2015: The Year in Breast Cancer   Leave a comment

BY GEORGE W. SLEDGE, JR., MD

 

GEORGE W. SLEDGE, JR., MD, is Professor of Medicine and Chief of the Division of Oncology at Stanford University. He also is Oncology Times’ Editorial Board Chair. His OT writing has been recognized with an APEX Award for Publication Excellence and a FOLIO: Eddie Honorable Mention award.

Breast cancer remains a fertile area of clinical research investigation, and 2015 revealed numerous surprises, involving local-regional therapy, adjuvant and neoadjuvant therapy, and metastatic disease. It is not a disease so much as it is a universe.

Screening Mammography
While there was nothing particularly new in terms of data in the screening field, screening mammography still made national headlines. The American Cancer Society presented its long-awaited updated screening recommendations, raising the age at which it recommends initiation of screening from 40 to 45. This follows the U.S. Preventive Services Task Forces recommendation to begin screening at age 50. The American College of Radiology, in turn, recommends beginning at age 40.

As all of these groups are operating off of the same data sets, it is important to realize that the differences in these recommendations largely represent differences in data interpretation, in particular the question of, «How many women does one need to screen (or how much money does one have to pay) to prevent a breast cancer death?» That ultimate guidelines committee—the United States Congress—has directed Medicare to ignore the USPSTF recommendations.

The differences between the different groups are confusing to women and physicians. My biases are these: 1) Even with the least aggressive guidelines, a significant percentage of the population does not undergo screening, so we need to improve access and education; 2) We are at the start of a process of diagnostic individualization—call it precision imaging—that will parallel the therapeutic individualization we have seen transform breast cancer. I suspect that a decade from now we will be taking a much more nuanced approach to estimating risk, and therefore a more individualized approach to screening recommendations; 3) As therapy for breast cancer improves, screening will necessarily have a lesser impact on outcome. We do not perform testis cancer screening because it would never be cost effective.

Radiation Therapy
Five years ago I thought I understood what optimal local-regional therapy was. I was wrong. We continue to alter our understanding of both surgery and radiation therapy for local disease. The role of post-mastectomy radiation therapy remains contentious. In 2014 the Early Breast Cancer Trialists’ Collaborative Group published a meta-analysis demonstrating that post-mastectomy radiation reduced disease-free and overall survival in all patients with positive lymph nodes.

This year saw two important new developments. The EORTC published the results of a large (greater than 4,000 patients) trial in women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement (NEJM 2015;373:317-27). Patients were randomized to undergo either whole breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole breast or thoracic wall irradiation alone (control group). Disease-free survival was improved (for both local-regional and distant recurrence) with what the authors described as a marginal effect (a 1.9% difference) in overall survival.

The NCIC’s MA.20 trial (NEJM 2015;373:307-16), published back-to-back with the EORTC trial, examined whether the addition of regional nodal irradiation to whole breast irradiation improved outcome in node-positive and high-risk, node-negative women. While the additional therapy reduced the rate of recurrence, it had no effect on overall survival. My sense, as a non-radiation oncologist, is that radiation beyond whole breast irradiation appears to add relatively little to long-term outcome, and some real toxicity.

Guidelines committees are re-evaluating their post-mastectomy guidelines. Part of the problem faced by these committees is that systemic therapy has also changed, and reduced local-regional and distant recurrence. Numerous institutional studies, some quite large, are showing lower local-regional failure rates than reported in the Oxford meta-analysis and older randomized trials.

Dem Bones, Dem Bones
Going back now over 20 years, we have had preclinical evidence suggesting that anti-osteoporotic agents (both bisphosphonates and RANK ligand inhibitors) could prevent breast cancer bone metastasis. A large number of randomized trials, mostly underpowered, were subsequently performed. This year saw several decades of work come to fruition.

Let’s begin with the Early Breast Cancer Trialists’ Collaborative Group’s meta-analysis of adjuvant bisphosphonate trials (Lancet 2015;386:1353-61). I have become somewhat uncertain of the value of Oxford meta-analyses in an era dominated (on the one hand) by quite large Phase III trials, and on the other hand by rapidly emerging trials based around small genomics-driven subsets. But this is the sort of meta-analysis that shows the continuing value of the Oxford studies.

To summarize a large body of data, bisphosphonate use reduces the risk of distant metastasis and improves overall survival for early stage breast cancer. The reduction in distant metastasis is attributable entirely to a reduction in bone metastasis, biologically predictable but disappointing to those who felt there might be some spillover effect to other organs. The meta-analysis was composed of an astonishingly diverse array of studies, with differing bisphosphonates, different durations of therapy, and different patient populations. The only subgroup to satisfy a formal test for interaction was menopausal status: all the benefit was confined to postmenopausal women.

We lack a huge database of studies when we turn from bisphosphonates to RANK ligand inhibition. At present we have one drug (denosumab) in one study (ABCSG-18), and that study is frustrating. The Austrians randomized postmenopausal women receiving an aromatase inhibitor to either every six-month denosumab 60 mg or a placebo. The study’s primary endpoint was the prevention of skeletal-related events, with disease-free survival as a secondary endpoint.

The paper on skeletal-related events was published in the Lancet (2015;386:433-43). This was a real success, with denosumab markedly reducing osteoporotic fractures (hazard ratio = 0.50, p < .0001). The fracture rate in the control arm was higher than what we might have suspected, suggesting that we may have been missing AI-induced osteoporosis.

The ABCSG18 investigators next looked at disease-free survival… and that is where frustration enters the picture. Because of the impressive bone result, the study’s data monitoring committee felt there was an ethical obligation to report the results to the patients, allowing those on the control arm to cross over to denosumab therapy, with subsequent pollution of disease-free survival (DFS) results. The trialists (Michael Gnant presented their data at the 2015 San Antonio meetings) performed their analysis at a time that was clearly earlier than one would have liked, and demonstrated a «close but not quite there» p value of .051.

Where does all this leave us? First, we have great evidence for therapeutic benefit with bisphosphonates in postmenopausal early stage breast cancer. But which drug should we use, and for how long and in what dosage? Perhaps the guidelines committees will help us out on this. The RANK ligand data—such as it is—looks similar to the bisphosphonate data, with appropriate caveats. We await more denosumab data, but given denosumab’s track record in the metastatic setting, I doubt it will prove inferior to bisphosphonate therapy. Given its convenience and somewhat better tolerability, it may prove the ultimate winner.

Palbo
Estrogen receptor positive breast cancer had been a sleepy therapeutic area for much of the past decade. That changed in recent years, first with the approval of the mTOR inhibitor everolimus, and now with the introduction of the cyclin dependent kinase inhibitor palbociclib. Basic biologists have known for some time that estrogen’s growth actions require a pathway that includes Cyclin D and CDK’s 4 and 6. Palbociclib blocks CDK4/6, and in cell line models was shown to have striking activity in ER-positive breast cancer cell lines.

In April of 2015 the Food and Drug Administration gave palbociclib an accelerated approval based on the PALOMA-1 results. PALOMA-1 was a randomized Phase II trial (or, rather, a mash-up of two underpowered randomized Phase II trials) comparing letrozole alone to letrozole plus palbociclib. The trial, published in Lancet Oncology (2015;16:25-35), showed a rough doubling (from 10.2 to 20.2 months) in progression-free survival. PALOMA-1 was followed in short order by PALOMA-3, also published in 2015 (NEJM 2015;373:209-219), repeating the same experiment in a Phase III setting with fulvestrant as the endocrine agent. PALOMA-3 demonstrated a significant (statistically and clinically) improvement in progression-free survival, going from 3.8 to 9.2 months.

Palbociclib, as those who use it know, removes some of the joys of endocrine monotherapy. It is obscenely expensive and it adds toxicity to the mix, albeit manageable toxicity. Because CDK 4/6 inhibitors also affect neutrophil production, low neutrophil counts are common and require evaluation and not infrequent dose modification. Though the PALOMA-1 trial saw no neutropenic fevers, out in the real world older and frailer patients get hospitalized with infections.

Two other CDK 4/6 inhibitors are in Phase III trials, and along with palbociclib they cover the entire ER-Positive waterfront. Palbo, in turn, has entered adjuvant trials. These are good things, but I wish I knew more about CDK inhibitors. I have had metastatic breast cancer patients respond for a decade to an aromatase inhibitor. Will I need to give Palbo for a decade as well, and if so, at what cost, both financial and in terms of inconvenience and toxicity? Will we be able to predict who benefits? What are the mechanisms of resistance? How long (assuming it works there) will I need to give a CDK 4/6 inhibitor in the adjuvant setting? If I start a patient on an AI plus Palbo and the patient progresses, should I then switch to fulvestrant plus Palbo? Lots of work for clinical trialists, and lots of questions of importance to patients.

Pertuzumab and Lapatinib
This year saw the updated results from the CLEOPATRA trial in front-line HER2-positive breast cancer (NEJM 2015;372:724-34). This trial compared combination HER2-targeted therapy to trastuzumab monotherapy in the presence of docetaxel. These results are stunning, with an improvement in overall survival from 40.8 to 56.5 months, far more than I would have guessed, and clearly establishing dual HER2-targeted therapy as the standard of care in front-line HER2-positive disease. We can only hope that these results will translate to the adjuvant setting when the APHINITY trial matures.

However, a cost-benefit analysis estimated the cost per quality-adjusted life year of adding on pertuzumab at $713,000 (J Clin Oncol 2015 Sep 8. pii: JCO.2015.62.9105 [Epub ahead of print]).

While the CLEOPATRA results were exceptionally positive, lapatinib disappointed. The long-awaited adjuvant lapatinib ALTTO trial, presented at the 2015 ASCO Annual Meeting’s plenary session (and subsequently published in the Journal of Clinical Oncology), was essentially a negative trial, closing out a decade of work for this kinase inhibitor.

What Do We Do with This Data?
Every year sees some studies that make me wonder whether my hard-won worldview is wrong; there were two of these this year. The first involved the anti-VEGF agent bevacizumab. Bevacizumab prolongs disease-free survival but not overall survival in front-line metastatic breast cancer in numerous Phase III trials. Bevacizumab does not prolong disease-free or overall survival in the adjuvant setting in multiple disease subsets in multiple Phase III trials. The world, myself included (and I devoted a decade of my academic career to anti-VEGF therapy), had given up on bevacizumab for breast cancer.

I was surprised, therefore, to read the NSABP’s trial of bevacizumab in the neoadjuvant setting (Lancet Oncol 2015;16:1037–48). Comparing the chemotherapy alone to the same plus bevacizumab in the preoperative setting, the investigators saw an improvement in both pathological complete response rate and overall survival (though curiously only a trend toward improved disease-free survival). Bevacizumab finally has a positive trial where it counts.

What do we do with this data? Is it real or is it just one of those statistical outlier results that pop up every now and then when one does enough trials with a drug? If it is real, why? I can come up with an explanation involving the use of anti-VEGF therapy in the presence of an intact primary tumor, perhaps with a bow to VEGF’s immune effects. But I am perplexed.

The other «I don’t know what to do with it» trial involves post-neoadjuvant capecitabine. A group of Japanese and Korean investigators, led by Masakazu Toi, MD, presented this trial at the San Antonio meetings (2015 San Antonio Breast Cancer Symposium, Abstract S1-07). HER2-negative patients with significant residual disease after chemotherapy were randomly assigned to post-neoadjuvant capecitabine (in the FDA-approved dose and schedule for metastatic disease) or to the control group. The analysis showed statistically significant improvements in both disease-free (74.1% versus 67.7%) and overall (89.2% versus 83.9%) survival. Benefits were seen in both triple-negative and HR-positive patients.

Adjuvant capecitabine, in several large, well-conducted trials (including the NSABP trial that was positive for bevacizumab), failed to alter the destiny of early stage breast cancer patients. Again, I am perplexed.

Drug development remains mysterious and unpredictable. Focus on what wonderful surprises 2016 will bring.

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Posted Φεβρουαρίου 26, 2016 by msofcrete in Uncategorized

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