2008 was a busy year in the field of breast cancer medicine, with thousands of abstracts presented at the ASCO, ASCO breast, and ESMO meetings and the San Antonio Breast Cancer Symposium in December, in addition to the many papers published over the course of the year (a PubMed search reveals that 5,252 papers published in the last year contained the words “breast cancer” in the title). Some of these developments rightly attracted considerable attention. Issues such as the potential impact of adjuvant bisphosphonates on breast cancer outcomes and the impact of the addition of bevacizumab to chemotherapy for metastatic disease garnered extensive coverage in both the oncology and the mainstream media. Yet, some stories, for one reason or another, passed under the radar and failed to get the attention they deserved. Perhaps they concerned the less glamorous topic of supportive medications rather than the “big-hitters,” the cytotoxics themselves. Perhaps they explored the schedule of treatment administration rather than novel treatment agents. Regardless, they contributed something to our knowledge of this disease. We have selected five of these developments that we think merit a closer look. Our criteria are simple: any story that potentially impacts our day-to-day practice, but which failed to make the news.
The first story concerns the use of gonadotrophin releasing hormone (GnRH) analogues in premenopausal women to preserve fertility. Motivated by promising evidence from animal models, non-randomized studies have been performed and have suggested an improvement in fertility preservation for patients undergoing cytotoxic chemotherapy who received GnRH analogues throughout their treatment course. Consequently, the use of GnRH analogues has entered clinical practice, despite a lack of randomized clinical trial data to support their use. An abstract at this year’s ASCO meeting detailed the first prospective randomized trial to examine this issue. In the study, 49 pre-menopausal women receiving (neo)adjuvant chemotherapy for breast cancer were randomized to receive goserelin versus no goserelin. Patients were stratified by age, ER status, and treatment type. Menstrual status, FSH, and Inhibin levels were monitored every six months. One of the salient points of this trial was the high rate of recovery of menstrual function in both the goserelin and the control group: 88% and 84%, respectively, at 18 months. This is in keeping with a previous analysis reporting an 85% recovery of menstrual function among patients age 40 years and younger who were treated with adjuvant anthracycline and taxane. No significant difference between the groups was observed in the current study. The major limitation of this trial is its small sample size. Nevertheless, it raises concerns regarding the widespread adoption of GnRH analogues as a means of preserving ovarian function in the face of chemotherapy treatment in pre-menopausal women. Several larger phase III trials are accruing or have recently completed accrual (Sidebar). The emerging data from these trials will help to clarify the role of GnRH analogues in fertility preservation for young women with breast cancer.
EGFR and ER Signaling
It has become increasingly apparent that the estrogen receptor exerts its effect in the context of a molecular milieu, which includes crosstalk with growth factor signaling pathways. More recently, it has been shown that high EGFR expression can indicate resistance to tamoxifen treatment in patients with ER+ breast cancer. An abstract from ASCO 2008 examined the role of combined signaling blockade with an aromatase inhibitor (anastrozole) and an EGFR inhibitor (gefitinib) in women with ER+ metastatic breast cancer. In this multi-center, double-blind phase II trial, 94 women were randomized to receive anastrozole with gefitinib or placebo. Patients had either received no prior hormonedirected therapy for their breast cancer or had progressed during/after adjuvant tamoxifen. Unfortunately, enrollment was stopped early due to slow accrual, limiting the statistical yield of this trial. Nevertheless, intriguing results were seen, namely a marked PFS advantage for the anastrozole plus gefitinib arm: median 14.5m versus 8.2m (hazard ratio 0.55, 95% CI 0.32-0.94). There were no unexpected toxicities. In a similar study presented at San Antonio in December 2007, patients with metastatic breast cancer were randomized to gefitinib or placebo in addition to tamoxifen. This trial demonstrated a non-significant improvement in PFS for patients with hormone therapy-naïve disease or who had completed adjuvant tamoxifen a year or more before study entry. Taken together, these provocative results suggest a role for continued exploration of combined ER and EGFR therapies in patients with ER+ breast cancer.
Molecular Characterization of Individual Tumors
This method has already entered routine clinical practice with the availability of the Oncotype DX™ assay to aid decision making regarding adjuvant chemotherapy in women with ER+ node-negative tumors. One question that has arisen is how this technology might interact with existing decision-making tools such as Adjuvant!, which estimates risk using clinicopathologic data. Does “molecular risk” trump “clinically calculated risk,” or is there a role for both? This issue was addressed by several presentations at San Antonio in December 2007. In the first study, tumor samples from women with 0-3 positive lymph nodes receiving chemotherapy and tamoxifen on clinical trial E2197 were assigned recurrence scores by Oncotype and were also assigned to low-, intermediate-, and high-risk groups by Adjuvant!. Recurrence score and Adjuvant! calculation were found to be independently associated with recurrence. For patients in low or intermediate Adjuvant! risk groups, the risk of recurrence was significantly increased for intermediate and high recurrence scores. The low recurrence score patients had excellent five-year survival, even in the setting of positive lymph nodes, a result supported by the analysis of S8814, which showed that recurrence score was prognostic in women with 1-3 positive nodes and suggested a lack of benefit for chemotherapy in women with in this group with low recurrence scores. It would seem to follow that we may soon witness a shift from the anatomic classification of breast cancer to a more biologic classification.
An integral part of the care of patients with breast cancer is the concept of survivorship: empowering women to return to full, healthy lives after completing their adjuvant therapies. A common question posed by women entering this phase of their cancer journey is, “what can I do to reduce my risk of a recurrence?” While we consider ourselves to be datadriven on chemotherapeutic interventions, lifestyle modifications are less well studied. An updated survival analysis from the women’s intervention nutrition study (WINS) provides some evidence basis for advice. A previous report had indicated a significant improvement in relapse-free survival for patients with resected breast cancer who received a dietary intervention targeting fat intake reduction, associated with significant weight loss. This update reveals a non-significant decrease in mortality for the intervention group. In an exploratory analysis of 362 women with ER- and PR- disease, a significant overall survival benefit was seen for intervention group participants (7.5% vs. 18.1%, cumulative mortality, RR 0.41, P=0.003). Whether this significant subset analysis is simply due to chance is unclear; certainly the cardiovascular benefits of low-fat diets are well established.
Trastuzumab Monotherapy in Metastatic Disease
Although it is known from the pivotal trial that monotherapy in metastatic breast cancer is associated with a response rate of approximately 15%, it is not known if initiating therapy with trastuzumab alone and deferring chemotherapy until disease progression will have a negative impact on patient outcome. A study reported at ASCO this year attempted to address this by randomizing patients to docetaxel plus weekly trastuzumab (Arm A) or trastuzumab followed by docetaxel at progression (Arm B). The response rates in the combination arm were not surprisingly higher (57% vs 34%, P=0.03). However, there was no significant difference in time to progression (9.1 months in arm A, and 9.8 months in Arm B)—although progression-free survival for the trastuzumab component was 3.9 months. This study suggests that there is a subset of women in whom a maximal response rate is not required (ie, no critical organ impairment), in whom initiation of cytotoxic therapy may be deferred with the use of trastuzumab monotherapy. A key weakness of the trial is that the trastuzumab was not continued with the chemotherapy agent. Results from another randomized trial presented at the same meeting revealed additional benefit for continuing trastuzumab after progression in patients commencing capecitabine. A significant improvement in time to progression was seen in patients continuing trastuzumab with their chemotherapy (8.5 vs 5.6 months), although no statistical overall survival benefit was shown. The outcome for patients who received trastuzumab monotherapy and then received trastuzumab plus chemotherapy on progression as compared to patients receiving combined therapy from the start is not known.
Dr. Murphy is a special fellow and Dr. Seidman is a medical oncologist, Department of Breast Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
ONGOING, NO LONGER RECRUITING