International Trials Reveal New Findings in the Management of Breast and Ovarian Cancers

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The European Society for Medical Oncology (ESMO) 2017 Congress, held in Madrid, featured important news including at least seven practice-changing or potentially practice-changing trials, which are covered in recent issues of The ASCO Post. Here we present additional highlights of studies in breast and ovarian cancer that augment our meeting coverage. 

Fulvestrant at 250 mg Adds No Benefit to Anastrozole

GEICAM 2006-10 was the first study exploring the efficacy of fulvestrant (Faslodex) in the adjuvant treatment of early breast cancer.1 Complete estrogen blockade with the combination of an aromatase inhibitor, to reduce serum estradiol levels to a minimum, plus a selective estrogen receptor degrader (SERD) to prevent the activation of tumor estrogen receptors, may be beneficial in the adjuvant treatment of hormone-responsive breast cancer, the investigators explained. 

Unfortunately, patients who received fulvestrant at 250 mg plus anastrozole had no improvement in disease-free survival over those receiving anastrozole alone, Manuel Ruiz-Borrego, MD, of the Hospital Universitario Virgen del Rocío in Seville, Spain, reported at the ESMO 2017 Congress. “The study failed to demonstrate a statistically significant increase in disease-free survival with the addition of fulvestrant (250 mg) to anastrozole, … although no formal conclusion can be extracted from this trial, because the sample size was less than half the planned size,” he commented, explaining that the study was stopped early. “We also know that 250 mg is not the right dose.” 

The study included 870 patients who had undergone surgery for early breast cancer, randomized to anastrozole at 1 mg/d for 5 years or anastrozole plus fulvestrant at 500 mg on day 0, 250 mg on days 14 and 28, and 250 mg every 38 days thereafter for the first 3 years. Approximately 60% of each arm also received adjuvant chemotherapy, and about 8% received neoadjuvant chemotherapy.

The 5-year disease-free survival rate was 91.0% with the combination and 90.8% with anastrozole alone (P = .3569). Breast cancer–specific survival was 93.2% and 92.4% (P = .5670), and overall survival was 95.3% and 94.8%, respectively (P = .5642).

Nadia Harbeck, MD, PhD

Nadia Harbeck, MD, PhD

The researchers said further testing of fulvestrant in the adjuvant setting is warranted using the current recommended dose of 500 mg, either alone, in sequence, or in combination with aromatase inhibitors.

Invited discussant Nadia Harbeck, MD, PhD, of the University of Munich (LMU), agreed. “I just want to urge that you don’t take this as evidence of nonefficacy of a SERD in the adjuvant setting. It’s a trial with an underdosed drug, and there could be better results with a novel compound to come or even with fulvestrant at the now registered higher dose,” she said.

‘Priming’ Tumor Microenvironment for Immunotherapy 

TONIC is the first trial to explore whether “immune induction” using radiation or chemotherapy could modulate the anticancer immune response—turn “cold” nonimmunogenic tumors into “hot” ones—and increase the activity of drugs targeting the programmed cell death protein 1 (PD-1). The first results of this phase II trial were presented at the ESMO meeting by Marleen Kok, MD, PhD, of the Netherlands Cancer Institute, Amsterdam.2

Marleen Kok, MD, PhD

Marleen Kok, MD, PhD

In 5 cohorts of 10 patients each, prior to treatment with nivolumab (Opdivo), 50 women with metastatic triple-negative breast cancer received a 2-week induction with radiotherapy to one metastatic lesion or low-dose chemotherapy (doxorubicin, cyclophosphamide, or cisplatin). One cohort was the control arm and received no induction therapy. 

For all patients combined, the objective response rate was 24%, and the clinical benefit rate was 26%. At a median follow-up of 10.8 months, the median duration of response was 9 months, and at 1 year, 83% of responders were alive compared to 13% of patients who did not respond to nivolumab. 

The researchers concluded that treatment with nivolumab is feasible after priming the tumor microenvironment with either radiotherapy or chemotherapy and results in a response rate that appears to be higher than expected, based on previous monotherapy studies of PD-1/programmed cell death ligand 1 (PD-L1) blockade in unselected patients. 

Importance of Tumor-Infiltrating Lymphocytes 

Two studies presented at the ESMO Congress showcased the emerging relevance of tumor-infiltrating lymphocytes in breast cancer.3,4 Tumor-infiltrating lymphocytes represent CD8-positive T cells, and their presence may indicate preexisting antitumor immunity. In early-stage triple-negative breast cancer, increased levels of tumor-infiltrating lymphocytes are prognostic for improved outcomes, including longer overall survival, but data have been limited on their importance in metastatic breast cancer.

Carmen Criscitiello, MD, PhD

Carmen Criscitiello, MD, PhD

An international research team developed a four-gene signature that predicted the extent of tumor-infiltrating lymphocytes in residual disease after anthracycline-based neoadjuvant chemotherapy in patients with triple-negative breast cancer.3 “We aimed to develop a genomic signature from pretreatment samples to predict the extent of tumor-infiltrating lymphocytes after neoadjuvant chemotherapy and then to test its prognostic value on survival,” said Carmen Criscitiello, MD, PhD, of the European Institute of Oncology in Milan, Italy. 

Using 99 pretreatment samples as the training set and 185 patients as the validation set, the researchers found that a 4-gene signature combining the expression levels of HLF, CSCL13, SULT1E1, and GBP1—genes associated with immune activation—predicted residual tumor-infiltrating lymphocyte levels. High expression of this profile, compared to low expression, was associated with improved disease-free and overall survival, Dr. Criscitiello reported. 

For patients with high expression, the hazard ratios were 2.12 for distant relapse–free survival (P = .016) and 2.34 for overall survival (P = .009) in the training data set. In the validation data set, the hazard ratios for distant relapse–free survival were 3.08 (P = .003) among patients with residual disease and 1.94 (P = .037) for the entire data set, Dr. Criscitiello reported. 

Discussing the study, Valentina Guarneri, MD, of the University of Padua in Italy, commented, “There is an opportunity in patients with low pre-neoadjuvant chemotherapy tumor-infiltrating lymphocytes to discriminate subjects with different probabilities of benefitting from chemotherapy-induced immune stimulation. In this context, this signature can improve the selection of patients who are candidates for alternative approaches.”

Sherene Loi, MD

Sherene Loi, MD

In metastatic triple-negative patients in the KEYNOTE-086 trial,4 the level of tumor-infiltrating lymphocytes, as measured on a simple hematoxylin and eosin–stained slide, was significantly associated with response to pembrolizumab, particularly in the first-line setting, according to Sherene Loi, MD, of the Peter MacCallum Cancer Center in Melbourne. Dr. Loi and her team measured tumor-infiltrating lymphocyte levels in 146 newly collected samples and 47 archival samples; 28.5% of the samples came from the primary tumor, and 71.5% were from a nonprimary site. The level of tumor-infiltrating lymphocytes significantly varied by study cohort and by the time and site of biopsy. The highest levels were observed in the lung, breast, and lymph nodes. 

Each 1% increase in tumor-infiltrating lymphocyte level was associated with a 2% increase in the odds of achieving a response. Tumor-infiltrating lymphocyte level was positively correlated with expression of PD-L1 and (along with lactate dehydrogenase) was an independent predictor of response. 

Neratinib in Early HER2-Positive Breast Cancer

The addition of neratinib (Nerlynx), a dual inhibitor of HER2 and epidermal growth factor receptor (EGFR), to the adjuvant treatment of patients with early-stage HER2-positive breast cancer previously treated with 1 year of trastuzumab (Herceptin) significantly improved invasive disease–free survival, according to 5-year follow-up of the phase III ExteNET trial.5

ExteNET enrolled 2,840 patients with early HER2-positive breast cancer and randomized them to receive oral neratinib at 240 mg/d or placebo for 1 year following adjuvant therapy with trastuzumab. 

The estimated 5-year improved invasive disease–free survival rate was 90.2% in the neratinib arm vs 87.7% in the placebo arm, representing a significant 37% reduction favoring neratinib (P = .008). A prespecified subgroup analysis suggested that the benefit was greater in hormone receptor–positive patients, 94% of whom received concurrent endocrine therapy.

“This analysis provides important evidence of the sustained clinical benefits neratinib can offer women with HER2-positive operable breast cancer previously treated with trastuzumab,” said lead author Miguel Martin, MD, PhD, of Hospital Universitario Gregorio Marañon, Madrid.5

Diarrhea was the most common cause of treatment discontinuation with neratinib, occurring in about 17% of patients, he said.

This analysis provides important evidence of the sustained clinical benefits neratinib can offer women with HER2-positive operable breast cancer previously treated with trastuzumab.
— Miguel Martin, MD, PhD

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Neratinib is not the first drug to show extended improved invasive disease–free survival in this setting, Dr. Martin noted. The APHINITY trial showed that the addition of pertuzumab (Perjeta) to trastuzumab achieved a 3-year improved invasive disease–free survival rate of 94.1% vs 93.2% with trastuzumab alone. 

“In neratinib and pertuzumab we appear to have two drugs that provide a slight improvement over trastuzumab alone, but further study is needed to determine which patients would benefit most from these treatments,” Dr. Martin said. 

Previous studies have suggested that about 24% of patients with early-stage HER2-positive breast cancer treated with adjuvant trastuzumab will experience a recurrence over the long term, suggesting that better treatments are needed.

ICON8 Reaffirms Standard of Care for Ovarian Cancer

According to results of the phase III ICON8 trial, weekly dose-dense chemotherapy with paclitaxel was tolerable but did not improve progression-free survival compared with every-3-week paclitaxel when both schedules were given in combination with carboplatin for first-line therapy of epithelial ovarian/fallopian tube/primary peritoneal carcinoma.6 Thus, standard 3-weekly paclitaxel remains the standard of care in this setting.

Dose-dense chemotherapy with paclitaxel as part of the first-line treatment of epithelial ovarian/fallopian tube/primary peritoneal carcinoma cannot be recommended as a standard-of-care treatment option for patients with epithelial ovarian cancer.
— Andrew R. Clamp, PhD

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“Dose-dense chemotherapy with paclitaxel as part of the first-line treatment of epithelial ovarian/fallopian tube/primary peritoneal carcinoma cannot be recommended as a standard-of-care treatment option for patients with epithelial ovarian cancer,” said lead investigator Andrew R. Clamp, PhD, of The Christie NHS Foundation Trust and the University of Manchester, UK.

Interestingly, the ICON8 results differ from those of the JGOG 3016 study in Japanese patients with ovarian cancer, which showed prolonged progression-free survival by 11 months for dose-dense weekly paclitaxel vs standard 3-weekly therapy.7 

“Thus, it remains appropriate to continue to offer weekly dose-dense paclitaxel as a treatment option to Japanese women,” Dr. Clamp stated.

“Platinum/paclitaxel for 6 to 8 cycles every 3 weeks has been the cornerstone of chemotherapy for the treatment of ovarian cancer. There has been a strong rationale for the evaluation of weekly dose-dense paclitaxel based on preclinical and clinical evidence, including the JGOG3016 trial,” he said.

ICON8 randomized 1,566 predominantly European patients with stage IC–IV disease to receive 6 cycles of standard every-3-week dosing of carboplatin/paclitaxel (carboplatin at AUC 5/6, paclitaxel at 175 mg/m2) vs two different regimens that included once-weekly dose-dense paclitaxel (arm 2: carboplatin at AUC 5/6, paclitaxel at 80 mg/m2 weekly; arm 3: carboplatin at AUC 2, paclitaxel at 80 mg/m2 weekly). All patients had primary surgery or received neoadjuvant chemotherapy with planned delayed surgery. No progression-free survival benefit was observed for either of the once-weekly regimens. 

Median progression-free survival was 17.9 months with standard dosing vs 20.6 months and 21.1 months in arms 2 and 3, respectively (hazard ratio = 0.92 [P = .45] for arm 2 vs arm 1, and 0.94 [P = .56] for arm 3 vs arm 1).

The rates of grade 3 to 4 toxicity were slightly increased in the weekly arms vs standard chemotherapy, primarily due to uncomplicated hematologic toxicity.■

DISCLOSURE: Drs. Harbeck, Criscitiello, Guarneri, and Martin reported no conflicts of interest. Dr. Kok’s institute has received an unrestricted research grant from BMS/ II-ON, and she has received travel support from Roche. Dr. Loi’s institution has received research fundng from Merck, and she is on advisory boards -(uncompenstated) for Merck.


1. Ruiz-Borrego M, Jimenez MM, Ruiz A, et al: Phase III trial evaluating the addition of fulvestrant to anastrozole as adjuvant therapy in postmenopausal women with hormone receptor-positive HER2-negative early breast cancer: GEICAM 2006-10. ESMO 2017 Congress. Abstract 148O. Presented September 8, 2017.

2. Kok M, Horlings H, van de Vijver K, et al: Adaptive phase II randomized non-comparative trial of nivolumab after induction treatment in triple negative breast cancer. ESMO 2017 Congress. Abstract LBA14. Presented September 9, 2017. 

3. Criscitiello C, Bayer M, Curigliano G, et al: A gene signature of chemo-immunization to predict outcome in patients with triple negative breast cancer treated with anthracycline-based neoadjuvant chemotherapy. ESMO 2017 Congress. Abstract 217O. Presented September 9, 2017.

4. Loi S, Adams S, Schmid P, et al: Relationship between tumor-infiltrating lymphocyte levels and response to pembrolizumab in metastatic triple-negative breast cancer: Results from KEYNOTE-086. ESMO 2017 Congress. Abstract LBA13. Presented September 9, 2017.

5. Martin Jimenez M, Ejlertsen B, Holmes FA, et al: Neratinib after trastuzumab-based adjuvant therapy in early stage HER2-positive breast cancer: 5-year follow-up of the phase III ExteNET trial. ESMO 2017 Congress. Abstract 149O. Presented September 8, 2017.

6. Clamp AR, McNeish I, Dean A, et al: OCON8: A GCIG phase III randomized trial evaluating weekly dose-dense chemotherapy integration in first-line epithelial ovarian/fallopian tube/primary peritoneal carcinoma treatment: Results of primary progression-free survival analysis. ESMO 2017 Congress. Abstract 929O_PR. Presented September 8, 2017.

7. Katsumata N, Yasuda M, Isonishi S, et al: Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): A randomised, controlled, open-label trial. Lancet Oncol 10:1020-1026, 2013.

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More Data From ESMO 2017

  • In GEICAM 2006-10, the addition of fulvestrant at 250 mg/d to anastrozole did not improve 5-year disease-free survival over anastrozole alone (91.0% vs 90.8%). 
  • “Immune induction” with chemotherapy or radiotherapy appeared to enhance response to nivolumab in women with metastatic triple-negative ...