The ASCO (American Society of Clinical Oncology) 2015 Annual Meeting just wrapped up on Tuesday. 30,000 specialists in oncology descended on Chicago to discuss the latest advances in cancer research. All in all, there were no major practice-changing studies at least in the breast cancer world, but there is a general buzz of excitement about the paradigm shift that is occurring in how we approach treating cancer. Two concepts support this shift:
#1 There are some breast cancers that behave more like other types of cancer (i.e. ovarian cancer) than other breast cancers. As we learn more about the molecular origins of a tumor, the defects that led to its development, we are able to guide therapy based on the pathways that have been disrupted rather than based on the organ in which the tumor originated. In fact, ASCO just announced the initiation of the TAPUR Study (Targeted Agent and Profiling Utilization Registry), which will assess off-label use of targeted therapies for various cancers based on a tumor’s particular genomic variation. The National Cancer Institute (NCI) also announced that they will start NCI-MATCH, the largest precision medicine oncology clinical trial ever attempted, which also aims at matching new targeted therapies with tumors demonstrating a particular molecular profile.
#2 We can successfully fight cancer by making our immune system do the fighting. This is the first time since the advent of chemotherapy that we have seen drugs work effectively across many different tumor types, including many challenging forms of cancer such as advanced melanoma and triple negative breast cancer. Most of the data at this year’s meeting using these new immunotherapy agents focused on melanoma and other malignancies. Clinical trials using these drugs in breast cancer are ongoing.
While there may not have been any practice changing breast cancer studies reported at ASCO this year, there were still some noteworthy trials reported that will no doubt have an impact on particular aspects of the breast cancer population. Here are my Top 5 Breast Cancer Highlights from ASCO 2015....
#1 NSABP B-35: Another option for women with DCIS
Women with DCIS, for the most part, do quite well. In fact, so well, there is great concern that we are over-treating women with this form of non-invasive breast cancer. The standard of care right now is for patients to undergo surgery +/- radiation depending on the type of surgery performed. In addition, an earlier study, NSABP B-24, demonstrated benefit in offering 5 years of tamoxifen therapy to women diagnosed with DCIS, as it was shown to reduce the risk of another breast cancer event by as much as 40%. Currently, we offer tamoxifen to women with DCIS more for prevention than for treatment and it is an option that only some women choose to take. The study reported last weekend was the NSABP B-35 trial, which randomized women to tamoxifen versus anastrozole, an aromatase inhibitor, used to treat hormone receptor positive breast cancer in postmenopausal women. The trial involved over 3000 postmenopausal women with DCIS who were treated with lumpectomy and radiation for their DCIS. They reported, after 9 years of follow up, anastrozole was superior at preventing new breast cancer events compared to tamoxifen (93.5% breast cancer-free interval vs. 89.2%). The improvement was greatest seen in women under 60. With regard to side effects, as predicted, the aromatase inhibitor group had slightly more fractures and the tamoxifen group had more blood clots and uterine cancer, though all events were fairly rare (ranging from <1% to about 2% for fractures in the aromatase inhibitor group) and have been reported in the past in other clinical trials.
The bottom line: for postmenopausal women with DCIS who are inclined to take a medication to prevent new breast cancer events, anastrozole is a potential alternative to tamoxifen.
#2 PALOMA 3: Adding palbociclib to fulvestrant in women with hormone receptor positive, metastatic breast cancer
Palbociclib, a CDK 4/6 inhibitor, is an oral drug that aims to prevent resistance to hormonal therapy. It has been the talk of the oncology world for the past couple of years as data continues to demonstrate fairly significant benefits of adding this drug to different types of hormonal therapy with very few side effects. In fact, the early data was so impressive that it led to an accelerated approval of palbociclib by the FDA in February 2015 to be added to standard aromatase inhibitor therapy in postmenopausal women with newly-diagnosed metastatic breast cancer. To date, the only data we have on this drug is in the metastatic setting, those with Stage IV breast cancer. The trial reported at ASCO was a large Phase III study looking at combining palbociclib with fulvestrant, a selective estrogen receptor down-regulator, in women with Stage IV breast cancer receiving second-line hormonal therapy. 500 women were randomized on a 2:1 basis to the fulvestrant + palbociclib arm vs. fulvestrant + placebo. The results showed an improvement of progression-free survival (PFS) of 9.2 months with fulvestrant + palbociclib compared to 3.8 months with fulvestrant + placebo. The side effects seen with the study arm were mainly related to an asymptomatic lowering of the blood counts.
The bottom line: this data further supports the FDA approval of palbociclib in women with advanced hormone receptor positive breast cancer and paves the way for ongoing studies in early-stage breast cancer patients.
#3 More data supporting the use of medicine to maintain bone density in women with early and late stage breast cancer
There has been great debate about the benefits/risks of adding bisphosphonate therapy to standard therapy in women with early stage breast cancer. Essentially, several trials have demonstrated some benefit, with regard to disease recurrence and bone density, of adding these drugs to breast cancer patients who are in a “low-estrogen” state, meaning either postmenopausal women or women who have been rendered postmenopausal by certain types of therapy. This latest study, ABCSG-18, reported on a different class of bone density-supporting drugs called RANK ligand inhibitors. The drug, denosumab (AKA Prolia), is currently FDA-approved for women with osteoporosis and for women at high risk for fracture on aromatase inhibitor therapy for breast cancer. The trial randomized over 3400 postmenopausal women with hormone receptor positive breast cancer to either denosumab given by subcutaneous injection every 6 months for 3 years or placebo injection. The study showed that denosumab helped reduced fractures, with 92 fractures occurring in the denosumab group, compared with 176 fractures in the placebo group. The benefit was seen in women with normal bone density and those with compromised bone density at baseline. With short follow up, there was no significant difference in adverse events between the denosumab group and the placebo group. Despite this benefit, there is still debate in the oncology community regarding whether the benefits of bone density medication outweigh the potential risks and costs of such therapy.
The second somewhat meaningful trial in the bone density arena was the CALGB 70604 trial which looked at women and men with metastatic disease to their bone from multiple myeloma, breast cancer or prostate cancer. Previous studies have demonstrated that giving monthly intravenous bisphosphonate (Zoledronic acid) therapy helps reduce fractures in these populations. This study asked if it was just as good to give it every three months instead of monthly, and the answer was yes.
The bottom line: postmenopausal women with early-stage breast cancer should be talking with their oncologists about the potential risks and benefits of initiating therapy for their bones while on an aromatase inhibitor. With regard to patients with metastatic cancer to the bones, getting therapy for the bones just got a little more convenient.
#4 Advances in Her2 positive breast cancer therapy
The next group of studies looked at some new therapies for women with Her2 disease. The first, called the ExteNET Study looked at using an oral anti-Her1, 2 and 4 drug called neratinib in early stage breast cancer patients with Her2 positive disease after they completed standard Her2-targeted therapy including chemotherapy and trastuzumab (Herceptin). Neratinib was given for one year. Follow up for this study is just at the 2 year mark now, so the data is early. Over 2800 women enrolled on the study and so far, they found a 2.3% absolute improvement in disease free survival (DFS) in the women taking neratinib over placebo. However, patients on neratinib experienced significant diarrhea which may limit its utility in this patient population unless better management strategies can be employed. Since this data is so young, only 2 years of follow up, and since the drug demonstrated some considerable side effects, it is unlikely that this trial will lead to approval of neratinib for early-stage Her2 positive patients.
The next study was the MARIANNE Study, looking at TDM-1 (AKA Kadcyla) +/- pertuzumab compared to a standard chemotherapy + trastuzumab (Herceptin) regimen as first line treatment in women with Her2 positive metastatic breast cancer. The Cliff Notes version of this study basically solidified TDM-1 as a solid second-line therapy for Her2 positive, metastatic breast cancer, leaving the CLEOPATRA regimen (Docetaxel/trastuzumab/pertuzumab) as the likely best first-line combination therapy in this population. Surprisingly, both TDM-1-containing regimens did not perform any better than the standard chemotherapy + trastuzumab arm of the study.
The last of the Her2 studies deserving honorable mention includes a very small, early-phase study of a drug currently named ONT-380. It is an oral small molecule inhibitor of Her2 which was used in combination with capecitabine (Xeloda) and trastuzumab (Herceptin) as third-line therapy for metastatic Her2 positive breast cancer. The most interesting thing about this drug is that it may have some activity in the central nervous system (CNS), for those with brain metastases. Again, the results are very, very early but were positive enough to trigger a Phase II larger study whose design is focused on prevention and treatment of CNS metastases in Her2 positive patients. It is also being looked at in combination with TDM-1.
The bottom line: nothing practice-changing for the Her2 positive population at this meeting, but interesting progress, nonetheless.
#5 Preventing breast cancer, final analysis of the NSABP P2 clinical trial (AKA STAR trial)
The STAR trial, Study of Tamoxifen and Raloxifene, is a prevention study that enrolled over 19,000 postmenopausal women who were felt to be at increased risk of developing breast cancer. These women were randomized to receive either tamoxifen or raloxifene for 5 years. The final data showed that raloxifene is about 81% as effective as tamoxifen at preventing invasive breast cancer or DCIS (non-invasive breast cancer). Side effects were lower in the raloxifene group, specifically with regard to uterine cancer and blood clots. Both drugs continued to demonstrate benefit at nearly 10 years of follow up, despite the drugs being stopped after 5 years.
The bottom line: for postmenopausal women who want to reduce their risk of developing breast cancer because of family history or other risk factors, either tamoxifen or raloxifene remain viable options.
Summing it all up…
We continue to learn more about breast cancer. The more we learn about it, the more we discover that we are truly treating many different types of disease, some that may even overlap considerably with cancers of other origin. The promising results of immunotherapy and targeted therapy in advanced cancers are now sparking a slew of trials aimed at defining cancer by molecular features, rather than location.
I mentioned “slow and steady progress” because although the advances seem to be happening rapidly now, the true test of the efficacy of these new strategies comes in demonstrating improved outcomes, especially in early stage cancer patients. This is the long-haul in oncology; difficult, expensive, and time-consuming work but one that has the potential for big payoffs. With the excitement surrounding these new agents including their improved toxicity profile and the promise of better efficacy, the hope is that clinical trial accrual will match this excitement and keep these advances marching, albeit slowly, forward into clinical practice.
I’m rooting for the tortoise.