Several clinical trials led by physician-scientists at Mass General are revealing the power of new targeted anticancer therapies in breast cancer.
In October 2011, José Baselga, MD, PhD, chief of the Division of Hematology/Oncology at Mass General and associate director of the Mass General Cancer Center, presented the results of the Breast Cancer Trials of Oral Everolimus (BOLERO-2) clinical trial, a 724-patient international phase 3 clinical trial for women with metastatic estrogen-receptor (ER)-positive breast cancer. The study found that combination therapy with two drugs, exemestane (Aromasin)—an aromatase inhibitor (hormonal therapy)—and everolimus (Afinitor), a drug approved for treatment of kidney and pancreatic cancers, significantly slowed the time to disease progression compared with treatment using exemestane plus a placebo. Specifically, the combination therapy delayed disease progression for a median period of 10.6 months compared with four months for women receiving exemestane alone.
The RAS and PI3 kinase pathways are activated by receptor tryosine kinases such as the EGF receptor family members HER2 and HER3. This leads to activation of pathways involved in tumor cell growth, proliferation, and survival.
Dr. Baselga believes the BOLERO-2 study is the most positive study ever in patients who are refractory to endocrine therapy. Endocrine therapy resistance is a major issue in the treatment of these patients. As a patient becomes resistant to one hormonal agent, the likelihood of responding to sequential treatment decreases significantly. Chemotherapy is largely ineffective for long-term control of disease in this patient population.
Dr. Baselga estimates that 50 to 60 percent of patients with metastatic breast cancer have ER-positive tumors, representing a large patient population who may benefit from this treatment.
Everolimus is a targeted therapy that works by zeroing in on the mTOR protein, which is regulated by the family of enzymes known as PI3 kinases (PI3K). In healthy cells, mTOR is involved in cell growth, cell proliferation, protein synthesis, and many other functions. In tumor cells, the mTOR pathway goes awry, leading to excess proliferation and a failure to respond to normal growth regulatory mechanisms [see Baselga J, et al. (2012). Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med, 366(6): 520-29].
Just two months after announcing the results of the BOLERO-2 study, in December 2011, Dr. Baselga presented the results of the phase 3 Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) trial, which bodes significant promise for women with metastatic HER2-positive breast cancer—a population estimated to be 20 percent of all women with metastatic disease. The phase 3 clinical trial in 800 women with this type of cancer compared a three-drug regimen consisting of a new targeted therapy: pertuzumab (Perjeta), the first anti-HER2 monoclonal antibody designed to block the pairing of HER2 receptors with other members of the same receptor family in breast cancer cells; trastuzumab (Herceptin), an approved anti-HER2 monoclonal antibody; and the chemotherapy drug docetaxel (Taxotere) with a regimen of trastuzumab and docetaxel alone.
Those who received the two targeted therapies (pertuzumab and trastuzumab) plus chemotherapy experienced significantly longer median progression-free survival—18.5 months—compared to 12.4 months for women who received the trastuzumab/docetaxel combination. Also, there was a survival improvement in the patients who received pertuzumab. To place this study in perspective and to predict what it may represent to patients with HER2-positive breast cancer, the results of the CLEOPATRA study are the best in this patient population to date [see Baselga J, et al. (2012). Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med, 366(2): 109-19]. Pertuzumab received FDA approval in June 2012.
These two studies will be practice changing for a majority of patients with advanced breast cancer. Yet, according to Dr. Baselga, the best is yet to come. Dr. Baselga is leading a large worldwide phase 3 study with pertuzumab in patients with newly diagnosed early HER2-positive breast cancer. In addition, Mass General has initiated a number of studies with everolimus and similar agents.
facts and figures50 to 60% of patients with metastatic breast cancer have ER-positive tumors, representing a large patient population who may benefit from this treatment
Routine Cancer Genotyping
To help guide the administration of appropriate targeted therapies for women seeking treatment for advanced breast cancer at Mass General Cancer Center, physicians have established a routine cancer genotyping program—the SNaPshot molecular fingerprinting technique—that assesses each patient’s tumor for known genetic mutations. The genotyping assay tests for 120 mutations across 16 cancer genes. A collaborative team of pathologists and oncologists, led by John Iafrate, MD, PhD, and Leif W. Ellisen, MD, PhD, developed a new test, based on the SNaPshot technology, to produce highly accurate gene mutation detection.
When there are available drugs for specific genetic mutations, patients are offered the appropriate therapy either as an approved medication or through enrollment in clinical trials that are directed to these mutations. Genotyping research shows that 25 to 30 percent of breast cancer patients have known mutations in one of the genes in the PI3K pathway, underscoring the importance of this pathway in breast cancer and the sizable opportunity new therapies against these targets represent. The routine genotyping of breast cancer in almost real time has enabled many patients with tumors harboring PI3K mutations to benefit from these new therapies. A Mass General–led study observed promising clinical activity, which was presented in a special symposium at the spring 2012 American Association for Cancer Research meeting.
Partial Breast Irradiation
Many women who choose not to have a mastectomy instead undergo breast-conserving surgery where only the tumor and a small margin of tissue are removed, followed by a six-week course of daily radiation to the whole breast. But many women find this lengthy course of treatment represents a significant burden in their daily lives.
Physicians at Mass General are leaders in the field of developing new radiation techniques, including those for partial breast irradiation, which targets only the area of the breast where the tumor was located. Alphonse Taghian, MD, PhD, chief of the Breast Service in the Mass General Hospital Department of Radiation Oncology, together with his colleagues, began developing these techniques in 2003. This approach is based on the hypothesis that the majority of recurrences present near the site of the original tumor. Radiation oncologists can now precisely pinpoint radiation at the tumor site. This means that patients can successfully complete the entire radiation course with five days of twice-daily treatments instead of six weeks. Furthermore, partial breast irradiation techniques spare the heart and lungs, sites commonly exposed during standard radiation treatment for left-side breast cancers.
Mass General physicians follow the 2009 treatment recommendations from the American Society of Radiation Oncologists categorizing women into three groups that are most likely to benefit from this procedure. The most favorable group includes those who are 60 or older with negative lymph nodes and tumors smaller than 2 cm.
Proton Beam Radiation
In other efforts to limit radiation-induced side effects such as cardiotoxicity, Mass General radiation oncologists are now recruiting women into a pilot clinical trial using proton beam radiation, instead of the standard photon beam. Studies performed at Mass General demonstrated that proton beam irradiation exposes the heart to one-tenth the radiation of photon beam radiation. When women with left-side breast cancer receive chemotherapy with cardiotoxic drugs, such as doxorubicin (Adriamycin, Rubex), paclitaxel (Taxol), trastuzumab (Herceptin), and others, followed by photon beam radiation, the radiation crosses part of the heart, resulting in cardiotoxic damage that may take up to 10 years to become apparent.
This is of special concern for young women, since they can expect to live many years after chemotherapy. Avoiding heart-damaging radiation through the use of proton beam techniques may decrease the chance that heart problems will develop over time.
Physicians in the Mass General Breast Service offer women a new approach to help prevent the onset of lymphedema—a condition affecting 10 percent of women after aggressive breast cancer surgery. Starting in 2005, physicians began a screening program for all women to identify swelling at its earliest stage. They have designed a phase 3 clinical study, directed by Dr. Taghian, which is now assessing whether early compression treatment for six to 12 weeks prevents the onset of permanent lymphedema.
To date, more than 2,600 women who have come to Mass General with breast cancer have had arm measurements at baseline. During follow-up, if swelling reaches a threshold of 5 percent over baseline, women are offered the opportunity to enroll in the early compression trial.
Two surgical advances available at Mass General are helping reduce complications and improve cosmetic appearance after breast cancer surgery.
A major research study known as ACOSOG Z0011 recently concluded that radiation may be just as effective as full axillary dissection for many patients with a positive sentinel lymph node. This minimizes discomfort and complications, including lymphedema.
This study confirmed results of a smaller study first conducted at Mass General, led by Michele Gadd, MD, showing that use of radiation instead of more extensive surgery provides the same protection for the patient but with fewer side effects. Instead of a 15 percent risk of lymphedema seen with full axillary dissection, risk with radiation is only 1 percent. Similarly, the risk of chronic pain or mobility problems drops to less than 1 percent compared with 10 percent in full axillary dissection.
Also, Mass General surgeons have perfected a technique to perform nipple-sparing mastectomies. After conducting extensive anatomical studies, Barbara Smith, MD, PhD, and other Mass General breast surgeons developed a new technique for saving the nipple in patients who need mastectomies either for prevention or for cancer. During mastectomy, the nipple and surrounding skin are salvaged intact. The nipple ducts are removed and tested, assuring removal of the tumor and at-risk ducts. Mass General plastic surgeons then perform reconstruction the same day, often in a single step so that the patient wakes up to a completed reconstruction, which includes her own nipple.
The result is a greatly improved cosmetic outcome. Women who are carriers of known risk gene mutations like BRCA1 and BRCA2 or who have other significant risk factors for breast cancer have found it easier to select preventive mastectomies because of the near-normal postsurgical appearance of the breast.Extensive Research Environment
Understanding of the biological pathways driving breast cancer has progressed tremendously. As a result, much more is known about the key drivers in breast cancer development and growth. Many new therapies being tested are in clinical trials at Mass General to help prevent or overcome drug resistance and to improve survival.
These new therapies include PI3K inhibitors, both as single agents and in combination with other drug classes, and a class of compounds known as PARP inhibitors. Steven Isakoff, MD, PhD, of the Mass General Cancer Center, is leading an investigation into PARP inhibitors. These have shown efficacy in women with BRCA1 or BRCA2 genetic mutations. He is also studying major cancer cell pathways, like PI3K and RAS, looking for new targets and new ways to intervene in the compensatory pathways that make cancer cells resistant to drug therapy. Several clinical trials are available that investigate combinations of PI3K inhibitors with other drug types, including MEK inhibitors. Another set of trials is investigating the potential of AKT inhibitors.
Mass General physicians are responding to the discovery that when the mTOR pathway is blocked, another pathway becomes activated, led by insulin-like growth factors (IGF). As a result, a new study is under way investigating combination therapy with inhibitors against mTOR and IGF signaling pathways.
Mass General is embracing the transformation in clinical trials design due to the avalanche of new targeted therapies. As researchers understand the mutations that are the focus of these new drugs, Mass General staff can match patients sooner after diagnosis with targeted clinical trials when the chances of benefit are greatest. The Mass General team of breast cancer specialists collaborates closely with patients’ primary treating physicians to identify appropriate clinical trials, facilitate enrollment, and provide follow-up care, ensuring the best available clinical trials experience. •
- Targeted therapies are offering new therapeutic options for women with historically difficult to treat breast cancer
- Accelerated partial breast irradiation consolidates treatment to an effective and more convenient one-week course, with reduced heart and lung toxicity
- Researchers are evaluating intervention in the earliest stages of lymphedema to minimize the chance of developing long-term lymphedema
- Surgical advances, such as minimal axillary surgery and nipple-sparing mastectomy, are reducing postsurgical side effects and improving cosmetic appearance
- Patients with breast cancer are offered access to innovative clinical trials at Mass General Cancer Center for a variety of new targeted therapies
Arvold ND, et al. (2011). Age, breast cancer subtype approximation, and local recurrence after breast-conserving therapy. J Clin Oncol, 29(29): 3885-91. Epub 2011 Sept. 6.
Baselga J, et al. (2012). Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.
N Engl J Med, 366(6): 520-29. Epub 2011 Dec. 7.
Baselga J, et al. (2012). Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med, 366(2): 109-19. Epub 2011 Dec. 7.
Juric D, Baselga J. (2012).Tumor genetic testing for patient selection in phase I clinical trials: The case of PI3K inhibitors. J Clin Oncol, 30(8): 765-66. Epub 2012 Jan. 23.
Taghian AG, et al. (2006). Initial dosimetric experience using simple three-dimensional conformal external-beam accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys, 64(4): 1092-99. Epub 2006 Jan. 6.
Massachusetts General Hospital Cancer Center
Steven Jay Isakoff, MD, PhD
Barbara L. Smith, MD, PhD
Alphonse G. Taghian, MD, PhD
Massachusetts General Hospital Cancer Center
An integral part of one of the world’s most distinguished academic medical centers, the Massachusetts General Hospital Cancer Center is among the leading cancer care providers in the U.S. Known for providing customized, innovative treatments and compassionate care to both adults and children, the Cancer Center comprises 23 fully integrated, multidisciplinary clinical programs and a vast array of support and educational services. Its network of affiliations extends throughout New England and the southeastern U.S. The Cancer Center’s commitment to eradicating cancer is fueled by scientific investigation conducted as part of one of the largest hospital-based research programs in the nation. Through a powerful synergy between laboratory scientists and bedside physicians, the Mass General Cancer Center fosters innovation in all phases of cancer research. Physician investigators conduct nearly 400 clinical trials annually.
To refer a patient or for more information, please call 877-789-6100 or visit massgeneral.org/cancer
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