COMMENTARY

Highlights From the European Cancer Congress: Breast Cancer

Giuseppe Curigliano, MD, PhD

Disclosures

October 23, 2015

Proffered Papers

Final Results of the TURANDOT Trial: Seeking a Niche for Bevacizumab in Metastatic Breast Cancer

Study background. Dr Thomas Brodowicz presented final results of the TURANDOT trial,[1] an open-label, randomized, phase 3 study designed to demonstrate noninferior overall survival (OS) with first-line bevacizumab and capecitabine vs bevacizumab and paclitaxel for locally recurrent and metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The interim analysis did not confirm noninferior OS (stratified hazard ratio [HR], 1.04).

At the European Cancer Congress (ECC), investigators reported the final OS analysis. Stratification factors were estrogen receptor (ER)/progesterone receptor status, country, and menopausal status. For the primary final OS analysis in the per-protocol population following death in 183 of 266 patients (69%) in the bevacizumab-paclitaxel arm and 201 of 265 (76%) in the bevacizumab-capecitabine arm (median OS, 30.2 vs 26.1 months, respectively), the stratified HR was 1.02 (97.5% repeated confidence interval [CI]: ‒0.9 to 1.26) indicating noninferiority.

However, the unstratified Cox model (HR, 1.13; 97.5% repeated CI: 0.9-1.39) was not supportive. Intention-to-treat analyses were consistent with the per-protocol results.

While the primary objective was met at the final OS analysis, inconsistency between stratified and unstratified OS results and heterogeneity between subgroups are being explored further.

Comment. It is common to end a clinical trial with the admonishment that the current study underscores the need for more research, and that call seems particularly hollow when more than five randomized trials, a large prospective treatment registry, and extensive reviews by American, UK, and European regulatory agencies are available. Some patients may benefit from a combination including chemotherapy plus bevacizumab, and data from the neoadjuvant setting should be taken into account. As clinicians, we need to determine whether bevacizumab plus chemotherapy is a genuine advance for metastatic breast cancer—including who benefits and at what cost—and whether or not bevacizumab-based treatment can serve as a practical foundation for subsequent developments in the field.

No Difference in Long-term Outcome After Neoadjuvant Chemotherapy With Trastuzumab or Lapatinib

Study background. Dr Michael Untch presented final data from the GeparQuinto trial.[2] In the HER2-positive setting, study patients received lapatinib or trastuzumab in addition to anthracycline-taxane–based neoadjuvant chemotherapy.

Safety data showed that the lapatinib combination was more frequently discontinued or reduced in dose, and a subsequent protocol amendment reduced the lapatinib dose from 1250 mg/day to 1000 mg.

The pathologic complete response (pCR) rate with lapatinib was significantly lower than in the combination with trastuzumab (22.7 vs 30.3%; P=.004). At ECC, investigators presented final data on distant disease-free survival (DDFS), disease-free survival (DFS), and OS analyses.

Patients with HER2-positive tumors of a median size of 4 cm were randomly assigned to neoadjuvant treatment with 4x epirubicin-cyclophosphamide followed by 4x docetaxel plus either lapatinib (1000-1250 mg/d orally daily for 24 weeks) or trastuzumab (6 mg/kg intravenously, with a starting loading dose of 8 mg/kg, every 3 weeks for 8 cycles) before surgery.

Patients completed postsurgery trastuzumab treatment for 1 year in both treatment groups. Endocrine therapy and radiation therapy were given according to the effective guidelines.

A total of 120 events were required to show a HR of 0.6 (P=.05) between the two treatment arms. The required number of events, including 58 deaths, was observed after a median follow-up of 54.9 months.

Overall, there was no statistically significant difference for patients receiving lapatinib as part of the neoadjuvant therapy (DDFS: HR, 0.96; P=.826; DFS: HR, 1.06; P=.766; OS: HR, 0.77; P=.313) compared with patients receiving trastuzumab. None of the predefined subgroups—hormone receptor (HR) positive vs negative; cT1-3 vs cT4a-c vs cT4d disease; pCR vs none; complete response vs partial response vs no change or progressive disease after first 4 cycles of chemotherapy—derived a benefit from lapatinib, except patients with locally advanced (cT4 or cN3) tumors, who showed an improved DDFS (HR, 0.45; P=.049; interaction test P=.028) and DFS (HR, 0.45; P=.044; interaction test P=.011), but not OS (HR, 0.43; P=.068; interaction test P=.118), by using lapatinib compared with patients with cT1-3/cN0-2 disease.

Comment. The 6-month landmark analysis demonstrated a significantly better OS for women achieving a pCR irrespective of the treatment. Only patients with locally advanced disease seem to benefit from lapatinib and/or the longer duration of anti-HER2 treatment. Lapatinib is more frequently discontinued or dose reduced due to toxicity. Finally, long-term results do not support the neoadjuvant use of lapatinib in addition to an anthracycline-taxane–based chemotherapy for patients with HER2-positive disease.

Targeting the AR in Triple-Negative Breast Cancer: In Search of a Predictive Assay

Study background. Dr Javier Cortes delivered a great lecture on the role of enzalutamide in triple-negative breast cancer. This is a heterogeneous disease composed of multiple subtypes and oncogenic drivers, including a subtype that may be driven by androgen receptor (AR) signaling. Enzalutamide, a potent AR signaling inhibitor, significantly improves OS in metastatic castration-resistant prostate cancer and is currently being developed for patients with breast cancer who have an androgen-driven gene signature.

The open-label, Simon 2-stage study evaluated enzalutamide in AR-positive, triple-negative breast cancer (AR >0% by immunohistochemistry).[3] The primary endpoint was clinical benefit (complete response, partial response, or stable disease) at 16 weeks. Secondary endpoints were OS, progression-free survival (PFS), clinical benefit at 24 weeks, response rate, and safety. An androgen-driven gene signature (PREDICT AR) was derived from gene-profiling analysis and evaluated in two additional independent datasets. Of 118 patients enrolled, 56 (47%) were AR-positive.

Fifty-three OS events were reported in the intention-to-treat population, with a median follow-up of 9.7 months. The median OS was 12 months (95% CI, 7.1-not yet reached) in the intention-to-treat population. For AR-negative (n=62) vs AR-positive (n=56) subgroups, the median OS was 7.1 months (95% CI, 4.8-11.2) vs not yet reached (95% CI, 12.8-not yet reached), and median PFS was 1.9 months (95% CI, 1.7-2.9) vs 3.7 months (95% CI, 3.1-6.3), respectively. The investigators concluded that enzalutamide may represent a novel therapeutic option in AR-positive patients who would otherwise receive cytotoxic chemotherapy.

Comment. Is the AR pathway a new target in triple-negative breast cancer? Probably yes in the androgen molecular subtypes. The benefit observed in AR-positive patients should be confirmed in a large, prospective, randomized trial. Proof-of-concept trials in molecularly selected patients should be designed, exploring the combination of enzalutamide with other targeted agents such as PIK3CA inhibitors.

Final Results of the PEGGY Trial: PI3K Inhibitors in the Treatment of HR-Positive/HER2-Negative Metastatic Breast Cancer

Study background. Dr Peter Vuylsteke presented the final results of the PEGGY trial,[4] a multicenter, randomized, placebo-controlled, phase 2 trial that was designed to test whether pictilisib, a class I phosphoinositide 3-kinase (PI3K) inhibitor, augments the antitumor activity of paclitaxel in patients with HR-positive, HER2-negative locally recurrent or metastatic breast cancer. At least one third of HR-positive, HER2-negative breast cancers are associated with PI3K pathway-activating mutations, and preclinical data suggest that pictilisib may potentiate the effect of taxanes and benefit patients with or without aberrant activation of the PI3K pathway.

Results from the protocol-specified planned interim analysis were reported at ECC.

Overall, 183 eligible patients not previously treated with intravenous chemotherapy for metastatic breast cancer were randomly assigned 1:1 to receive paclitaxel (90 mg/m2 weekly for 3 out of 4 weeks in every 28-day cycle) with either 260 mg pictilisib or placebo (daily on days 1-5 of every week).

The primary endpoint was PFS in the intention-to-treat population and in patients with PIK3CA mutations. Secondary endpoints included overall response rate (ORR), duration of response, and safety. Safety analyses were based on patients who received at least one dose of study drug and by actual treatment received.

Median PFS in the intention-to-treat population was 8.2 months with pictilisib (n=91) and 7.8 months with placebo (n=92; HR for progression or death, 0.95; 95% CI, 0.62-1.46; P=.83). In patients with PIK3CA mutations, median PFS was 7.3 months with pictilisib (n=32; 35.2%) and 5.8 months with placebo (n=30; 32.6%; HR, 1.06; 95% CI, 0.52-2.12; P=.88). ORR was similar with pictilisib or placebo (22% and 20%, respectively). Median treatment duration in the intention-to-treat population was 5.4 months with pictilisib and 5.8 months with placebo, while median pictilisib and placebo dose intensities were 91.7% and 98.6%, respectively. Proportions of grade 3 or greater adverse events (AEs), serious AEs, and dose reductions or discontinuations due to AEs were higher with pictilisib than with placebo. The safety profile of pictilisib was consistent with previous reports, including grade 3 or greater AEs in 67.0% of patients, serious AEs in 36.3%, AEs leading to dose reduction in 30.8%, and AEs leading to pictilisib discontinuation in 17.6%.

PEGGY did not meet its primary endpoint in either the intention-to-treat or PIK3CA-mutant populations and revealed that there is no significant benefit to adding pictilisib to paclitaxel for patients with HR-positive, HER2-negative locally recurrent or metastatic breast cancer.

Comment. The results of the PEGGY trial are quite disappointing. PI3K inhibitors are a promising new class of agents in the treatment of breast cancer. The FERGI trial, presented at the San Antonio Breast Cancer Symposium last year, explored the combination of fulvestrant and pictilisib in metastatic, ER-positive breast cancer and failed to demonstrate a benefit in terms of response rate and PFS. Toxicity-induced drug reduction and discontinuation were confirmed in the PEGGY trial.

Are all PI3K inhibitors the same? Should we expect less toxicity from alpha-selective PI3K? What are the clinical utility and clinical validity of PI3K mutations in predicting response to PI3K inhibitors? We will wait for upcoming results of many randomized phase 3 trials to have answers to all of these questions.

Navigating the Road of Precision Medicine: The Driver Landscape of Breast Cancer Metastasis and Relapse

Study background. Dr Lucy Yates from the Wellcome Trust Sanger Institute presented exciting data at ECC on the genomic landscape on metastatic breast cancer.[5]

Up to 80% of patients presenting with primary breast cancers are cured by current treatment, but in more than 20% of cases, local or distant relapse occurs. The current understanding of the driver landscape of breast cancer is drawn from datasets derived almost entirely from primary breast cancers, yet we do not know how representative these are of the cancers that fail to be cured by existing treatments.

To determine how the driver landscapes of primary and relapsed breast cancers differ, the investigators analyzed massively parallel sequencing data from 1000 subjects' breast cancers. They identified somatic mutations in 365 genes known to be involved in or related to cancer processes. For 161 patients, samples were derived from local relapse and/or distant metastatic deposits and were sequenced. For comparison, they gathered the previously published mutation calls from exome sequencing of 839 primary, localized breast cancers. De novo driver mutation discovery was performed, and individual mutations were annotated with likely driver status based upon recurrence and known driver status in previously published, well-curated datasets and databases. The incidence of each driver mutation in the primary and relapse datasets was compared using Fisher's exact tests and using the Benjamini Hochberg correction for multiple testing.

Multiple samples were available for 66 subjects, including local or distant relapse samples in all cases and a sample from the primary tumor in 21 cases. Multisample analysis permitted relative temporal ordering of driver mutation accumulation. Driver mutations arising late in evolution were sampled from a greater set of driver genes than those occurring early. A novel tumor suppressor role for some cancer genes was established. Among established tumor suppressor genes, TP53 and ARID1A were the genes most strongly associated with relapse and metastasis in ER-positive disease.

Aberrations in the PI3K-AKT pathway were frequent in both ER-positive (57%) and, surprisingly, triple-negative (37%) cancers at relapse, while the role in the latter was infrequent among primary tumors. Mutations in the estrogen signaling genes FOXA1 and ESR1, but not GATA3, were enriched at relapse and metastasis.

The investigators demonstrated that there are clear differences within the driver landscapes of relapsed cancers, suggesting that this probably reflects a combination of predisposition to relapse and of differences in the mutations acquired during the relapse and metastasis phase. Understanding these differences will help to identify high-risk groups and guide the application of targeted therapies in the relapse setting.

Comment. The mutational landscape of breast cancer relapse or metastasis is major topic of discussion because identification of driver mutations may offer therapeutic opportunities in the adjuvant setting. It is very interesting to highlight the role of ESR1 mutations enriched in metastases of ER-positive breast cancers. This observation has a potential therapeutic impact. DNA sequencing will allow better treatments for small niches of patients, maximizing benefit and minimizing toxicities.

DETECTing Discordant HER2 Phenotype Between Primary Tumors and Circulating Tumor Cells

Study background. The last talk in the Breast Cancer Proffered Paper Session was delivered by Dr Wolfgang Janni.[6] He presented the results of the DETECT study, including data on both the prevalence and HER2 phenotype of circulating tumor cells (CTCs) in patients with HER2-negative metastatic breast cancer screened and their association with primary tumor and patient characteristics.

The number of CTCs and their HER2 status were evaluated in 1123 women with HER2-negative metastatic breast cancer. Patients were defined as CTC positive if at least one CTC was detected in 7.5 mL of peripheral blood, and patients were defined as having a positive HER2 status on CTCs if at least one CTC with a strong (+++) immunocytochemical HER2 staining intensity was found.

CTCs were detected in 711 (63.3%) of 1123 screened patients (median 7 CTCs, range, 1-35,078). Out of the 711 CTC-positive patients, 139 (19.5%) had one CTC, 184 (25.9%) had two to five CTCs, 90 (12.7%) had six to 10 CTCs, 175 (24.6%) had 11 to 50 CTCs, and 123 (17.3%) had more than 50 CTCs. The presence of CTCs was significantly associated with a higher proportion of pN2/pN3 tumors (28.3% vs 19.9%; P=.008) and a higher proportion of lobular carcinomas (22.5 vs 9.5%; P<.001) but not with grading (P=.326) or HR status (P=.103) of the primary tumor. In addition, the presence of CTCs was not associated with age at screening (P=.313), menopausal status at screening (P=.823), or the time interval between primary diagnosis and screening (P=.992).

At least one HER2-positive CTC was found in 134 (18.8%) of the 711 HER2-negative MBC patients with CTCs (median, two HER2-positive CTCs; range, one to 80), indicating frequent discordance between primary tumor and CTCs with regard to HER2 status. Out of the 134 patients with HER2-positive CTCs, 51 (38.1%) had one HER2-positive CTC, 48 (35.8%) had two to five HER2-positive CTCs, 15 (11.2%) had six to 10 HER2-positive CTCs, 16 (11.9%) had 11 to 50 HER2-positive CTCs, and four (3.0%) had more than 50 HER2-positive CTCs.

The presence of HER2-positive CTCs was associated with HR-positive primary tumors; in other words, patients with triple-negative tumors were less likely to have HER2-positive CTCs than patients with HER2-negative but HR-positive tumors (6.1% vs 21.9%; P<.001).

Based on a large cohort of patients with HER2-negative metastatic breast cancer, the data confirmed discordance in HER2 status between primary tumor and CTCs in 18.8% of patients. Furthermore, the presence of HER2-positive CTCs was associated with HR-positive tumors. The efficacy of individualized breast cancer treatment based on the HER2 phenotype of CTC is currently being investigated in the randomized DETECT III trial.

Comment. The clinical implications of the DETECT study are relevant. Is it possible to use liquid biopsy to select targeted therapies in patients with metastatic breast cancer? Does the phenotype of CTCs reflect the biology of metastatic clones?

We should deal with heterogeneity in breast cancer and, maybe, in the future, we may use liquid biopsy instead of biopsy of the metastatic site to select and to predict response or resistance to targeted agents.

Scientific Symposium: Triple-Negative Breast Cancer—Biomarkers and Opportunities for Individualized Therapy

Background. Triple-negative breast cancer comprises a highly diverse collection of cancers. There is diversity both in terms of gene expression subtypes and the repertoire of molecular events. Transcriptomic analyses of triple-negative breast cancer have revealed at least six subtypes; luminal AR cancers are the most distinct triple-negative breast cancer subtypes associated with PIK3CA mutations and apocrine histology. The immunomodulatory subtype is likely composed of all other subtypes, with the gene-expression consequences of lymphocytic infiltration dominating the gene-expression subtyping. Although current data suggest that BRCA1-mutant triple-negative breast cancer cell lines fall in the basal-like 1 triple-negative breast cancer subtype, it is unclear if this association will also be seen in other triple-negative breast cancers.

Distinct from the gene-expression subtypes, a diverse set of genetic events have been described in triple-negative breast cancer, with a number of potentially targetable genetic events found although all at relatively low frequency. Trials to define the clinical impact of therapies targeting these low-frequency events will require substantial screening efforts to identify sufficient numbers of patients. Set against the diversity of triple-negative breast cancer, clinical studies of patients with triple-negative disease will need to be either focused on molecularly defined subsets with upfront molecular stratification or powered for a secondary endpoint analysis of a molecularly defined subset. Such approaches will be crucial to realize the potential of precision medicine for patients with triple-negative breast cancers.

Comment. Discussion during this multidisciplinary session was quite exciting. The complexity of triple-negative breast cancers and the poor prognosis could lead to a nihilistic view of our ability to treat this subset of cancers. Due to molecular characterization, there is space to design challenging clinical trials; and if recent advances in technology are incorporated into the armamentarium of oncologists and pathologists to define the genetic make-up of cancers, we may identify the most appropriate targeted therapy for each individual patient. By combining pathology with next-generation sequencing, gene-expression profiling, and bioinformatics, it will be possible to address the diversity of triple-negative breast cancers on a large scale and to start tackling the rare subtypes of triple-negative breast cancer.

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