Rugo Offers Window Into Evolving Views of ER-Positive Disease

OncologyLive, August 2013, Volume 14, Issue 8

Research efforts are under way to improve the efficacy of hormone therapy in the management of advanced estrogen receptor-positive (ER) breast cancer, including new strategies for targeting the PI3K/ mTOR pathway.

Hope Rugo, MD

Research efforts are under way to improve the efficacy of hormone therapy in the management of advanced estrogen receptor-positive (ER) breast cancer, including new strategies for targeting the PI3K/ mTOR pathway.

During the 12th International Congress on the Future of Breast Cancer, Hope Rugo, MD, tackled this question: Which patients with ER-positive disease should receive PI3K/mTOR blockade as a way to reverse resistance to, or enhance the efficacy of, hormone therapy?

A professor of Medicine and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, Rugo focused her talk on clues generated by the research community about the ideal patient population for the recently approved mTOR inhibitor everolimus and similar drugs in development, while also highlighting the mysteries that still cloud this issue.

Also during the conference, held July 18-20 in Huntington Beach, California, Rugo shared details about guidelines for the treatment of advanced breast cancer set by an international consensus panel, of which she was a member, in 2011.

Her presentation came as the panel readies to update those initial guidelines in November.

In an interview with OncologyLive during the conference, Rugo summarized key points of her talks and looked ahead at other promising developments in breast cancer treatment.

Q: How are investigators trying to learn which patients are most likely to benefit from PI3K/ mTOR blockade? What data are available so far?A:Our current research path stemmed from a failed first-line study, the phase III HORIZON trial1 of letrozole with or without mTOR inhibitor temsirolimus, published this year by Antonio Wolff in the Journal of Clinical Oncology, showing that there wasn’t a benefit from temsirolimus in patients with ER-positive locally advanced or metastatic breast cancer.

Those results raised some questions: Was the lack of efficacy of temsirolimus dosage-related, was it the schedule, was it the drug itself, or simply that mTOR inhibition wouldn’t help in ER-positive breast cancer? So, we followed up with a phase II neoadjuvant trial, Study 22222, of letrozole with or without everolimus, and saw a benefit from the addition of everolimus: a decrease in Ki67 and improved clinical response. Despite having serial tumor samples, detailed analyses of downstream markers were not able to identify a biologic marker that predicted response to neoadjuvant everolimus.

Given the lack of a defined predictive marker, the phase III BOLERO-23 trial of exemestane with or without everolimus was designed to rely on clinical criteria to choose the patients with HR [hormone receptor]-positive breast cancer who were most likely to have activation of the PI3K pathway. A number of studies have suggested that cancers that have been treated with hormone therapy and then recurred have a greater frequency of mutations in PI3K. BOLERO-2 enrolled patients whose cancers had previously been treated with nonsteroidal aromatase inhibitors, and that strategy actually panned out. Treatment with everolimus resulted in better progression-free survival, with more than a doubling in time.

Then, as a prospective planned study, tissue samples were collected from a subset of the patients in BOLERO-2, whose outcomes reflected those of the overall group. NextGen sequencing was done on those tumor samples, and different pathways were analyzed, including PI3K. It turned out that almost half of the tumors had a mutation in PI3K and the rest had less-common mutations that included cell cycle pathway markers as well as fibroblast growth factor receptor and others. Despite these individual mutations, all patients benefited from the addition of everolimus, which was quite curious. It didn’t matter whether the patients had an activation in the PI3K pathway or not.

In addition, the small subset of patients whose tumors had mutations in multiple pathways seemed to have the worst overall outcome, and did not benefit from the addition of everolimus. This is intriguing, and suggests that we could identify a subgroup of patients who require additional targeted therapy and should be considered for enrollment in clinical trials.

After the presentation of our data by Gabriel Hortobagyi at ASCO 2013, colleagues who had worked on the phase II TAMRAD trial4 of tamoxifen plus everolimus in HR-positive advanced breast cancer, in France, presented interesting retrospective data. Investigators evaluated tissue samples from a subset of patients enrolled in TAMRAD and evaluated a number of pathways, including PI3K, an energy pathway that’s marked by a protein called LKD1, and downstream pathway indicators. Their findings suggested that having an abnormality in these markers may have correlated with response to everolimus in the TAMRAD trial, including activation in PI3K. As a result, we are now beginning to understand that our thinking, not just about ER-positive disease but about HER2-positive disease, has been too simplistic and not creative enough. Looking at abnormalities in a single protein, enzyme, receptor, etc, is not good enough. What we need to do now is look at changes in pathways, including all the markers that are part of a specific pathway abnormality, and look at them as indicators of response and resistance.

This will require complex pathway analyses using computer programs, and is clearly the future as we look at combining PI3K pathway inhibitors, mTOR inhibitors, and inhibitors of cyclin dependent kinases 4/6, an exciting new way to try and improve response to hormone therapy. As the complexity of treatment increases, along with the options for therapy, understanding and identifying which tumors and which patients are most likely to benefit from specific strategies will be even more important.

Selected Agents Targeting the PI3K/mTOR Pathway

Agents under study are depicted in the blue boxes; everolimus (Afinitor) already has been approved in certain advanced breast cancer settings. The signaling cascade includes downstream proteins and kinases (gray boxes).

Adapted from Rugo HS. New directions in hormone therapy for advanced breast cancer: who benefits from PI3K/mTOR blockade? Presented at: 12th International Congress on the Future of Breast Cancer; July 18-20, 2013; Huntington Beach, CA.

Q: Are any trials already planned that will look at these factors?A:The majority of trials are enrolling patients based on prior treatment, but a number are also looking at patients whose tumors have mutations in the PI3K pathway to see if these tumors are more likely to benefit from this treatment strategy. A phase I trial evaluating the PI3K inhibitor BYL719 is enrolling patients whose tumors are either wild type or those that have a mutation in PI3K. This approach will allow a better understanding of the usefulness of this specific selection strategy.

The neoadjuvant strategy is particularly important, as tumors can be followed for clinical and pathologic response, and it is possible to analyze tumor tissue before treatment, during therapy, and at surgery. One neoadjuvant approach that’s really significant is the concept that’s embodied in the I-SPY trial design, where patients are randomized to standard chemotherapy with or without a series of novel agents; the primary endpoint is pathologic complete response. Patients have both biopsies and specialized MRI imaging before the start of therapy, three to four weeks into paclitaxel plus novel agent or paclitaxel alone, and tumor tissue is collected at the time of surgery. The main goal of this ongoing multicenter trial is to test multiple novel agents and identify reproducible predictive biomarkers for successful agents. This could then direct us to much smaller trials in the future that are directed appropriately to patients whose tumors have the right biology for the specific agent to be tested.

Q: What kinds of new agents or drug classes are in development to target PI3K/mTOR?A:There are a number of agents in development to target PI3K and mTOR. There are TORC1/2 combo inhibitors, which appear to have a fair amount of toxicity; alpha-specific PI3K inhibitors such as BYL719; pan-PI3K inhibitors such as BKM120; and then inhibitors that block both the mTOR and PI3K (ie, XL765). Some of these drugs are in phase II and III trials and some are still in earlier development, but there are multiple agents in studies, and it will be interesting to see what the effectiveness is in various tumor subsets and compare that to the toxicity of these agents. Some of the toxicities don’t overlap, so it may be that we could avoid some of the troublesome toxicities of mTOR inhibitors but gain the benefits by using these pan-PI3K inhibitors.

Q: During the conference, you also discussed guidelines for the management of advanced breast cancer. What were your key messages?A:As you know, there’s been a panel in St Gallen,Switzerland, bringing together international experts every other year to issue consensus statements on therapeutic options for early-stage breast cancer, based on the data available when the meeting occurs.

Fatima Cardoso, MD, and others had been working on creating guidelines for several years within the international community in the setting of metastatic breast cancer, the group of patients we treat for the longest, and where treatment decisions tend to be less directed by guidelines overall. From this effort the Advanced Breast Cancer (ABC) consensus conference was created.

The first meeting, called ABC1, took place in Lisbon, Portugal in 2011, and was run by Fatima Cardoso, Alberto Costa from the European School of Oncology, Eric Winer, Larry Norton, and others. We talked about some of the most important questions we have to answer in patients with advanced breast cancer: Do we treat based on biology, and in which situations? How do we use hormone therapy, chemotherapy, imaging? What are our goals in therapy? These are a lot of the questions that now are dealt with on an individual basis between the physician and their practice and the patient, so it’s nice to have these guidelines, which are the first standard, global recommendations to be issued for the treatment of metastatic breast cancer.

The first guidelines are always just the beginning, and the second meeting, ABC2, will occur in Lisbon, Portugal, in November of 2013. I think we’ll make significant progress again in discussing how we can take new data and incorporate it into the guidelines.

Q: What are some of the specific recommendations in the first set of guidelines?A:We make recommendations about when to change therapy; for example, not to use tumor markers alone as a marker to change therapy. We also discuss what kind of imaging you should be doing, and state that a PET with a nondiagnostic CT isn’t really adequate, and may lead you to overinterpret progression of disease when, in fact, a patient actually has stable disease. Quality of life is also discussed in the publication summarizing the consensus guidelines published by Fatima Cardoso.

When we met at ABC1, there were limited data on BOLERO-2, so we’ll be able to include that in the next set of guidelines, as well as data from CLEOPATRA, EMILIA, and BOLERO-3.

Q: How should these guidelines factor into decision making in the treatment of advanced breast cancer?A:There’s a collaboration between guidelines like St Gallen, and now ABC, with, for example, NCCN guidelines and also ASCO guidelines, which are not yearly but take into account all the published information and deal with the major topics we face in clinical oncology. They are all interrelated and help us standardize our treatments using published information, guided by the studies that are done with the best information and the most power to answer a question, rather than by individuals or small randomized trials. It’s a great step in terms of treating patients in the best possible way.

That said, in terms of guidelines for metastatic breast cancer, these should be taken back to the clinic, and taken in context. It is critical to make decisions together with the patient and discuss goals of therapy. This was all information that can be incorporated to develop the best treatment plan at each decision point.

Timeline of Hormone Strategies to Treat Breast Cancer

Adapted from Rugo HS. New directions in hormone therapy for advanced breast cancer: who benefits from PI3K/mTOR blockade?

Presented at: 12th International Congress on the Future of Breast Cancer; July 18-20, 2013; Huntington Beach, CA.

Q: Where can the ABC1 guidelines be found?A:The important thing about the guidelines is not just having the meeting and the consensus, but spreading that information internationally. Fatima Cardoso and the members of the consensus panel published the guidelines5 shortly after the meeting, and we expect that the ABC2 data will be published fairly quickly after the conclusion of our next meeting.

Q: When you look ahead at breast cancer treatment, what developments stand out as being particularly promising?A:There are a lot of exciting things going on in breast medicine now. We’re excited to see rapid advances in other cancers where there weren’t as many options before, and one of the areas we hope to translate into effective therapy for breast cancer is immune modulation, either through vaccine therapy (several are in clinical trials in the adjuvant and metastatic setting, including one that targets tumors with minimal expression of HER2, and another that targets the carbohydrate antigen Globo H on breast cancer cells) or with other approaches, for example blocking activated macrophages to modulate the host immune response to tumor.

Research by Lisa Coussens6 and colleagues now at Oregon Health & Science University, suggests that blocking macrophages may enhance chemotherapy antitumor effects in resistant breast cancers. Based on these data, we have started a very exciting clinical trial, funded by a Komen Promise Grant, combining the chemotherapy drug eribulin with the macrophage inhibitor PLX3397 in patients with triplenegative breast cancer.

This is an exciting time for metastatic breast cancer with multiple new agents being investigated based on strong preclinical data, like cyclin-dependent kinase inhibitors for hormone receptor-positive disease. Immunotherapy is a new area of exploration for breast cancer, and I think we’re now just at the verge of being able to have success in this area.


  1. Wolff AC, Lazar AA, Bondarenko I, et al. Randomized phase III placebo- controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer [published online ahead of print December 10, 2012]. J Clin Oncol. 2013;31(2):195-202.
  2. Baselga J, Semiglazov V, van Dam P, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer [published online ahead of print April 20, 2009]. J Clin Oncol. 2009;27(16):2630- 2637.
  3. Baselga J, Campone M, Piccart M, et al. Everolimus in Postmenopausal Hormone-Receptor—Positive Advanced Breast Cancer [published online ahead of print December 7, 2011]. N Engl J Med. 2012;366(6):520-529.
  4. Bachelot T, Bourgier C, Cropet C, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor— positive, human epidermal growth factor receptor 2–negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study [published online ahead of print May 7, 2012]. J Clin Oncol. 2012;30(22):2718-2724.
  5. Cardoso F, Costa A, Norton L, et al. 1st international consensus guidelines for advanced breast cancer (ABC1) [published online ahead of print March 16, 2012]. Breast. 2012;21(3):242-252.
  6. Ruffell B, Au A, Rugo HS, et al. Leukocyte composition of human breast cancer [published online ahead of print August 8, 2011]. Proc Natl Acad Sci U S A. 2012;109(8):2796-2801.