PHARMACEUTICAL NEWS

Adjuvant Imatinib for Resected GIST Approved in Europe

On March 19, 2009, the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMEA) issued a positive opinion supporting approval of Novartis’s imatinib (Glivec^®/Gleevec^®) as first adjuvant treatment for patients at significant risk of relapse following removal of Kit (CD117)–positive gastrointestinal stromal tumors (GIST). The recommendation for approval was based on positive results from a randomized, double-blind, placebo-controlled phase III study showing that imatinib administered post-surgery significantly improved recurrence-free survival (RFS) at 1 year compared to placebo (98% vs 83%, hazard ratio [HR] 0.35, P<.0001; DeMatteo RP, et al. Lancet. 2009;373(9669):1097-1104).

This new indication for imatinib was approved by the US Food and Drug Administration in December 2008.

From the Business World: Swiss Roche Bought US Genentech

On March 12, 2009, the pharmaceutical giant Roche agreed to pay nearly $47 billion to buy the 44% of the biotech pioneer Genentech that it does not already own. This buyout is the third big pharma deal this year, following Merck & Co.’s announcement just a few days earlier that it would acquire Schering-Plough Corp. and Pfizer’s pending acquisition of Wyeth.

This deal gives Roche, whose best-known products include capecitabine (Xeloda^®), interferon alfa 2a (Roferon-A^®), and ceftriaxone (Rocephin^®), control of all revenue of Genentech’s highly profitable anticancer drugs bevacizumab (Avastin^®) and trastuzumab (Herceptin^®), as well as its promising research pipeline. This reflects the industry’s urgency to acquire biotech assets to compensate for a shortage of new products and push for cost savings. Roche has said that Genentech’s research and clinical trials operations will retain autonomy so that Genentech’s innovative culture can be preserved.

FROM THE ST GALLEN BREAST CANCER CONFERENCE

The remainder of this issue will be dedicated to important updates and discussions from the 11th International Conference on Primary Therapy of Early Breast Cancer held in St Gallen, Switzerland, on March 11-14, 2009. Topics addressed by international breast cancer experts included recent progress in the biology of breast cancer, diagnosis and follow-up including late-term side effects, local therapies (surgery and radiotherapy), and adjuvant systemic therapies for the individual patient (current role of genomic profiles, treatment of premenopausal and postmenopausal endocrine-responsive disease, targeted therapy, and adjuvant treatment of triple-negative [TN] breast cancer).

What’s New Since the 2008 San Antonio Breast Cancer Symposium?

The 4-year and 5-year follow-up results from the HERceptin Adjuvant (HERA) and Finland Herceptin (FinHER) trials were presented:

• In the large HERA trial, women who received adjuvant trastuzumab for 1 year after adjuvant chemotherapy had a significant reduction of 24% in the risk of recurrence compared to those who did not receive trastuzumab (disease-free survival [DFS] HR 0.76, P<.0001), and after 4 years of follow-up, nearly 90% of the trastuzumab-treated women were still alive. In addition to demonstrating a significant treatment benefit, trastuzumab showed acceptable long-term safety, including good cardiac safety that was maintained throughout the follow-up period.
  
  
• In the much smaller FinHER trial, in which patients with HER2-positive tumors received a short course (9 weeks) of trastuzumab concomitantly with chemotherapy (docetaxel or vinorelbine), patients with positive lymph nodes showed significantly improved distant disease-free survival (DDFS) after 5 years of follow-up (HR 0.57, P = .047). In an exploratory analysis, improved DDFS was observed in patients who received docetaxel, trastuzumab, and FEC (fluorouracil, epirubicin, cyclophosphamide) (HR 0.32; P = .029) or vinorelbine, trastuzumab, and FEC (HR 0.31; P = .020) when compared to those who received chemotherapy only. However, no overall survival difference was observed.

Satellite Symposium

Key messages are presented from the discussions of 5 important and compelling topics presented during “Early Breast Cancer: Making the Difficult Choices,” a PRIME Oncology satellite symposium held on March 13, 2009. The symposium was co-chaired by Cliff Hudis, MD, and Martine Piccart-Gebhart, MD, and faculty included José Baselga, MD, Angelo Di Leo, MD, PhD, Monica Castiglione, MD, Georde Sledge, MD, and Adam Brufsky, MD, PhD.

Click here to view the Webcast.

Triple-Negative Early Breast Cancer: Is There an Optimal Treatment Strategy?

Triple-negative breast tumors (ER-/PR-/HER2-) exhibit an aggressive phenotype with a poor prognosis. These tumors are highly sensitive to chemotherapy, and optimal adjuvant chemotherapy with anthracyclines and taxanes has markedly improved survival in this patient population. These patients have also derived benefit in metastatic and neoadjuvant settings from cisplatin and ixabepilone. Novel biological agents that are currently under investigation in this patient population include antiangiogenesis agents, poly (ADP-ribose) polymerase (PARP) inhibitors, and epidermal growth factor receptor (EGFR) inhibitors.

Key messages:

• The first step clinicians should take when treating this patient population is to confirm that the patient indeed has a TN tumor. Due to the possibility of false-negative estrogen receptor (ER) results on pathology reports, clinicians should ask themselves if they can trust the pathology outcome.
  
  
• Currently, in clinical practice, breast cancer patients with BRCA1 mutations are included in the TN group. However, once data on the PARP inhibitors become available, patients with BRCA1 mutations could potentially be differentiated from the other TN patients.
  
  
• The faculty indicated that they give chemotherapy to patients with <1-cm TN tumors, and hormone therapy to those with even low expression of ER/PgR receptors.
  
  
• Overall, the treatment strategy for patients with TN early breast cancer is not clear and thus, clinicians should encourage this patient population to participate in clinical trials.

Taxanes: Are They an Essential Component of Adjuvant Therapy for All Patients Regardless of ER/HER2 Status?

The taxanes docetaxel and paclitaxel are 2 of the most active cytotoxic agents and have emerged as cornerstones in the treatment of breast cancer. Whether they are an important part of adjuvant therapy for all patients remains controversial.

Below are key messages from a discussion of 2 hypothetical cases and treatment with taxanes:

• Regarding Case 1 (42-year-old, healthy, premenopausal woman with grade 3 TN ductal breast cancer [pT 0.7 cm, N 0/18, Ki-67 40%, no vascular invasion]), the faculty concurred that they would use chemotherapy, including anthracyclines and/or taxanes.
  
  
• Regarding Case 2 (52-year-old, healthy, premenopausal woman with grade 1 node-positive [4/17] lobular breast cancer [pT 2.5 cm, ER & PgR 90%, Ki-67 5%, HER2-, vascular invasion]), there were disparate views regarding treatment. Some faculty members indicated that they would give chemotherapy, including taxanes, due to the risk of metastasis associated with the 4 positive lymph nodes, while others said they might give chemotherapy but without taxanes. One member questioned whether this patient should even receive adjuvant chemotherapy and thought that she may derive more benefit from optimized endocrine therapy. The faculty indicated that in this case they would feel comfortable using a nonanthracycline-based regimen such as TC (docetaxel/cyclophosphamide).
  
  
• Whether to treat with docetaxel or paclitaxel cannot be determined based on ER status.

Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: Does One Strategy Fit All?

Adjuvant therapy with tamoxifen has historically been the standard of care for postmenopausal women with hormone receptor–positive breast cancer. However, the introduction of adjuvant aromatase inhibitors (AIs), such as letrozole, exemestane, and anastrozole, has challenged the clinical benefit of adjuvant tamoxifen therapy alone in these patients.

The following are key messages from the discussion:

• There has been a lot of discussion lately about the role of CYP2D6 as a predictor of response to endocrine therapy. Studies have shown that “poor metabolizers” of CYP2D6 do not benefit from tamoxifen and thus, CYP2D6 analysis prior to giving tamoxifen may be useful. In this era of concerns about cost, certainly the ability to give tamoxifen instead of a more expensive newer agent may be important to many patients.
  
  
• Based on the BIG 1-98 data presented at the San Antonio Breast Cancer Symposium, there is now support for initiating therapy with an AI upfront, especially in a patient with node-positive breast cancer; however, in some patients with node-negative disease and low recurrence scores, tamoxifen may still be a good option.
  
  
• The panel indicated that outside of the clinical trial setting they would not ablate ovarian function and give an AI in premenopausal women with high-risk breast cancer.
  
  
• Overall, studies have demonstrated DFS benefit for adjuvant AIs in endocrine-responsive postmenopausal patients with breast cancer, and practice guidelines support their use either as up-front therapy or after a period of tamoxifen therapy.

Should Gene-Expression Profiles Be Routinely Used OR Are Standard Prognostic Factors Adequate?

Gene-expression profiling has transformed the way breast cancer is viewed. It has confirmed the heterogeneity of breast cancer and revealed molecular signatures that could influence clinical care. Large prospective studies are being conducted to compare genomic testing and traditional clinical factors in making treatment decisions.

The following are highlights from the discussion:

• Apart from being a prognostic indicator, certain genomic signatures—such as the 21-gene recurrence score assay (Oncotype DX^®)—demonstrated that they also may have predictive benefits, such as the ability to identify patients that may not benefit from chemotherapy.
  
  
• Gene expression profiles probably should not be ordered in a patient that is going to receive chemotherapy anyway; however, they could be valuable in cases where the pathology report is unclear or unreliable.
  
  
• The cost of gene expression profiles is an issue for many clinicians and payors. A panel member noted, however, that if the cost of chemotherapy for a patient who may not need it and the cost to treat side effects associated with that chemotherapy are considered, these tests seem less costly.
  
  
• Although genomic signatures such as the 70-gene profile (MammaPrint^®) and Oncotype DX are commercially available for the prediction of clinical outcome in patients with breast cancer, many clinicians do not have access to these tests.
  
  
• The faculty indicated that they would order an Oncotype DX test for a patient with a 7-mm, 30% ER-positive tumor, to assist with risk assessment and treatment planning.
  
  
• Overall, gene arrays add to, but do not replace, current clinical risk stratification. Although current clinical predictors are considered to be “houses built on sand,” they are, nevertheless, helpful.

Should Bisphosphonates Be Part of Adjuvant Therapy for Breast Cancer?

Bisphosphonates, in particular zoledronic acid (Zometa^®), have been shown in a variety of clinical models to interfere with several steps involved in tumor metastasis. These antitumor effects result in decreased bone and non-bone metastasis, and decreased contralateral breast and locoregional recurrence, which may improve DFS and RFS in women. Based on results from clinical trials, adjuvant zoledronic acid appears to provide DFS and disease recurrence improvements including benefits outside of bone in premenopausal women with ER-positive breast cancer who are receiving adjuvant gonadotropin-releasing hormone (GnRH) analogues with hormonal therapy.

The following are key messages from the discussion:

• In women who are at risk for osteopenia or osteoporosis, adjuvant bisphosphonates may be a good choice to include in any adjuvant therapy regimen.
  
  
• When patients inquire about adjuvant bisphosphonate therapy, clinicians could either encourage them to participate in one of the bisphosphonate trials or, outside of the clinical trial setting, give adjuvant bisphosphonates to those with a low bone mineral density (T-score -1.5 and below) for the bone protective effects, knowing that it possibly also could result in decreased in likelihood of recurrence.
  
  
• Overall, bisphosphonates have acceptable safety profiles; however, because of the rare risk of osteonecrosis of the jaw, patients should consult with a good dentist prior to initiating therapy.
  
  
• Clinicians should be aware that, at present, adjuvant bisphosphonate therapy may not be covered by the patient’s insurance.
  
  
• Currently, there are no clinical toxicology data available to address concerns about teratogenicity in women who become pregnant after having received zoledronic acid.
  
  
• Further randomized trials are awaited to determine whether bisphosphonates should be used for the prevention of bone metastasis.

Traditional St Gallen Consensus Conference

The expert consensus meeting on March 14, 2009, represented the final session of the St Gallen Breast Cancer Conference. During this session, a multidisciplinary international panel of 43 breast cancer experts under the chairmanship of Professors Aron Goldhirsch of Milano, Italy, and James Ingle of Rochester, Minnesota, sought consensus based on evidence, or at least shared opinions where evidence was lacking, on the more controversial topics of adjuvant multidisciplinary treatment. Ten areas of controversy were discussed, including surgery (axilla, margins), radiation therapy (ductal carcinoma in situ [DCIS], accelerated, post-mastectomy), pathology (ER, PgR, Ki-67, grade), multigene signatures, endocrine therapies, chemotherapies, targeted therapies, neoadjuvant systemic therapy, fertility, and male breast cancer. Responses to approximately 80 questions were obtained from each of the panel members, whose answers (yes/no/abstain) were summarized in percentages.

Overall, the panel agreed on many topics where evidence-supported data are confirmed in several trials; however, much controversy remains on several issues. Below are highlights from the discussion of some of the topics:

• Role of Surgery in Sentinel Node Evaluations and DCIS—the panel suggested using sentinel node biopsy as a standard for invasive, clinically node-negative breast cancer. Controversy remains as to whether re-excision of DCIS is needed if the margins are negative but less than 2 mm.
  
  
• Role of Radiation Therapy in Breast Cancer—the panel suggested giving radiation therapy after mastectomy in patients with ≥4 positive nodes and in selected patients with 1-3 positive nodes. The following topics on radiation therapy remain controversial: whether to avoid radiation therapy in low-grade DCIS and elderly patients with breast cancer, and the role of radiation therapy in T1N0M0 elderly patients with endocrine-responsive tumors receiving endocrine therapy.
  
  
• Pathology of Breast Cancer: Focus on ER, PgR, Ki-67, HER2, and Grade—panel members agreed with the reporting of percent ER stain and that the definition for highly endocrine-responsive disease should require more than 50% ER staining. Furthermore, the panel discussed the urgent need for a widely available assessment system for ER/PgR status. Remaining controversies in the area of pathology include the use of Ki-67 for selecting endocrine therapies, consideration of PgR for prognosis evaluation, use of immunohistochemistry intensity for making anti-HER2 treatment decisions, use of high grade as a sufficient marker for chemotherapy decisions, utility of UPA and PAI1 in early breast cancer, and tumor size >2 cm for the definition of low-risk tumors.
  
  
• Endocrine Therapies in Premenopausal and Postmenopausal Women—the panel agreed with the use of tamoxifen in premenopausal patients with endocrine-responsive tumors, and they thought the combination of ovarian suppression and tamoxifen is a reasonable option. It was accepted that AIs are part of standard endocrine therapy in postmenopausal women with endocrine-responsive breast cancer. In contrast with the 2007 expert consensus, a vast majority of the panelists thought AIs should be given upfront. Topics that remain controversial in this area include the role of CYP2D6 testing for selecting endocrine therapy, use of ovarian suppression therapy alone as endocrine therapy in premenopausal patients, duration of AI therapy and the type of endocrine therapy in HER2-overexpressed or HER2-amplified patients, and duration of neoadjuvant endocrine treatment.
  
  
• Role of Gene-Expression Profiles—another update from the 2007 expert consensus was acceptance of the use of molecular gene profiles as an adjunct to high-quality standard histopathologic assessment in patients with endocrine-responsive breast cancer if uncertainties exist about the administration of adjuvant chemotherapy. However, optimally, these patients should be enrolled in appropriate clinical trials.
  
  
• Role of Chemotherapy in Breast Cancer—the panelists agreed that chemotherapy is less useful in patients with highly endocrine-responsive and HER2-negative tumors. Additionally, they concurred that chemotherapy should be the same in the adjuvant and neoadjuvant setting and more than half of the panel thought that it should contain taxanes. In patients with HER2-positive tumors, neoadjuvant regimens should contain an anti-HER2 therapy. However, the panelists provided disparate opinions on the type of chemotherapy that should be used in HER2-positive patients and the use of TC as standard chemotherapy regimen.
  
  
• Fertility Preservation—the panel could not concur on proven methods that could preserve fertility during chemotherapy.
  
  
• Role of Bisphosphonates in Adjuvant Therapy—available results are intriguing but this remains an area where additional clinical trials data are required.
  
  
• Male Breast Cancer—the panel members mutually agreed that adjuvant tamoxifen and not AIs should be the primary endocrine therapy for men with endocrine-responsive breast cancer.

Based on this expert consensus session, the panel will prepare highlights of the meeting and updated recommendations, which are useful tools for practicing breast cancer specialists. These recommendations will be published in a major oncology journal.

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