto the official San Antonio Breast Cancer Symposium web site at www.sabcs.org.
Docetaxel primary chemotherapy in breast cancer: a five-year update of the Aberdeen trial
Presenter: Hutcheon AW
Chemotherapy before surgery, neo-adjuvant therapy, is a standard treatment option for locally advanced breast cancer. Studies show that response rates approximate 80% and can convert a planned mastectomy to a simple lumpectomy. The surgical specimen is removed and sent to the pathologist. If the pathologist does not see any cancer cells in the specimen, the patient is said to be in pathologic complete remission (pCR). Complete pathological responses are used to predict survival – those who achieve pCR have a better outcome. Along with the NSABP B27 trial, this trial, known as the Aberdeen trial, has shown that the addition of docetaxel to primary chemotherapy results in more pCR. Data presented at the 2003 San Antonio conference added to the known benefit of docetaxel by reporting of an improved five-year survival.
Patients with large or locally advanced breast cancers who entered the trial all received four cycles of the same chemotherapy called CVAP (cyclophosphamide, vincristine, doxorubicin, and prednisone). At the completion of this phase of therapy, all patients were evaluated. Those who did not respond to initial therapy received four cycles of docetaxel; those who did get a response were randomized to either four cycles of docetaxel or four additional cycles of CVAP. Final assessment was done at the time of surgery at the completion of both phases of chemotherapy. The five-year overall survival was 97% for the docetaxel arm and 78% for the CVAP arm. Put another way, there was a 19% absolute difference in survival between the two regimens favoring treatment with docetaxel.
This study underlined that docetaxel not only improves pCR, but also significantly improves five-year survival.
TAC improves disease free survival and overall survival over FAC in node positive early breast cancer patients, BCIRG 001: 55 month follow up
Presenter: Pienkowski MM
The benefit of a taxane in the treatment of breast cancer has been investigated previously. The CALGB 9344 and the NSABP B-28 trials are the most well known. In these trials, all patients received chemotherapy with doxorubicin and cyclophosphamide, (AC) but some were randomized to receive four additional cycles of taxol. Although, both studies showed a taxane benefit, there were a number of confounding issues. One often-sited criticism is that some of those who were randomized to receive AC alone only got four cycles of chemotherapy. By contrast, patients randomized to the Taxol arm, actually got a total of eight cycles of chemotherapy. To answer such challenges, this study was designed to assess the value of a taxane by offering patients equal number of chemotherapy cycles.
This trial accrued over one thousand patients over the course of two years. The first planned interim analysis with a median follow up of 33 months was presented at ASCO 2002 and showed a significant improvement in disease free survival (DFS) favoring the docetaxel, doxorubicin, and cyclophosphamide regiment. These data show results from a 55-month follow up at the second planned interim analysis.
Patients with node positive breast cancer were enrolled and randomized into two groups: TAC (docetaxel, doxorubicin, and cyclophosphamide) or FAC (5-fluorouracil, doxorubicin, and cyclophosphamide). Both of these regiments were given at an every three-week schedule for six cycles. By an intention to treat analysis, there was a clear benefit to the TAC arm for disease free survival. At 55 month follow-up, the disease free survival for TAC was 75% versus 68% for FAC. Overall survival (OS) also favored TAC by a 6% difference (87% for TAC and 81% for FAC). The benefit of the TAC regimen seemed to hold true regardless of the number of lymph nodes involved.
Of importance, all three multi-institutional trials demonstrated an improved DFS with the addition of a taxane for this population of patients. TAC in particular seems to have achieved the highest benefit in DFS and OS, and should be strongly considered in the treatment of node positive breast cancer.
Analysis of time to recurrence in the ATAC trial according to estrogen receptor and progesterone receptor status
Presenter: Dowsett M et al
The famed ATAC – anastrozole, tamoxifen, alone or in combination – trial looked at adjuvant hormone therapy. Over 9,000 postmenopausal women with early breast cancer were given five years of treatment with anastrozole, tamoxifen or both. This enormous effort included 381 medical centers and 21 countries. The study aimed to evaluate risk of recurrence and the risk of a new contralateral breast cancer. Initial results showed that anastrozole alone worked better than either tamoxifen alone or in combination with anastrozole. The status of ER and PR were known in 7993 patients. The study presented at the San Antonio 2003 meeting was a retrospective analyses done to determined the time to tumor recurrence by the estrogen receptor (ER) and progesterone receptor (PR) positivity. Patients were divided into four distinct groups: ER+/PR+, ER-/PR-, ER+/PR-, ER-/PR+ and analyzed. Not surprisingly, the results showed that there was little benefit to hormone therapy if the tumor were ER-/PR-. However, unexpectedly, the group that benefited most from treatment was the ER+/PR- population. In fact, there seemed to be a greater efficacy in ER+/PR- tumors than in those expressing ER+/PR+. This fascinating finding should be interpreted with caution, as prospective confirmation is necessary. The significance of this finding is not yet clear but we will see much more on this topic at ACSO 2004.
Randomized placebo-controlled trial of letrozole in postmenopausal women with early breast cancer completing five years of tamoxifen
Presenter: Gross PE
This abstract was presented in San Antonio following a full paper publication in the New England Journal of Medicine one month previously. In addition, OncoLink chose this study as one of the most seminal trials of the year 2003. This multi-institution, double blind, placebo controlled trial of five years of adjuvant letrozole to early stage breast cancer in postmenopausal women after the completion of five years of tamoxifen. The primary end point of the study was DFS with OS and quality of life being secondary end points. The absolute improvement in DFS was 6% favoring the letrozole arm. Survival impact was seen in both node negative and node positive disease.
The study included only those women who completed tamoxifen only a few months earlier. The more difficult question is should we advise women who have been off tamoxifen for over six months to commit to five additional years of hormone therapy with letrozole. There has not been a consensus statement issued from either San Antonio or ASCO on the matter and most experts present at the symposium seemed to agree that they would consider this option only if the woman were a very high risk for recurrence. However, this decision must be made with careful consideration of all aspects, including medical, psychological, and practical issues.
Randomized trial comparing docetaxel and paclitaxel in patients with metastatic breast cancer
Presenter: Jones S
Both docetaxel and paclitaxel are widely used in the treatment of patients with breast cancer. In previous randomized trials, the response rate for docetaxel has ranged from 30-50% and those for paclitaxel from 15-30%. However, there has never been a direct comparison of these two taxanes. This study directly compared docetaxel to paclitaxel in patients with metastatic breast cancer after failing anthracyclines.
Patients with metastatic breast cancer were randomized to receive one of the two taxanes every three weeks until disease progression. Of note, there was no prophylactic growth factor support or antibiotics given. The primary end-points were response rate and an evaluation of toxicity. Secondary end-points included duration of response, time to progression, overall survival, and quality of life. All patients must be anthracycline resistant. This was defined as having either received an anthracycline containing regimen for first line metastatic treatment or as adjuvant or neoadjuvant therapy and then relapsing within 12 months. Of the 499 randomized patients, only 394 were evaluable at the study completion. There were many reasons why the number of patients randomized did not equal the number of patients evaluated, but this is one of the more powerful criticisms of the trial. An intent-to-treat analysis showed that both time to tumor progression and overall survival favored the docetaxel arm. These data were found to be statistically significant. Time to tumor progression was 5.7 months for docetaxel and 3.6 months for paclitaxel. However, this came at a price. The docetaxel arm saw 93% hematologic toxicities including grade 3/4 neutropenia. There were four treatment related deaths; three of which are due to febrile neutropenia. The paclitaxel arm had a 55% grade 3/4 neutropenia. Anemia and thrombocytopenia were also more common in the docetaxel arm. Other non-hematologic grade 3/4 toxicities that were also more common for docetaxel included asthenia (lack of strength or energy), stomatitis (inflammation of the oral mucosa), infection, and peripheral edema.
The conclusions that could be drawn from this study include: the response rate was higher for docetaxel than paclitaxel in this population (37% vs. 25.9%, p <0.05), duration of response was longer for docetaxel than paclitaxel (7.5 months vs. 4.6 months, p<0.05), time to tumor progression was better for docetaxel than paclitaxel (5.7 months vs. 3.6 months, p 0.0001), and overall survival was better for docetaxel than paclitaxel (15.4 months vs. 12.7 months, p=0.03). However, treatment with docetaxel was associated with an increased incidence of grade 3/4 toxicities. One wonders whether growth factor support or dose reduction would have decreased this incidence with similar clinical outcomes.