	Treating estrogen receptor (ER)—positive breast cancer without sparking resistance is a complex endeavor that should involve simultaneously targeting the hormone-signaling and PI3 kinase (PI3K) molecular pathways

, according to Sarat Chandarlapaty, MD, PhD.

	Chandarlapaty focused on how the two pathways cooperate in breast tumor progression, and discussed the development of combination treatments to target both channels during a presentation at the 11th International Congress on the Future of Breast Cancer, held in July in Coronado, California.

	The PI3K/AKT/mTOR cascade is a nuclear pathway that is commonly activated in breast cancer, particularly in ER-positive disease. That and other pathways control normal cell physiology, such as growth, size, division, movement, and survival, but are frequently modified in ER-positive breast cancer, Chandarlapaty said.

 mutations were found in 35% of ER-positive tumors versus 14% of ER-negative tumors,

	In addition, he said, alterations in the PI3K/AKT/mTOR pathway can take the form of HER2 amplification, loss of tumor suppressor PTEN, mutations in AKT, and other aberrations.

	The result, Chandarlapaty said, is not only breast cancer, but also resistance to several endocrine therapies. And while in primary breast cancer patients with 

 mutations tend to experience better overall survival than those with wild-type disease

, he said that advantage does not necessarily remain after the disease progresses or metastasizes.

	Moreover, the doctor said, the ER and PI3K pathways are linked by their activation in breast cancer, and together correlate with resistance to endocrine-based treatments. When just one of the pathways is targeted with medication, the other becomes more active, and vice versa, Chandarlapaty said.

	“This becomes something of a Whac-A-Mole,” he said, referring to the popular arcade game. “If you hit one pathway, you activate the other.”

	Chandarlapaty and colleagues demonstrated such reciprocal feedback regulation between PI3K and the androgen receptor in PTEN-deficient mouse models of prostate cancer.

			Mutational Activation of PI3K/AKT/mTOR Pathway

			Adapted from Chandarlapaty S. Nuclear hormone receptors and the PI3 kinase pathway. Presented at the11th International Congress on the Future of Breast Cancer; July 26-28, 2012; Coronado, CA.

	Based on preclinical evidence, the doctor said, a similar pattern of reciprocal feedback seems to occur between the PI3K and ER pathways in ER-positive breast cancer. In one such study, researchers found that hyperactivation of PI3K predicts a poor response to adjuvant endocrine therapy in patients with the disease,

	One promising strategy has been a dual pathway approach. A randomized, placebo-controlled, phase II trial in postmenopausal women with operable ER-positive breast cancer found that everolimus (Afinitor), an mTORC1 inhibitor, increased the efficacy of letrozole (Femara), an aromatase inhibitor (AI) (

	In the phase III BOLERO-2 trial, everolimus plus exemestane (Aromasin) was found to improve progression-free survival in postmenopausal women with metastatic, hormone-refractory breast cancer compared with treatment with placebo plus exemestane (

In July, the FDA approved that combination for the treatment of postmenopausal women with hormone receptor—positive, HER2-negative breast cancer after the failure of letrozole or anastrozole (Arimidex).

	Since patients still progress on combination therapy, Chandarlapaty said, researchers must develop more, and better, strategies for targeting both pathways at once.

	That process should involve conducting trials of more potent hormonal treatments and mTOR inhibitors, although that will carry the risk of more potent toxicities, the doctor suggested. He added that the development of drugs that target the PI3K pathway should address the various potential locations for inhibition there, as well as the identification of biomarkers that will guide patient selection by revealing when PI3K is driving resistance, and where along the pathway a mutation has occurred.

	“There is a need to do these trials,” he said, “and determine if better drugging of the pathway will lead to better effects.”

				Chandarlapaty S. Negative feedback and adaptive resistance to the targeted therapy of cancer [published online ahead of print March 22, 2012]. 

. 2012;2(4):311-319. doi: 10.1158/2159-8290.CD-12-0018.

				Saal LH, Holm K, Maurer M, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. 

				Kalinsky K, Jacks LM, Heguy A, et al. 

 mutation associates with improved outcome in breast cancer [published online ahead of print August 11, 2009]. 

 2009;15(16):5049-5059. doi:10.1158/1078-0432.CCR-09-0632.

				Carver BS, Chapinski C, Wongvipat J, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. 

				Miller TW, Hennessy BT, Gonzalez-Angulo AM, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer [published online ahead of print June 7, 2010]. 

. 2010;120(7):2406-2413. doi: 10:1172/JC141680.

				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]. 

. 2009;27(16): 2630-2637. doi: 10.1200/JCO.2008.18.8391.

				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]. 

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Articles

Treating estrogen receptorâ€“positive breast cancer without sparking resistance is a complex endeavor that should involve simultaneously targeting the hormone-signaling and PI3 kinase molecular pathways

Dual Pathways Must Be Targeted in ER-Positive Breast Cancer

		Co-Director, Breast Cancer Research, Baylor Charles A. Sammons Cancer Center, Texas Oncology/US Oncology, Dallas, TX

Despite the trend toward targeted therapies, cytotoxic drugs remain a mainstay of metastatic breast cancer (MBC) treatment, and new therapies in that class are needed, according to Joyce A. O’Shaughnessy, MD.

While capecitabine, gemcitabine, carboplatin, and taxanes are widely used and proven agents, the anthracyclines, vinorelbine, and the cyclophosphamide-methotrexate- 5-fluorouracil combination are not supported by as much efficacy data, are associated with toxicity concerns, and may result in cross-resistance with previous treatments, said O’Shaughnessy.

She made her comments during a presentation at the 11th International Congress on the Future of Breast Cancer in Coronado, California, in July, where she served as program director. O’Shaughnessy is co-director of Breast Cancer Research at the Baylor Charles A. Sammons Cancer Center, Texas Oncology/US Oncology, in Dallas.

New cytotoxic agents are needed to treat patients whose tumors are resistant to existing therapies, whether cytotoxic or targeted, O’Shaughnessy said. There is a particular need for effective therapies for triple-negative breast cancer (TNBC), O’Shaughnessy pointed out, and for new cytotoxic agents that exhibit lower toxicity than existing drugs, yet have equivalent or superior efficacy.

O’Shaughnessy discussed the work of Nik-Zainal and colleagues, who examined the genomes of 21 breast tumors.

 In this study, very large numbers of clonal mutations were mapped and several clusters of discrete subclones were revealed, each representing a fraction of tumor cells. O’Shaughnessy called the heterogeneity of MBC “sobering.”

“In the curative setting, it’s the rationale for using combination chemotherapy to kill off as many subclones as we can, and in the metastatic setting, we can see that we need sequential therapies because these subclones will grow out over time once they have become resistant to the current therapy the patient is receiving,” she said.

One approach to systemic therapy that has been a focus over the last decade targets the microtubule to impede proliferation, invasion, and metastasis. There are different binding sites for three types of antimitotics:

 the vinca alkaloids (such as vinblastine), the taxanes (such as paclitaxel), and a new agent, eribulin mesylate, a synthetic analog of the naturally occurring compound halichondrin B.

Eribulin (Halaven) was approved in the United States in 2010 for the treatment of MBC after at least two treatment regimens including an anthracycline and a taxane, based on the results of an open-label, randomized, phase III study of eribulin monotherapy (the EMBRACE trial) in patients with locally recurrent or MBC.

In that study, investigators sought to determine whether eribulin would be cross-resistant with taxanes, and so selected patients who had been heavily pretreated with an anthracycline and a taxane and, in 73% of participants, with capecitabine, O’Shaughnessy said. Eribulin was compared with the treatment of physician’s choice (TPC).

EMBRACE turned out to be the only single-agent trial in this population to show a survival advantage, O’Shaughnessy said. While there was only a modest improvement in overall survival (OS) with eribulin versus TPC (median 13.2 months vs 10.5 months; 

 = .014), the results were unusual in such late-stage patients, she said.

Another trial, Study 301, comparing eribulin with capecitabine in MBC refractory to recent chemotherapy, showed no statistically significant difference between the two treatments, although it did demonstrate a trend toward improved OS with eribulin, O’Shaughnessy said.

The doctor added that there are four ongoing, phase II, single-arm eribulin trials in early-line MBC, including a single-agent study, studies combining eribulin with capecitabine or trastuzumab, and a safety study. The aim of the trials, she said, is to determine whether eribulin looks promising enough in early-stage disease to warrant large adjuvant or neoadjuvant studies comparing it with current standard treatments, particularly taxanes.

Also tested in MBC patients has been ixabepilone (Ixempra), which, according to the National Cancer Institute, binds to tubulin and promotes tubulin polymerization and microtubule stabilization.

The drug, in combination with carboplatin, was evaluated for the treatment of MBC in HER2-negative patients, following approximately two cycles of chemotherapy.

 The primary endpoint was the overall response rate (ORR) by hormone receptor (HR) status. The ORR was similar but slightly better for HR-positive versus TNBC patients (32.1% vs 29.8%), but median duration of response was longer for those with TNBC (10.2 months vs 6 months). Because the drug was active and well tolerated in both sets of patients, O’Shaughnessy said, it will have clinical utility in practice.

		Halaven (eribulin mesylate) Injection is a synthetic analogue of the marine sponge 

A new oral taxane, tesetaxel, showed significant activity as first-line treatment in HER2-negative MBC in a phase II study, O’Shaughnessy reported. In 44 patients, she said, the ORR was 45%. A first-line, phase III trial in the same population is planned.

Meanwhile, two topoisomerase-1 inhibitors, one a pegylated active metabolite of irinotecan (PEG-SN38)

 and the other a polymer conjugate of irinotecan (NKTR- 102), showed significant activity and acceptable tolerability in phase II studies of pretreated patients, including those with TNBC, O’Shaughnessy said. NKTR-102 is currently being evaluated in a phase III trial.

Amid the looks at new therapies, O’Shaughnessy said, one team considered the value of long-term continuation of standard treatments that have been effective in patients with MBC, and found evidence to support that practice.

KCSG-BR 0702 was a phase III trial of maintenance therapy versus observation in MBC patients who had experienced a clinical response to gemcitabine plus paclitaxel as first-line treatment.

 Patients were followed for a median of 33 months. The median progression-free survival (PFS) rate for maintenance therapy was superior as compared with the rate for observation, with a 27% improvement from 3.8 months to 7.5 months (

 = 0.031), and OS rates were 35% better, with survival improved by about eight months in patients who continued treatment (

 = .048). Toxicity was manageable and quality of life acceptable. The study’s authors recommended this course of treatment in patients with HR-negative, visceral MBC with a high tumor burden, and O’Shaughnessy agreed.

In another look at current uses for older MBC therapies, O’Shaughnessy discussed the results of the GeparTrio trial

, which showed that patients with highly proliferative estrogen receptor (ER)-positive, HER2-negative breast cancer who had stopped responding to TAC therapy (docetaxel, doxorubicin, and cyclophosphamide) benefited from a switch to combination vinorelbine and capecitabine.

An important message can be drawn from those results, O’Shaughnessy said.

“This is an example of patients with a very specific clinical phenotype getting a benefit, and it would be nice to know who those patients are up front,” she said. “In their very important 

 Ellis, Mardis, and colleagues have given us a lovely blueprint of the key molecular changes in luminal breast cancer, and it will be very interesting to go into very well-defined clinical phenotypes and take a look, because I bet we’ll find genotypes that are fairly understandable and uniform. Then, we may be able to do prospective studies to select those patients up front and see whether or not, for example, a vinorelbine/capecitabine might be a better therapy for them.”

			Nik-Zainal S, Van Loo P, Wedge DC, et al. The life history of 21 breast cancers [published online ahead of print May 17, 2012]. 

. 2012;149(5):994- 1007. doi: 10.1016/j.cell.2012.04.023.

			Jordan MA, Kamath K. How do microtubule-targeted drugs work? An overview.

			Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study [published online ahead of print March 2, 2011]. 

. 2011;377(9769):914-923. doi:10.1016/S0140-6736(11)60070-6.

			Osborne C, Challagalla JD, Fanning SR, et al. Phase II trial of ixabepilone plus carboplatin in patients with metastatic breast cancer: the ECLIPSE study. 

			O’Shaughnessy JA, Osborne CRC, Steinberg MA, et al. Phase II, open-label study of of EZN-2208 (PEG-SN38) in patients with previously treated metastatic breast cancer.

			Im Y-H, Park YH, Jung KH, et al. A phase III, multicenter, randomized trial of maintenance versus observation after achieving clinical response in patients with metastatic breast cancer who received six cycles of gemcitabine plus paclitaxel as first-line chemotherapy (KCSG-BR 0702, NCT00561119). 

			Von Minckwitz G, KuÌˆmmel S, Vogel P, et al. Intensified neoadjuvant chemotherapy in early-responding breast cancer: phase III randomized GeparTrio study [published online ahead of print April 8, 2008]. 

 2008;100(8):552-562. doi: 10.1093/jnci/djn089.

			Ellis MJ, Ding L, Shen D, et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. 

Despite the trend toward targeted therapies, cytotoxic drugs remain a mainstay of metastatic breast cancer treatment, and new therapies in that class are needed.

A Mainstay of Breast Cancer Treatment, Cytotoxics Class Must Grow

		Fred Hutchinson Cancer Research Center Director, Breast Medical Oncology

	While osteoclast-targeting agents are proven treatments for bone metastases and the preservation of bone-mineral density in patients with breast cancer, their use in preventing recurrences in early-stage disease is not as well established.

	In a presentation during the 11th International Congress on the Future of Breast Cancer in July, Julie R. Gralow, MD, gave an overview of studies looking at the potential of osteoclast inhibitors in the prevention of breast cancer recurrences in the adjuvant setting, and discussed which patients might reap the greatest benefits.

	“The area of preventing recurrences is where the newest data are—and the most confusion and controversy,” Gralow said.

	She also addressed the possibility that osteoclast inhibitors may help prevent breast cancer in healthy women, as well as the idea that the drugs might have a direct antitumor effect, which could make them useful as a supplement, or a less-toxic alternative, to chemotherapy for breast cancer patients.

	In explaining how osteoclast inhibitors work, Gralow outlined the “vicious cycle” in the interaction between metastatic breast cancer and the bone microenvironment (

). The tumor cells secrete a peptide—parathyroid hormone-related protein (PTHrP)&mdash;and other osteoclast-stimulating factors, such as interleukins and prostaglandins, and, downstream, RANK ligand (RANK-L).

		Figure. Breast Cancer and the Bone Microenvironment

Osteoclast inhibition, “X” at right, is aimed at breaking the “vicious cycle.”

		Gralow J. Osteoclast inhibition: when and for whom in early stage breast cancer? Presented at: 11th International Congress on the Future of Breast Cancer; July 26-28, 2012; Coronado, CA.

	Tumor cell activity releases growth factors, such as IGF, PDGF, and TGF-β, which promote tumor growth in the bone. Osteoclast inhibitors may interfere with this process, possibly preventing bone from becoming the first site of recurrence—which could lead, in turn, to fewer recurrences in the liver and lungs, Gralow said.

	The drugs may work particularly well in patients whose ovarian function is suppressed, Gralow said. Other predictors of success with osteoclast inhibitors might be tied to menopausal status, excessive bone resorption, a lack of treatment with chemotherapy, a presence or history of estrogen receptor (ER)-positive tumors, tumors with biomarkers such as PTHrP or RANK-L, and/or involvement of bone marrow at diagnosis—yet those remain “unanswered questions,” the doctor said.

	Gralow is involved in some of the latest research into adjuvant therapy with osteoclast-targeted agents in breast cancer; she is serving as principal investigator for the phase III SWOG 0307 study comparing zoledronic acid versus clodronate versus ibandronate in primary breast cancer. Three other phase III trials are evaluating zoledronic acid adjuvant therapy with various regimens, and two additional phase III trials are studying denosumab, which targets RANK-L.

	Investigators have also gleaned information from nearly 10 completed clinical trials of adjuvant bisphosphonate therapy aimed at reducing cancer recurrence, Gralow said.

	That body of work includes four randomized trials in early-stage breast cancer of oral clodronate, which is not approved in the United States but is marketed elsewhere for the treatment of bone metastases, as well as for the treatment and prevention of osteoporosis. Two of the placebo-controlled studies showed that clodronate resulted in a survival benefit for patients, while the other two did not.

	Another bisphosphonate, ibandronate, is approved in the US for the treatment of osteoporosis and in Europe for the treatment of both osteoporosis and bone metastases. The GAIN trial, with 3023 patients, compared adjuvant oral ibandronate plus aggressive chemotherapy with aggressive chemotherapy alone. Disappointingly, Gralow said, ibandronate had no effect on either disease-free survival or overall survival.

	Gralow said it is possible that chemotherapy may prevent the same recurrences that bisphosphonates do, negating the benefit of the osteoclast inhibitors.

	Three primary trials of adjuvant zoledronic acid versus controls (hormonal therapy) saw variable results when it came to meeting their endpoints of reducing the recurrence of breast cancer—in most cases, ER-positive disease&mdash;and improving overall survival, Gralow said. A trial titled ABCSG-12 demonstrated a 28% reduction in breast cancer recurrences (

 = .048), Gralow reported, and the combined ZO-FAST/Z-FAST trial found a reduction in recurrences with upfront versus delayed zoledronic acid.

	Conversely, AZURE demonstrated no differences in disease-free or overall survival, the doctor said. However, she said, in all three studies, there appeared to be an association between a favorable response to adjuvant zoledronic acid and ovarian suppression, whether postmenopausal or induced by goserelin.

	Looking at a subgroup of patients in the AZURE trial, it appears that patients who received chemotherapy plus zoledronic acid, and then underwent surgery, experienced an antitumor effect; their residual invasive tumors were 28 mm after treatment, as compared with 42 mm for the chemotherapy-alone group (

 = .002), and the complete pathologic response rate in the breast and axilla was 10.9% for the experimental group versus 5.8% for the control arm (

	Evidence of an antitumor effect also came out in the ABCSG-12 trial, she said, since the reduction in recurrences demonstrated with zoledronic acid in that study affected not only distant but also local/ regional tumor sites.

	Finally, the doctor said, data supporting the idea that bisphosphonates can help prevent breast cancer in healthy women came out of a Women’s Health Initiative (WHI) trial, a set of studies of postmenopausal women whose results were reported in 2010. In the trial, 2816 out of more than 150,000 participants were taking bisphosphonates (mainly alendronate, for osteoporosis). After a mean of 7.8 years’ follow-up, the incidence of invasive breast cancer was 32% lower among those who used oral bisphosphonates (

	As investigators consider whether to continue studying osteoclast inhibitors for the prevention of breast cancer, Gralow said, the data from the WHI should add “fuel to the fire.”

An overview of studies looking at the potential of osteoclast inhibitors in the prevention of breast cancer recurrences in the adjuvant setting.

Julian Kaye

Articles

Dual Pathways Must Be Targeted in ER-Positive Breast Cancer

A Mainstay of Breast Cancer Treatment, Cytotoxics Class Must Grow

Osteoclast Inhibitors May Prevent Recurrences in Early-Stage Disease