Breast Cancer 2014: SOFT Proves Year's Best

Lidia Schapira, MD


December 24, 2014

Editor's Note: This year in breast cancer was marked by significant developments, including long-awaited results on endocrine therapy in premenopausal patients, "unprecedented" survival data in HER2-positive disease, and gains in individualization of treatment. Medscape asked Lidia Schapira, associate professor, Harvard Medical School, Boston, Massachusetts, to provide her perspective on what she considers the highlights in breast cancer in 2014.

Optimal Endocrine Therapy for Premenopausal Women With HR-Positive Disease

If we look strictly at clinical trial data, the results from the SOFT[1,2] and TEXT trials clearly top the list. These international studies have taken many years to complete and were designed to answer fundamental questions that come up in clinic every day. Last year I commented on the results of ATLAS[3] and aTTom[4] and reviewed emerging data supporting the use of tamoxifen for up to 10 years.

Tamoxifen has been recommended for premenopausal women with hormone receptor–positive breast cancer for decades. However, the value of therapeutic suppression of ovarian estrogen production in premenopausal women who receive tamoxifen is uncertain. The American Society of Clinical Oncology (ASCO) endorsed guidelines[5] recommending that ovarian suppression not be routinely prescribed for all premenopausal women with hormone receptor–positive breast cancer, although prior studies have shown that chemotherapy-induced ovarian suppression confers a reduction in the risk for relapse.

In 2003, the International Breast Cancer Study Group initiated two randomized phase 3 trials: the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT). Olivia Pagani[1] presented at the annual ASCO meeting in June the results of two arms of the SOFT and TEXT studies,both using ovarian suppression plus either the aromatase inhibitor exemestane or tamoxifen. After a median follow-up of 68 months, disease-free survival (DFS) was 91% in the exemestane arm and 87% in the tamoxifen arm. The duration of follow-up was not sufficient to assess whether the significant reduction in risk for distant recurrence will eventually translate into an overall survival benefit. In the combined analysis, 12% of women also had HER2-positive cancers and did not appear to derive an advantage from exemestane as compared with tamoxifen.

Prudence Francis presented the results of the SOFT study at the San Antonio Breast Cancer Symposium in December, which were simultaneously published in the New England Journal of Medicine.[2] Investigators randomly assigned 3066 premenopausal women with early-stage breast cancer that was hormonally sensitive and who regained their menses after chemotherapy or were premenopausal and did not receive chemotherapy, to (1) tamoxifen alone, (2) ovarian suppression plus tamoxifen, or (3) ovarian suppression plus the aromatase inhibitor exemestane. With a median follow-up of 67 months, DFS was 86.6% in the ovarian suppression-plus-tamoxifen arm compared with 84.7% in the tamoxifen arm. Among patients who did not receive chemotherapy, more than 95% remained disease free in all arms. Most recurrences were in women who received chemotherapy and thus were identified as being at higher relapse risk from the time of diagnosis. Among these women, there was a benefit in favor of ovarian suppression, and the greatest benefit was seen for those under the age of 35 treated with ovarian suppression plus exemestane.

These studies show that the addition of ovarian suppression to adjuvant tamoxifen did not significantly improve DFS for the entire cohort. For women older than 40 years with small, node-negative tumors, there seems to be no compelling reason to add ovarian suppression to tamoxifen alone. However, for women under 35 and for those who remained premenopausal after chemotherapy and were at high risk for relapse, the addition of ovarian suppression—and, more specifically, the combination of ovarian suppression with an aromatase inhibitor—led to meaningful reductions in the 5-year risk for distant relapse. The magnitude of this benefit was 7.7%. The decision to recommend ovarian suppression needs to be individualized on the basis of estimates of disease recurrence and balanced with the known side effects associated with early menopause.

Quality of Life: Lessons Learned From RCTs

Researchers have been approaching quality-of-life studies with scientific rigor, and this is great news for clinicians searching for recommendations to help their patients maintain their quality of life during treatment and into survivorship.

One study that caught my attention this past year was by Kiecolt-Glaser and colleagues[6] on the benefits of hatha yoga. They reported results of a randomized controlled trial of 200 breast cancer survivors assigned to either 12 weeks of 90-minute, twice-per-week hatha yoga classes, or a wait-list control. The main outcome measures were inflammatory cytokines and scores on validated instruments used to assess fatigue and quality of life. They found a benefit in self-reported vitality and a decrease in fatigue in the group practicing hatha yoga, and these improvements correlated with a decline in inflammatory cytokines.

An important concern for young women is the impact of treatment on ovarian function. Researchers have been studying the potential role of luteinizing hormone-releasing hormone (LHRH) agonists administered during chemotherapy to protect ovarian function, and we are now learning about these results. At the ASCO annual meeting, Dr Halle Moore[7] presented results of the POEMS-S0230 trial.In that trial, 135 patients with ER-negative breast cancers undergoing chemotherapy were randomly assigned to either receive or not receive an LHRH analog during treatment. Researchers found an improvement in rates of ovarian failure: 22% in the control arm vs 8% in the arm assigned to LHRH analog, and a doubling in the number of pregnancies (22 vs 12).

In September, at the ASCO Breast Cancer Symposium, we also heard an update on results of the PROMISE study,[8] an Italian study launched in 2008 to investigate the role of LHRH analogs during chemotherapy to help preserve ovarian function and subsequent fertility. Results also favor the use of LHRH analogs using the same indicators of success—ie, resumption of menses and future pregnancies. It is noteworthy that the patients in the Italian study were not limited to those with ER-negative disease.

The HER2-Positive Story

Neoadjuvant therapy. Prior studies have shown that achieving a pathologic complete response (pCR) after neoadjuvant chemotherapy was associated with improvement in event-free survival and overall survival. The NeoALTTO[9] investigators previously reported that dual HER2 blockade using trastuzumab and lapatinib with paclitaxel chemotherapy led to higher rates of pCR than trastuzumab alone. Women with HER2-positive early breast cancer were randomly assigned to receive oral lapatinib, intravenous trastuzumab, or lapatinib at a reduced dose plus trastuzumab in combination for 6 weeks, followed by an additional 12 weeks of the assigned anti-HER2 therapy in combination with weekly paclitaxel (80 mg/m2). Definitive surgery was done 4 weeks after the last dose of paclitaxel. After surgery, women received three cycles of FEC (fluorouracil 500 mg/m2 plus epirubicin 100 mg/m2 plus cyclophosphamide 500 mg/m2) given intravenously every 3 weeks, followed by 34 weeks of the same assigned neoadjuvant anti-HER2 therapy. The primary endpoint was pCR. Secondary endpoints included event-free and overall survival, and the association between pCR and event-free or overall survival. These data were published this year.[10]

Event-free survival did not differ between the lapatinib and trastuzumab groups, nor between the combination and trastuzumab groups. Three-year overall survival was 93% for lapatinib, 90% for trastuzumab, and 95% for combination therapy. Overall survival did not significantly differ between the lapatinib and trastuzumab groups, nor between the combination and trastuzumab groups. Landmark analyses showed that 3-year event-free survival was significantly improved for women who achieved pCR compared with those who did not, as was 3-year overall survival. This benefit was more robust for those patients with HER2-positive/ hormone receptor–negative cancers.

Adjuvant therapy. Edith Perez and colleagues[11] published a definitive joint analysis of early adjuvant trastuzumab studies, NSABP B-31 and NCCTG N0831, that totaled more than 4000 patients.They found a 37% reduction in mortality risk, which was observed across subgroups according to hormone receptor status, age, tumor size, and nodal involvement.

Metastatic disease. The treatment of metastatic HER2-positive breast cancer is evolving rapidly with the development of effective targeted therapies. Trastuzumab emtansine (Kadcyla®) is an antibody–drug conjugate that delivers DM1 directly to HER2-expressing tumor cells, where it is internalized by lysosomes and promotes apoptosis. This drug was approved in the United States and the European Union as a single-agent treatment for patients with HER2-positive metastatic breast cancer who have previously received trastuzumab and a concurrent or sequential taxane in any setting, on the basis of results from the phase 3 EMILIA trial.[12]

In June, Krop and colleagues[13] published results of the TH3RESA trial,a randomized, open-label clinical trial that compared trastuzumab emtansine (TDM-1) with another regimen left up to the choice of the treating physician, for patients with metastatic breast cancer after progression on two lines of therapy. Progression-free survival was significantly improved with TDM-1 compared with physician's choice, yielding a median of 6.2 months vs 3.3 months. Overall survival analysis showed a trend favoring TDM-1.

And here's another drug to consider. In 2012 the US Food and Drug Administration approved pertuzumab on the basis of early results of the CLEOPATRA trial.[14] This study assigned more than 800 patients with HER2-positive metastatic breast cancer to receive trastuzumab+ docetaxel +/- pertuzumab. Sandra Swain[15] presented the latest results from the CLEOPATRA study final overall survival analysis at the European Society for Medical Oncology (ESMO) meeting in September.The median overall survival for patients receiving pertuzumab plus trastuzumab and docetaxel was 15.7 months longer than for patients who received trastuzumab alone. Dr Swain described it as "unprecedented in first-line treatment."

Inroads in Individualizing Risk and Treatment

Genetics. We are learning more about genes that confer susceptibility to breast cancer and now have access to testing panels that look beyond BRCA1 and BRCA2. The problem is that we cannot offer precise counsel to patients who have some of these less well-understood mutations. One article that received considerable attention was published in the New England Journal of Medicine. Antonis Antoniou and colleagues[16] showed that loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer.

Imaging. Many patients are requesting or demanding preoperative MRIs, and practices vary tremendously, supported by little evidence. Nehmat Houssami and colleagues[17] conducted a meta-analysis of patient personal data and used it to investigate time to recurrence and to estimate the hazard ratio for MRI. They used four studies that provided data on more than 3000 cases. They found no significant benefit in terms of local or distant recurrences detected within the first 8 years for patients who had the more extensive imaging evaluation using MRI.

Predicting response to therapies.Preclinical data suggested that a PIK3CA mutation may confer resistance to trastuzumab. Sibylle Loibl and coinvestigators[18] from the German Breast Group evaluated the association between the presence of PIK3CA mutations and response to anti-HER2 therapy in specimens collected from participants in three prospective neoadjuvant trials.[18] Their data show that patients with a PIK3CA mutation had lower rates of pCR. It is interesting to distinguish these findings from those of previous studies that showed a positive association between PIK3CA mutations and hormone receptor–positive status for HER2-negative breast cancer, and to remind ourselves that this tumor biomarker is an interesting target for studying tumor biology but is not quite ready to inform treatment choices.

More options for prevention. Jack Cuzick[19] reported mature results of IBIS-II,an international study that recruited postmenopausal women between 2003 and 2012. Participants had an increased risk for breast cancer according to age-defined criteria. A total of 1920 women were randomly assigned to receive anastrozole and 1944 to placebo. With a median follow-up of 5 years, they found 40 cases of breast cancer in the anastrozole group and 85 in the placebo group. The predicted cumulative incidence of all breast cancers was 5.6 % in the placebo group and 2.8% in the anastrozole arm. The magnitude of benefit is similar to that of previously reported prevention studies using the aromatase inhibitor exemestane,[20] as well as the SERM's tamoxifen and raloxifene. These studies tell us that for women at greater than average risk who are willing to take medication, we have quite a few choices that can be considered in counseling.

Taking Stock

The incidence and mortality of breast cancer are on the rise worldwide.[21] The incidence of breast cancer is highest in Western Europe, with Northern Europe and Southern Europe not far behind. It is important to remember the magnitude of the impact of this disease on women all over the world and how urgent it is to find ways to improve access to screening and early detection, to provide proper guidance for those with the disease or at high risk, and to develop new and personalized treatments to improve outcomes.


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