July 2006: Targeted Therapies: What is Right for You?

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New targeted therapies being studied?

Question from MarciaL: What targeted therapies are being studied now in breast cancer? Are there new ones that look promising?

Answers —Andrew Seidman, M.D.: Let me put targeted therapy into context. For potential end users of these agents, it's important to know something of the history of developing targeted agents, and also to understand the phase of development in which they presently exist. The targeted agents that most of us have been aware of recently include Herceptin, also known as trastuzumab, the monoclonal antibodies that target the HER2 receptor, and more recently, the monoclonal antibody known as Avastin, also known as bevacizumab, which targets the epidermal growth factor receptor (in other words, interferes with the blood vessels that supply tumors with their necessary nutrients). In addition, we heard very promising data regarding an oral drug called Tykerb, otherwise known as lapatinib, which was studied in a Phase 3 trial in women with advanced breast cancer and whose cancer had progressed despite Herceptin. In addition, it's important to note historically that in a sense, targeted therapy has been with us for over a century. By this, I mean that it was in the 1800s that the observation of estrogen dependency for breast cancer growth was made and strategies to deprive breast tumors of estrogen, including surgical removal of the ovaries in premenopausal women, might be considered, in a sense, the pioneer of targeted therapies.

Jennifer Armstrong, M.D.: I think that's a great opening—thank you.

Herceptin and aromatase inhibitor?

Question from Joan: When is a therapy combining Herceptin and an aromatase inhibitor (and which one?) indicated?

Answers —Andrew Seidman, M.D.: The use of Herceptin and hormonal therapies in combination has not yet been tested in randomized clinical trials, unlike the situation of Herceptin and chemotherapy, where we clearly understand both the benefits and the risks of combination of chemotherapy agents and Herceptin. While laboratory data would lead us to suspect a benefit for the combination of Herceptin and aromatase inhibitors, it is hard to recommend this as a standard of care since we still await the results of definitive clinical trials to clarify the use of this strategy.

Jennifer Armstrong, M.D.: Dr. Seidman, are you aware if these studies are ongoing at this time?

Andrew Seidman, M.D.: The studies are ongoing. I'm not aware of how close to completion they are. I believe one trial was focused on the use of Femara (chemical name: letrozole) plus or minus Herceptin in patients with estrogen-receptor-positive and HER2-positive metastatic breast cancer.

What is EGFR?

Question from Zaundra: Can you explain what EGFR is? I keep hearing about drugs that go after it in some way.

Answer —Andrew Seidman, M.D.: This is a very good question. EGFR stands for Epidermal Growth Factor Receptor. It's also known as HER1 and is a member of the so-called HER family of receptors or the epidermal growth factor "super-family." The HER family receptors including HER1, HER2, HER3, and HER4 are characterized by partnerships or couplings between individual family members. For example, the HER1/HER2 coupling (dimer) is felt to be the most important stimulus for breast cancer growth in HER2-positive breast cancers. Indeed, the drug Tykerb targets a protein involved in the signals transmitted by this EGFR/HER2 partnership.

Treatments for triple-negatives?

Question from Photot: What, if anything, is available for those of us who are "triple negative"? Is there anything on the horizon for these types of cancers?

Answers —Andrew Seidman, M.D.: I think that is an excellent question and it begs clarification for those who are reading who might not be familiar with the term "triple negative." This refers to tumors that lack significant expression of estrogen receptor (ER), progesterone receptor (PR), as well as HER2. This is a clinical setting where we recognize the lack of expected benefit for hormonal therapies, as well as Herceptin, and thus we rely primarily on cytotoxic chemotherapy drugs to improve patient outcomes. Ongoing research is focusing on this group of patients to identify whether specific chemotherapeutic agents that currently exist may be more beneficial in triple-negative breast cancer, and also efforts are ongoing in the laboratory and the clinic to develop unique tailored strategies for this group of patients. There is some evidence in the laboratory that the platinum compounds and also the chemotherapeutic agent Camptosar (chemical name: irinotecan) may have particular promising activity in triple-negative breast cancers. Also, medications that target HER1 (also known as the epidermal growth factor receptor, or EGFR)—such as Erbitux (chemical name: cetuximab), Tarceva (chemical name: erlotinib), and Iressa (chemical name: gefitinib)—are currently being studied individually and together for these challenging tumors. I also want to point out that even the term "triple-negative breast cancer" is an oversimplification. Within those breast cancers that lack ER, PR, and HER2 are many sub-classes of tumors that have even further differences in gene and protein characteristics. It is likely that future breast cancer treatments will become even more tailored to specific genetic sub-types well beyond the simple classification by ER, PR, and HER2.

Jennifer Armstrong, M.D.: Thank you Dr. Seidman. That was an incredibly thorough and informative explanation. I also want to add that patients with triple-negative tumors are candidates for treatment with Avastin in the metastatic setting. I am not aware of whether Avastin is being studied in the adjuvant setting in breast cancer.

Andrew Seidman, M.D.: Because of the results of the randomized trial known as ECOG-2100, where the addition of Avastin to weekly Taxol (chemical name: paclitaxol) was of significant benefit in advanced breast cancer, clinical trials will soon begin that will randomize patients with early stage breast cancers to receive Avastin or not. Currently, smaller Phase 2 so-called "pilot studies" are going on that are more focused on addressing the safety of combining Avastin with chemotherapy as part of the adjuvant and indeed neo-adjuvant treatment of early stage breast cancer. I am not aware of any evidence to suggest that Avastin or other anti-angiogenic agents would be preferentially more or less effective as a function of estrogen receptor, progesterone receptor, or HER2 receptor status. There are some laboratory data to suggest that targeting the HER2 receptor in combination with an anti-angiogenic approach such as Avastin could make sense for patients. However, to date, we only have preliminary data from Dr. Mark Pegram and colleagues at UCLA. This practice should not be used outside of clinical trials.

Jennifer Armstrong, M.D.: Avastin now has compendial listing (in breast and lung cancer), which means that based on the studies that Dr. Seidman was just referring to, patients with advanced breast cancer can be considered for treatment with Avastin and will be able to receive it.

New treatments for metastatic cancer?

Question from DJR: I was diagnosed with breast cancer in 2000, and did Adriamycin and Cytoxin. In 2004 I had metastasis to the liver and did taxol/carboplatin/Herceptin for 8 months. (It didn't help, so I did holistic for a year which lowered markers to normal and I felt great for a year.) I am now on my 6th treatment of Herceptin and Navelbine, which is lowering my markers. Since this is salvage treatment and will only work for so long, what treatment options are next? Is there anything new in the near future?

Answers —Andrew Seidman, M.D.: Thank you for sharing your case with us, because I think it allows us to reflect on the management of breast cancer that has progressed despite Herceptin/chemotherapy combinations. Many physicians choose to continue Herceptin even when cancer progresses during its use with the hope that it will enhance the effectiveness of yet another chemotherapy drug that would be administered next. Unfortunately, whether this is true has never been studied in a clinical trial. The only study to show benefit for using a HER2 targeted therapy in a patient with advanced breast cancer with progression despite Herceptin was a study presented at ASCO (American Society of Clinical Oncology) just this past spring. In this trial, 528 women with HER2-positive metastatic breast cancer who, like yourself, had previously been exposed to an anthracycline such as Adriamycin (chemical name: doxorubicin) and a taxane such as Taxol were randomized to receive Xeloda (chemical name: capecitabine), or Xeloda plus lapatinib, also known as Tykerb. In this study presented by Dr. Charles Geyer, there was a significant improvement in the time it took for cancer to progress when lapatinib was added to Xeloda, compared to Xeloda alone. The drug lapatinib is not yet FDA approved, although its manufacturer, GlaxoSmithKline, has created an expanded use program which may be relevant for your future care and for the care of other women like yourself whose cancers have progressed despite Herceptin.

Jennifer Armstrong, M.D.: There are also other chemotherapy agents that you may not yet have been exposed to, which might include Xeloda or Gemzar (chemical name: gemcitabine).

What does ASCO stand for?

Question from Sue: What does ASCO stand for?

Answer —Jennifer Armstrong, M.D.: ASCO stands for American Society of Clinical Oncology, which has interestingly become an international center of oncologic research.

What does anti-angiogenic mean?

Question from Lutasgram: I'm not clear on the meaning of anti-angiogenic approaches.

Answer —Andrew Seidman, M.D.: The word "anti-angiogenic" refers to any strategy that inhibits the blood vessels that provide oxygen and nutrients to cancer cells. The ideal anti-angiogenic drug would be specific only for the blood vessels that supply tumors and have no effect on other blood vessels that provide blood supply to normal organs and tissues in the body. Unfortunately, even "targeted" agents such as Avastin are not purely specific for tumor blood vessels. As evidence of this, Avastin can occasionally cause high blood pressure, blood clots, bleeding, and kidney injury. Hopefully, newer anti-angiogenic drugs will overcome some of these deficiencies. One such agent, Sutent (chemical name: sunitinib), is an oral anti-angiogenic drug that has been approved for treatment of kidney cancer and that has also shown promising effectiveness in breast cancer.

Radiation or targeted therapy?

Question from Sunflake: I was diagnosed with Stage III breast cancer and had 7 chemos and a mastectomy. The pathologist's report after surgery stated that the removed breast had had no cancer cells and the lymph nodes were negative. Do I proceed to radiotherapy or targeted therapy?

Answers —Andrew Seidman, M.D.: I'll make a couple of comments within the limitations of the information provided. First, it's delightful to hear that following pre-operative chemotherapy that there was no evidence of cancer in the surgically removed breast tissue. This is what we commonly refer to as a Pathological Complete Response. Similarly, the absence of cancer in any lymph nodes portends a very favorable long-term recurrence-free survival. The response as pertains to the use of radiation would depend upon other features of your initial presentation, such as the tumor size, the presence or absence of skin involvement, or inflammatory breast cancer; thus, I cannot render any opinions about the advisability of radiation based on the information provided. As far as targeted therapy goes, this would be determined presently based on the presence or absence of estrogen receptors, progesterone receptors, and HER2. Again in the absence of knowing these, I cannot comment on the relevance of hormonal therapy or Herceptin in this specific scenario.

Jennifer Armstrong, M.D.: These are very good questions and I encourage you to talk to your own physician and engage him or her in conversation to address the issues that Dr. Seidman brought up.

Are aromatase inhibitors anti-angiogenics?

Question from Janis: Are aromatase inhibitors also anti-angiogenic drugs? Are they targeted therapies as well?

Answers —Andrew Seidman, M.D.: I don't think of aromatase inhibitors as anti-angiogenic drugs. These are anti-estrogens that work by a different mechanism of action than tamoxifen. Aromatase is an enzyme that results in the production of estrogen outside of the ovaries in places such as the adrenal glands, which are sitting on top of the kidneys, as well as in fat, muscle, and in the liver. Aromatase is responsible for most estrogen production in the post-menopausal woman whose ovaries are no longer producing estrogen. The aromatase inhibitors (Arimidex, Femara, and Aromasin) all inhibit this enzyme and thus create a very low estrogen environment. This is thought to be the major mechanism by which aromatase inhibitors "target" estrogen receptor-positive breast cancer. It is important to also note that aromatase inhibitors should only be used in postmenopausal women or in premenopausal women whose ovarian function is suppressed by other means such as drugs or surgery.

Jennifer Armstrong, M.D.: Dr. Seidman, would you not agree that the latter reference (i.e., the use of aromatase inhibitors in premenopausal women undergoing ovarian suppression) is not yet considered standard of care?

Andrew Seidman, M.D.: Yes. The current optimal anti-estrogen treatment for premenopausal women with metastatic breast cancer is largely regarded as ovarian function suppression plus tamoxifen. The standard anti-estrogen therapy for premenopausal women with ER-positive early breast cancer is tamoxifen only. The role of ovarian function suppression as well as aromatase inhibitors is presently being studied in several large randomized Phase 3 trials.

Iressa to treat breast cancer?

Question from GranBelle: I've heard different things about Iressa—that it works in breast cancer, and that it doesn't work in breast cancer. Which is it?

Answers —Andrew Seidman, M.D.: When you phrase the question that way, the answer is it doesn't work in breast cancer. By this, I refer to at least four Phase 2 clinical trials that have shown either no or very minimal effectiveness for Iressa when used as a single agent or single drug. However, based on the evidence that inhibiting the epidermal growth factor receptor and estrogen receptor may translate into benefit not only in the laboratory but in patients, there are still clinical trials examining the potential for Iressa and anti-estrogen strategies such as tamoxifen and aromatase inhibitors in combination.

Jennifer Armstrong, M.D.: Excellent question, and excellent response. Thank you very much.

Alternatives to tamoxifen?

Question from Tri: What is the latest research on a premenopausal woman, estrogen-positive but cannot take tamoxifen due to a clot disorder (Factor V Leiden)?

Answers —Andrew Seidman, M.D.: I will answer the question in the absence of knowing what stage of disease you are at and what other therapies may or may not have been administered. As a general comment, for a premenopausal woman with ER-positive breast cancer of any stage for whom tamoxifen could not safely be administered, the intervention that comes to mind as being safe and effective returns to my earlier comment of targeted therapy in the 1800s—simply suppression of ovarian function either chemically, using agents called LHRH analogues, such as Lupron (chemical name: leuprolide) or Zoladex (chemical name: goserelin) or surgical oophorectomy (removal of the ovaries). To reiterate an earlier point, aromatase inhibitors, while they do not carry the risk of blood clots that tamoxifen does, cannot be recommended for a premenopausal woman with any stage of breast cancer.

Jennifer Armstrong, M.D.: While there is a lack of data concerning the safety of the use of tamoxifen with anti-coagulation such as Coumadin (chemical name: warfarin) for patients with Factor V Leiden deficiency (or other underlying hyper-coagulable state), depending on the individual history (and whether there had been previous venothromboembolic disease, or clots, and/or the severity of previous clots), this could be a consideration.

When will Tykerb be available?

Question from Mauryne: When will Tykerb be available for use?

Answers —Andrew Seidman, M.D.: I would just point out that it is not a foregone conclusion that Tykerb will be available for use, since it is up to the Oncology Drug Advisory Committee and ultimately the Food and Drug Administration to carefully review the data to decide about the merits of this promising drug. Having said that, the data presented recently are very encouraging, and one would hope for an expeditious review of the data. While this is awaited, there is an expanded use program available for women with similar characteristics to the patients who participated in the randomized trial reported by Dr. Geyer at ASCO this spring. Patients who think this drug might be relevant for them should ask their medical oncologist if this could be a good option.

Jennifer Armstrong, M.D.: I wouldn't be surprised if we didn't see it widely available until 2007.

Editor's Note: Tykerb was approved by the FDA in March 2007.

Treatment for bone metastases?

Question from Dolphin: If you have metastases to bone at age 26, first diagnosed at age 24 and carry both genes and first treatment did not work, will there be any new hope for metastases to bone at such a young age?

Answers —Andrew Seidman, M.D.: I would first comment that certainly breast cancer in patients under the age of 30 represents a very small percentage of all breast cancers. Undoubtedly, there are unique aspects to the biology of breast cancer in younger women. In general, the principles that we apply in selecting treatment for a 36-year-old premenopausal woman are the same that we would apply for a 26-year-old woman. Here I refer to the use of anti-estrogen treatment when indicated, based on estrogen receptor and progesterone receptor status, the use of Herceptin when indicated based on HER2 status, and the use of chemotherapy in general. With respect to bone specific management, the use of bisphosphonates such as zoledronate, also known as Zometa, can often be helpful in reducing skeletal complications of metastatic breast cancer such as bone pain, fracture, and a high calcium level in the bloodstream or hypercalcemia. At the ASCO meeting this spring, we heard about a new promising bone targeted agent called Denosumab, also known as AMG 162, which is a monoclonal antibody that inhibits the activity of a molecule called RANKL, which ultimately shuts off the process of bone destruction that can occur when breast cancer travels to bones. Dr. Alan Lipton presented some preliminary data, and a recent report in the New England Journal of Medicine suggests that this agent may play an important future role, either in addition to or instead of existing bone targeted drugs.

Jennifer Armstrong, M.D.: There is absolutely hope. While the tumor you described sounds quite aggressive, there are many treatments currently available and as Dr. Seidman has so impressively detailed, more coming out. You should have every reason to expect that the quality of your life can be improved. Hang in there.

Overcoming resistance to Herceptin?

Question from Joan: Dr. Seidman, what are the available and under-investigation options to overcome resistance to Herceptin?

Answer —Andrew Seidman, M.D.: Currently, the only agent that has been shown to improve the effectiveness of conventional therapy in Herceptin resistant breast cancer is Tykerb, or lapatinib, based on the trial we spoke of earlier. Another promising agent reported by my colleague Dr. Shanu Modi at the ASCO meeting this spring is an agent known as 17AAG. This is also known as KOS-953. This novel agent inhibits a molecule known as heat-shock protein 90 and causes degradation of the HER2 receptor. Dr. Modi reported responses with this agent in combination with Herceptin in patients whose cancer had recently progressed on other chemotherapy with Herceptin. There is also data from Dr. Storniolo from the San Antonio Breast Cancer Symposium in December 2005 demonstrating the role for Tykerb and this might perhaps in the future be observed with other tyrosine kinase inhibitors. We have also studied Cox-2 inhibitors, such as Celebrex (chemical name: celecoxib), based on laboratory evidence, but unfortunately found no evidence that this strategy had any effectiveness in Herceptin-resistant breast cancer. Other strategies under investigation include tumor vaccines, the agent pertuzimab, which is a monoclonal antibody targeting a different portion of the HER2 receptor than Herceptin, among others.

Grapefruit interferes with targeted therapies?

Question from Joan: Grapefruit is said to inhibit one of the P450 enzymes involved in the metabolism of some chemotherapy drugs. Is it also potentially able to interfere with targeted drugs like Herceptin and Tykerb? If so, should grapefruit (and other citrus fruits?) be banned from the diets of patients on Herceptin and Tykerb?

Answer —Andrew Seidman, M.D.: Very good question, and I honestly don't know if those specific drugs require this enzyme and how critical it is for the metabolism. It is certainly true that grapefruit juice as well as other food products can interfere with P450, but I'd have to refer this question to the drug manufacturer.

New gene/tumor tests?

Question from Cheryl58: Are new gene/tumor tests being developed, such as the Oncotype test, that will allow use of a broader range of targeted therapies for use on all tumors (besides ER/PR+)?

Answers —Andrew Seidman, M.D.: Yes, this is an excellent question and while we've spent most of this chat focusing on targeted therapies and drugs, the other side of the coin is to use diagnostic tests and molecular analysis of specific tumors to enrich the population of patients who will benefit from a given treatment even before one chooses to use the treatment. The Oncotype DX is one such tool. This is a test that is performed on the primary breast tumor and it examines 21 key genes that play an important role in breast cancer metastasis. This test, which is commercially available, provides the patient and her physician with a "recurrence score" which can provide a more accurate and refined estimate of her chance to be cured when diagnosed with early stage breast cancer. Specifically, studies have shown that for patients with lymph node-negative, ER-positive breast cancer, a low recurrence score argues strongly against the use of chemotherapy and a high recurrence score argues strongly in favor of the need for chemotherapy. A large national randomized trial known as Tailor x is getting underway to better determine whether patients whose tumors are characterized as "intermediate risk" based on this Oncotype DX assay will benefit from chemotherapy, or whether perhaps they may be best served by the use of hormonal therapy alone. Thus my long-winded answer to your very direct, specific question is that indeed, tests that analyze tumors well beyond the usual suspects of ER, PR, and HER2 are already beginning to impact our therapeutic approach to breast cancer.

Jennifer Armstrong, M.D.: While I am not aware of specific new assays under development, this general area of research is often referred to as genomic or proteomic research, and is an active area of research. Stay tuned!

Aromatase inhibitors reduce new cancers?

Question from Marilyn: Are there data indicating that aromatase inhibitors reduce the occurrences of new primary breast cancers in general, and more specifically in the presence of BRCA mutations?

Answers —Andrew Seidman, M.D.: Yes to the first part of the question. Clinical trials in which aromatase inhibitors have been given as adjuvant therapy for invasive breast cancer have indeed demonstrated lower rates of new primary breast cancer formation, either in the same breast assuming breast conserving surgery, or in the opposite breast. The magnitude of this apparent breast cancer prevention effect seems similar to that already observed for tamoxifen. To date, however, we have no data from a randomized prospective study that would support the use of aromatase inhibitor therapy as a breast cancer prevention strategy in a woman without a personal history of breast cancer. I am not aware of any differential effect of the ability of aromatase inhibitors to prevent breast cancers based on BRCA mutation status.

Jennifer Armstrong, M.D.: I concur. Before we run out of time, I want to thank Dr. Seidman for his incredible contribution. His depth and breadth of knowledge, and his ability to communicate all of it in such an honest and straightforward manner make sharing the evening with him an absolute pleasure. It has been an honor and a privilege. Thank you.

Andrew Seidman, M.D.: It has been my privilege to be able to participate in this unique forum, which allows for honest and open interchange of thoughts and ideas. Inasmuch as the chemotherapy era began in the 1960s, this decade I think can rightfully be called the beginning of the end of the chemotherapy era. Our ability to unravel the biology of not only breast cancer but other cancers, and to translate that knowledge into the development of rationally designed targeted therapies, only gives me much reason for optimism for the future of breast cancer therapy. My sincere best wishes for the good health of all those participating in this program.