Challenge Moving Forward in Breast Cancer Treatment: To Show That New Approaches Change Outcomes

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William Gradishar MD, FASCO

William Gradishar MD, FASCO

ADVANCES IN treating breast cancer over the past 20 years have brought us to the point where treatment can be confidently de-escalated for some patients, and immunotherapy and precision decision-making may change the way breast cancer is treated for others, William Gradishar MD, FASCO, told the more than 700 participants at the 2018 Lynn Sage Breast Cancer Symposium in Chicago. Dr. Gradishar, Symposium Chair, reviewed some major milestones and a few missteps in breast cancer treatment over the past 20 years as well as newer approaches using advanced tools and technology.1

“The challenge as we go forward is demonstrating these approaches make a difference in terms of outcomes,” Dr. Gradishar said. Genomic testing can provide data that “are technically actionable,” he commented, “but we need to demonstrate clinical utility.” Dr. Gradishar is the Betsy Bramsen Professor of Breast Oncology and Chief of Hematology/ Oncology at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, which hosts the annual Lynn Sage Breast Cancer Symposium.

Tamoxifen and Aromatase Inhibitors

CLEARLY, TAMOXIFEN made a “huge impact, stated Dr. Gradishar. It “remains a fundamental advance that is critically important today and still the most widely used cancer drug around the world.” In 1995, however, the National Cancer Institute issued a Clinical Alert reporting that results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-14 evaluating adjuvant tamoxifen for early-stage breast cancer “indicate no advantage for continuation of tamoxifen beyond 5 years in women with node-negative, estrogen receptor–positive breast cancers.”

Then, “the aTTOM and ATLAS trials came along, and they suggested that with longer durations of therapy, perhaps there is an additional benefit. And we did see that the second period of 5 years does translate into an improved outcome,” Dr. Gradishar said.

“Genomic testing can provide data that are technically actionable, but we need to demonstrate clinical utility.”
— William Gradishar, MD, FASCO

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“Starting in the 1990s, we addressed the issue: There must be something better than tamoxifen,” he continued. Development and testing of aromatase inhibitors resulted in more options for patients and incremental improvements in outcomes. Trials suggested there may be some small initial difference with the longer duration, Dr. Gradishar said, but “you have to be selective if you are considering longer durations because all aromatase inhibitors have associated side effects.”

The SOFT trial, now with more than 8 years of follow-up, “demonstrated that adding tamoxifen to ovarian suppression does improve disease-free survival,” Dr. Gradishar said. “The take home message” of joint analysis of the SOFT/TEXT trials, he added, is “high-risk patients, for whom clinicians may empirically start on chemotherapy, tended to get the most benefit from the addition of an aromatase inhibitor, particularly exemestane, added to ovarian suppression.”

The HER2 Story

FOR THE 20% TO 25% with HER2-positive disease, trastuzumab was responsible for “clearly changing the approach and fundamentally improving the outcome when added to chemotherapy,” Dr. Gradishar mentioned. Trials combining different anti-HER2 therapy “basically demonstrated the same fundamental thing: If you target different aspects of the HER2 pathway, you can amplify the effect you are trying to achieve.”

The CLEOPATRA trial, Dr. Gradishar noted, provided “proof of principle that by adding dual therapy [trastuzumab plus pertuzumab] to chemotherapy vs trastuzumab and chemotherapy alone, you markedly improve overall survival. This became a standard in the metastatic disease setting.”

“The HER2 space is very crowded, which is a good thing. It means options for patients,” he added.

Treatment of Advanced Disease

IN THE UPDATED National Comprehensive Cancer Network® Clinical Practice Guidelines in Oncology (NCCN® Guidelines) for invasive breast cancer, “there is this theme of partnering endocrine therapy with targeted therapy,” Dr. Gradishar said. “In patients for whom everolimus is added to exemestane, you see an incremental improvement in outcome, a doubling of the time until the disease progresses, at some cost in terms of side effects.”

“The big story over the past 3 years is understanding what happens when retinoblastoma protein is phosphorylated or not, which helps monitor or modulate disease progression through the cell cycle,” Dr. Gradishar explained. “The almost simultaneous emergence of data from large randomized trials with competing agents and various designs has addressed this particular pathway in estrogen receptor–positive disease,” he said, and shown “incremental improvement in progression-free survival.”

Adding the cyclin-dependent kinase 4/6 inhibitor palbociclib to the aromatase inhibitor letrozole nearly doubled progression-free survival over letrozole plus placebo—from 10.2 to 20.2 months in the PALOMA-1 trial and from 14.5 months to 24.8 months in the PALOMA-2 trial. “It has resulted in a remarkable improvement in outcome,” Dr. Gradishar said.

Massimo Cristofanilli, MD

Massimo Cristofanilli, MD

Overall survival results from PALOMA-3, comparing palbociclib and fulvestrant vs placebo and fulvestrant, were subsequently presented by Massimo Cristofanilli, MD, at the European Society for Medical Oncology (ESMO) 2018 Congress.2 Patients with hormone receptor–positive, HER2-negative advanced breast cancer who had relapsed or whose disease progressed on hormonal therapy had “a clinically meaningful improvement in overall survival.” The median overall survival increased by 6.9 months in the patients receiving palbociclib/fulvestrant and 34.9 months vs 28 months for patients receiving placebo/fulvestrant. Among patients with a sensitivity to prior endocrine therapy, the absolute improvement in median overall survival was even greater, 10 months.

“This is very important for patients, as it shows that the improvement in progression-free survival observed in previous studies may have a positive impact on overall survival, an ultimate goal of treatment, therefore improving the chance for a long-term life despite advanced disease,” according to Dr. Cristofanilli, Professor of Medicine at Robert H. Lurie Comprehensive Cancer Center. The results were also published in The New England Journal of Medicine.3

Although patients with triple-negative breast cancer continue to have a poor prognosis, “some data suggest that perhaps platinums may work better, particularly in those with a germline BRCA1/2 mutation,” Dr. Gradishar said. He cited the TNT trial. Among the 43 patients with germline BRCA1/2 mutations, the overall response rate was 68% with carboplatin vs 33% with docetaxel. Among the 273 patients without BRCA1/2 mutations, the response rate was 28.1% with carboplatin and 36.6% with docetaxel.4

‘Rising From the Ashes’

“ABOUT 5 YEARS AGO,” poly (ADP-ribose) polymerase (PARP) inhibitors were considered as “the therapy that was going to change everything,” according to Dr. Gradishar. “This was based largely on the notion that if you can interrupt some of the DNA repair mechanisms, then you can drive the cell toward cell death. And because cells are constantly being exposed to things that will cause DNA damage, we have a number of redundant DNA repair mechanisms.”

An early trial combining chemotherapy and a PARP inhibitor against triple-negative breast cancer “led to overwhelming enthusiasm that we were on the cusp of something new,” Dr. Gradishar said. Although the results of the initial trial “were compelling,” they were not duplicated in a larger trial, and the drug failed to receive approval from the U.S. Food and Drug Administration.

The “strong rationale for developing PARP inhibitors” remained, however, and the OlympiAD trial led to the approval of olaparib.5 Progression-free survival was 7 months with olaparib vs 4.2 months with physician’s choice chemotherapy (vinorelbine, capecitabine, or eribulin) in women with BRCA-associated breast cancer. The corresponding response rate was 59.9% vs 28.8%. “This became an option for patients who had BRCA-mutated cancers,” Dr. Gradishar said.

“A number of these drugs are now in development,” he noted, with talazoparib “potentially being the most potent.” In the EMBRACA trial,6 1-year progression-free survival was 37% with talazoparib vs 20% with physician’s choice chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine).

De-escalation of Therapy

“THE TAILORX TRIAL has refined how we think about using chemotherapy,” Dr. Gradishar revealed. The study found that most women with hormone receptor–positive, HER2-negative, axillary node–negative early-stage breast cancer and a mid-range recurrence score on the 21-gene Oncotype DX assay may be spared chemotherapy.

“Now we can confidently say no chemotherapy for certain cases, whereas in others, we feel there is a chemotherapy benefit,” Dr. Gradishar said. “Yet there are still nuances,” he cautioned, particularly when considering chemotherapy for younger women.

Dr. Gradishar pointed out that the use of recurrence scores has “been embedded in the NCCN Guidelines for some time.” The more recent version of the Guidelines, he added, “encompasses the options for physicians and really reflects contemporary medicine.”

Trials looking at shorter durations of therapy “have fallen short by statistical design,” Dr. Gradishar noted, but results suggest “an equal or acceptable benefit” from shorter durations. “Three of four studies failed to show noninferiority” with shorter durations of the anti-HER2 therapy trastuzumab, Dr. Gradishar reported. A more recent trial “suggested that 6 months may be noninferior.”7

Appreciating the Microenvironment

THE TUMOR microenvironment “is incredibly important,” Dr. Gradishar said. “We’ve now come to appreciate that the presence of tumor-infiltrating lymphocytes may identify patients more likely to do well or not and also may help us define which patients are most likely to benefit from immunotherapy.”

“Atezolizumab in combination with nab-paclitaxel is the first targeted treatment to improve survival in metastatic triple-negative breast cancer. It is also the first immune therapy to improve outcome in this cancer.”
— Peter Schmid, MD, PhD

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The programmed cell death ligand 1 (PD-L1) antibody atezolizumab plus nab-paclitaxel improved survival vs chemotherapy alone in patients with metastatic triple-negative breast cancer, as reported in the phase III IMpassion130 trial presented at the European Society for Medical Oncology (ESMO) 2018 Congress.8 The combination therapy reduced the risk of disease progression or death by 20% overall and by 38% in patients expressing PD-L1.

The results “will change the way triple-negative breast cancer is treated,” according to the study’s first author, Professor Peter Schmid, MD, PhD, Clinical Director, St. Bartholomew Breast Cancer Centre, Queen Mary University of London, UK. “Atezolizumab in combination with nab-paclitaxel is the first targeted treatment to improve survival in metastatic triple-negative breast cancer. It is also the first immune therapy to improve outcome in this cancer.”8,9 If “the improvement in outcome is sufficient,” Dr. Gradishar said, “we may see a new therapy for metastatic breast cancer.”

DISCLOSURE: Dr. Gradishar is a consultant/advisor for Genentech/Roche. Dr. Cristofanilli has received personal fees from Pfizer, Novartis, and Merus. Dr. Schmid has an immediate family member employed with Roche; has received honoraria from AstraZeneca, Pfizer, Novartis, and Roche; is a consultant/advisor for Pfizer, Novartis, Eisai, Celgene, AstraZeneca, Merck, Boehringer Ingelheim, Bayer, Puma Biotechnology; and has received institutional research funding from AstraZeneca, Astellas Pharma, Medivation, OncoGenex, Novartis, Genentech, Merck, and Roche.


1. Gradishar W: Lynn Sage Distinguished Lecture: A frontline view of the last 20 years and where wo go next. 2018 Lynn Sage Breast Cancer Symposium. Presented October 13, 2018.

2. Cristofanilli M, et al: Overall survival with palbociclib plus fulvestrant in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Analyses from PALOMA-3. ESMO 2018 Congress. Abstract LBA2_PR. Presented October 20, 2018.

3. Turner NC, et al: Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med 379:1926-1936, 2018.

4. Tutt A, et al: Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: The TNT trial. Nat Med 24:628-637, 2018.

5. Robson M, et al: Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377:523-533, 2017.

6. Litton JK, et al: Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 379:753-763, 2018.

7. Earl HM, et al; PERSEPHONE trial investigators: Persephone: 6 versus 12 months of adjuvant trastuzumab in patients with HER2 positive early breast cancer. 2018 ASCO Annual Meeting. Abstract 506. Presented June 4, 2018.

8. Schmid P, et al: IMpassion130: Results from a global, randomised, double-blind, phase 3 study of atezolizumab + nab-paclitaxel (nab-P) vs placebo + nab-P in treatment-naive, locally advanced or metastatic triple-negative breast cancer. ESMO 2018 Congress. Abstract LBA1_PR. Presented October 20, 2018.

9. European Society for Medical Oncology (ESMO): Some patients with metastatic triple negative breast cancer live longer with immunotherapy. ESMO 2018 Congress. Press release, October 20, 2018.