The American Society of Clinical Oncology (ASCO) meeting was held last week in Chicago. Dr. Julie Gralow, a medical oncologist practicing in Seattle and specializing in breast cancer, summarized some of the more important studies that were presented. To hear more from Dr. Gralow, follow her on twitter. ~DJA
See ASCO’s “Research Roundup” for patients for additional information on some of the abstracts described below: http://www.cancer.net/sites/cancer.net/files/2014_am_rr.pdf
Abstract LBA4: ALTTO Trial of adjuvant trastuzumab (Herceptin) and lapatinib (Tykerb) in early-stage HER2 positive breast cancer
The Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial enrolled over 8,000 women with HER2-positive, early stage breast cancer in 44 countries. All patients underwent surgery, then all received chemotherapy with a randomization to one of 4 options: 1.) trastuzumab, which continued for a full year (the current standard of care), 2.) lapatinib, an oral HER2 agent that also blocks EGFR or HER1, 3.) both HER2-targeted drugs together, or 4.) trastuzumab for 12 weeks followed by lapatinib to complete one year. The study hypothesis was that exposure to 2 HER2 agents would result in less breast cancer recurrences and deaths than a single HER2 agent. A companion study conducted in the preoperative setting called the neoALTTO trial, previously reported, also tested chemotherapy with both HER2 either agents either alone or combined. The neoALTTO study showed that the combination of 2 HER2 agents resulted in a higher likelihood of having no cancer remaining at the time of definitive breast surgery (also called a pathologic complete response) compared to chemotherapy with just one HER2 drug. Studies have shown that regimens that result in more complete responses in the preoperative setting usually translate to less recurrences and deaths on longer follow-up. It therefore came as a surprise to find that in the ALTTO trial to find that the standard of care arm with trastuzumab alone did just as well as the arms that received both drugs either in combination or in sequence. Giving both HER2 agents also had more side effects, including rash, diarrhea, and liver effects. The single agent lapatinib arm had been closed down early during the study because it did not appear to be as effective as the trastuzumab arm (those women were then offered to receive a year of trastuzumab), and these results were not shown at ASCO.
Despite being labeled a “negative” trial that will not change the standard of care, there are many positives about it, and it remains an important study. First, it was shown that with an average of over 4 years of follow-up, patients with HER2 positive breast cancer, which used to be considered highly aggressive with poor survival, had a 94% chance of being alive. Second, the incidence of serious heart toxicity, a known side effect of HER2 agents, was less than 1% in all arms. Third, the tumor specimens collected in this study, which were required on all patients, will provide an important opportunity to better study HER2-positive breast cancer and understand which tumors do well and which will recur despite state-of-the-art treatment, so we can work on better strategies for this group. It may even be that there is a subgroup that does better with lapatinib or the combination! The translational studies will continue for years to come. And 4th, this trial was an impressive example of a true partnership between industry and government-supported clinical trials groups, and between countries all over the world – something we will need increasingly in an era where government funding for clinical trials is being reduced dramatically.
LBA1: Combined analysis of the SOFT and TEXT trials in ER-positive, premenopausal, early stage breast cancer patients receiving ovarian suppression and randomized to tamoxifen or exemestane (Aromasin)
SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen EXemestane Trial) are 2 separate studies that studied hormonal therapy in premenopausal women. The TEXT trial had 2 arms – everyone received a drug called triptorelin to shut down the ovaries (or women could choose to have their ovaries removed or radiated), and they were then randomized to tamoxifen or exemestane, an aromatase inhibitor. Giving ovarian suppression to young women with early stage breast cancer is more common in Europe, where this study was primarily conducted, than in the US. The SOFT trial had 3 arms, comparing the standard of care in the U.S., tamoxifen alone, to tamoxifen plus ovarian suppression or exemestane plus ovarian suppression. Aromatase inhibitors including exemestane have shown superiority to tamoxifen in reducing recurrences in ER-positive postmenopausal breast cancer patients, but do not work in premenopausal women with ongoing ovarian estrogen production – hence the need to shut down the ovaries. We were not shown the results of the tamoxifen-only arm of the SOFT trial (there are not enough breast cancer events to analyze that study in full yet), so we do not have an answer to the question of whether ovarian suppression adds to tamoxifen in reducing recurrences and improving survival. By combining the ovarian suppression arms of the 2 trials, the trialists’ were able to perform an analysis of the tamoxifen versus exemestane question. The primary study endpoint was disease-free survival – the number of women who had not had a breast cancer recurrence of any type (metastatic, local in the breast or lymph nodes, or a second breast cancer) or death. With an average of 5.5 years of follow-up, 87% of the women in the tamoxifen group and 91% in the exemestane group were alive without recurrence, for an absolute difference of 4%. No difference between the arms was observed in overall survival – the percent of women alive. Osteoporosis, muscle and joint pain, and fractures were more common in the exemestane-treated patients, and blood clots were more common in the tamoxifen patients. A higher percentage of women in the exemestane arm discontinued their assigned treatment (16%) than in the tamoxifen arm (11%).
The conclusion from this study is that the combination of ovarian suppression with exemestane is an option for premenopausal women with ER-positive, early stage breast cancer. A prior study from Austria showed the opposite result – which leaves some questions about which subgroups of young women and which tumor subtypes benefit most from which drugs (the Austrian study only gave 3 years of anti-estrogen therapy). Additionally, there is no data at present suggesting that women live longer with this new combination, and so it will not immediately replace tamoxifen alone as the standard of care in the U.S, but will be discussed as an option. Other recent trials have shown other strategies that have better outcomes compared to 5 years of tamoxifen, and we don’t know how these might compare to the ovarian suppression/exemestane combination. The ATTOM and ATLAS studies previously showed that 10 years of tamoxifen use is superior to 5 years (with differences in recurrences of 3-4%, in the same range as the SOFT/TEXT analysis, with less deaths seen for longer tamoxifen). Additionally, for women who go through menopause while on tamoxifen, studies such as MA-17 have shown that switching to an aromatase inhibitor after 5 years of tamoxifen further reduces recurrences compared to 5 years of tamoxifen alone. Ovarian suppression induces menopause, and the long-term consequences of this treatment strategy on bone, heart and gynecologic health will need to be followed in this young group of women, many of whom will likely be cured of their breast cancer and live a long life. Aromatase inhibitors have additional negative effects on bone and cholesterol, while in the potsmenopausal setting tamoxifen can have favorable effects in these areas. Discussions of the expected benefits in reducing breast cancer contrasted to the possible short and long-term side effects will have to be carefully undertaken with each patient before deciding which endocrine regimen is right for her.
The SOFT/TEXT combined analysis has also recently been published in the New England Journal of Medicine:
LBA505: S0230 Prevention of Early Menopause (POEMS) study of the use of short-term ovarian suppression during chemotherapy to preserve ovarian function in premenaopausal, ER-negative early stage breast cancer
Early menopause is a common side effect of chemotherapy in young breast cancer patients, resulting in hot flashes, night sweats and other menopausal symptoms, as well as long-term effects on the bones, heart and gynecologic tissues, as well as infertility. Sometimes the ovaries recover and menses resumes after completion of chemotherapy, but many times this effect is permanent. The S0230 study tested whether temporarily shutting down the ovaries in premenopausal women about to start chemotherapy – and continuing the ovarian suppression during the chemotherapy – would lead to less permanent menopause. All women in the study had ER-negative, early stage, premenopausal breast cancer and were about to start chemotherapy (a group chosen so as not to confuse the possible interaction between ovarian function suppression and chemotherapy in ER-positive breast cancer). Half of the women received an injection of an drug that temporarily shuts down the ovaries called goserelin (Zoladex) starting a week before chemotherapy and then monthly during chemotherapy. The other half received standard chemotherapy without goserelin. The study showed that women treated with the goserelin plus chemotherapy not only had better preserved ovarian function at 6 months and 2 years, but also had improved fertility and more successful pregnancies than women treated with standard chemotherapy. At 2 years, 22% of patients in the chemotherapy-alone arm had ovarian failure, while only 8% in the goserelin/chemotherapy arm did. There were 12 successful pregnancies (healthy babies born) in the chemotherapy alone group, and 22 in the goserelin/chemotherapy group. Unexpectedly, the combination also led to less recurrences and deaths.
The study’s conclusion is that premenopausal, ER-negative breast cancer patients beginning chemotherapy should consider this new option to prevent premature ovarian failure. There was discussion about whether we could safely apply this to ER-positive breast cancer (there is some concern, mostly hypothetical, about ovarian suppression possibly making chemotherapy less effective in ER+ breast cancer), and whether it would work in other chemotherapy regimen in other types of cancers (lymphoma patients receive chemotherapy regimens that are very similar to breast cancer regimens, so it will likely work in that setting).
Abstract LBA9500: OPTIMIZE 2 study of less frequent Zoledronic Acid (Zometa) dosing intervals in breast cancer patients with bone metastases
Zoledronic acid, a bisphosphonate that inhibits bone breakdown, is commonly used to reduce bone complications such as fractures, the need for surgery or radiation, or spinal cord compression in breast cancer patients with bone metastases. It is given once monthly by vein, and guidelines state that treatment should continue indefinitely as long as the patient is doing well. There have been concerns that continuing the monthly schedule long-term may increase the risk of side effects like kidney problems and osteonecrosis of the jaw (ONJ), a condition in which exposed bone in the jaw doesn’t heal. The OPTIMIZE 2 phase III randomized clinical trial was designed to test whether the time between zoledronic acid doses could be safely and effectively extended from monthly to every 3 months after several months of treatment. in this trial, 403 breast cancer patients with bone metastases who had been receiving zoldronic acid monthly for about a year were divided into two groups. One group continued to receive zoledronic acid every month, and the other group switched to every three months. The study found that the percentage of women who developed fractures, spinal cord compression, or needed radiation or surgery because of bone metastases was similar in both groups (22% in the monthly group compared with 23% percent in the every 3 month group). There were no differences in kidney or other side effects between the two arms, although two women in the monthly group developed osteonecrosis of the jaw compared with none in the every 3 month treatment group.
The conclusion of this study is that women taking zoledronic acid for breast cancer that has spread to the bones can safely switch to a 3 month dosing schedule after receiving a year of monthly treatments. Whether this will apply to cancer patients receiving denosumab (Xgeva), another agent used to treat bone metastases that is in a drug class called RANK ligand inhibitors, is unknown.
New Agents and Pathways in Metastatic Breast Cancer
ASCO 2014 included a lot of discussion about cancer genomics, novel targeted therapies, and combining the two into more “personalized cancer medicine.” Within the breast cancer sessions there were no major blockbuster new drugs immediately impacting treatment of metastatic disease. This is frustrating, but that doesn’t mean that there isn’t a lot of important research being done. It’s expected that several new targeted agents will be approved for breast cancer in the near future, and a review of the poster sessions reveals promising early phase presentations on drugs with activity in at least subsets of breast cancer.
The PI3 kinase (PI3K)/AKT/mTOR pathways may be associated with tumor progression and resistance to metastatic therapies, and several drugs targeting these pathways are in development. One drug, everolimus (Affinitor), an mTOR inhibitor, has recently been approved in overcoming resistance to endocrine therapy in metastatic breast cancer and is being studied in earlier stage disease. Abstracts 516 and 533 provide early data on the PI3K inhibitor BYL719, and abstract 553 presents results using the AKT inhibitor MK-2206 combined with hormonal therapy.
Results from trials of cell cycle inhibitors targeting cyclin-dependent kinases 4 and 6 (CDK4/6), including the drugs LY2835219, LEE011, and palbociclib, were presented in abstracts 527, 534 and 535. These CDK 4/6 inhibitors are advancing in ongoing Phase II and III studies. Palbociclib has received FDA breakthrough status in breast cancer based on exciting Phase II results, and will likely be submitted for approval later this year.
Poly(ADP ribose) polymerase (PARP) inhibitors have shown promising responses in BRCA+ breast cancer and generated interest in triple negative breast cancers. Abstracts 1021 and 2569 showed interesting results for the PARP inhibitor veliparib that will be followed up with subsequent trials.
Although more commonly associated with prostate cancer, the androgen receptor is also expressed on many estrogen receptor-positive breast cancers as well as a subset of triple negative breast cancer. A trial of the androgen receptor-targeted agent enzalutamide given with the anti-estrogen therapy exemestane (abstract 545) showed early data in breast cancer. Several larger trials of anti-androgen receptors are ongoing in metastatic breast cancer.
DNA wraps around histones, and DNA expression, needed for cell growth and division, requires enzymes that remove and add acetyl groups from DNA. Histone deacetylase (HDAC) inhibitors are already approved for some non-cancer diseases as well as some types of cancer. They may have activity in breast cancer, as was shown in a small trial of the HDAC inhibitor vorinostat to overcome resistance to endocrine therapy (abstract 556).
While immunotherapy has generated a lot of buzz in the general cancer community, learning how to exploit promising new immunotherapy drugs and strategies in breast cancer has proven to be not so simple. There were, however, a couple of interesting early immunotherapy posters in the breast sessions. Abstract 1098 evaluated iplilumumab’s effect on tumor-infiltrating lymphocytes in early stage breast cancer. This drug, already approved in melanoma, activates the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system. Abstract 616 showed early results of a HER2 vaccine in stage III and IV breast cancer, proving that robust T cell responses to a tumor antigen can be achieved.
An important upcoming trial that combines cancer genomic profiling with access to dozens of experimental targeted agents is being funded by the National Cancer Institute (NCI). The NCI MATCH (Molecular Analysis for Therapy Choice) trial is in development, and will be run through the National Clinical Trials Network. It will enroll patients with advanced stage solid tumors (including breast cancer) and lymphomas, and will include genomic analysis of the tumor matched to access to the NCI’s large portfolio of experimental anti-cancer drugs. More information on this trial can be found in this slide set from the NCI: http://deainfo.nci.nih.gov/advisory/ncab/164_1213/Conley.pdf
While the studies I’ve described above include agents generally not yet available for treating breast cancer, and some of them may never be approved due to lack of confirmed benefit in larger, better powered studies, I’ve included them to highlight the vast amount of research ongoing that is aiming to improve options and outcomes for all breast cancer patients.