Prognostic Indicators Incorporated Into Breast Cancer Guidelines

SUITABILITY REQUIREMENTS FOR RADIATION TARGETS

"When we're treating, we really want to define what the target is," said Kilian E. Salerno, MD, director of breast radiation and soft tissue/melanoma radiation, Roswell Park Cancer Institute. Targets for radiation in breast cancer include whole-breast irradiation, partial-breast irradiation (PBI), radiation to the chest wall, and regional nodal irradiation (RNI).

A meta-analysis from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) informed the need for radiation therapy following surgery in the guidelines, showing that radiation therapy reduced the incidence of locoregional recurrence, overall recurrence, and breast cancer mortality in patients with ≥ 4 positive nodes.²

In women treated with whole-breast irradiation, an appropriate margin under the latest guidelines is 2mm in women with ductal carcinoma in situ (DCIS) and no tumor on ink for women with stage I-II invasive carcinoma.

The preferred method of delivering radiation therapy, according to the NCCN, is hypofractionation, which employs a shorter treatment course that uses larger doses per fraction. Hypofractionation achieves local control and breast cosmesis that is at least equivalent to that achieved with conventional fractionation, said Salerno.

“I hope that we move away from this concept of standard fractionation being conventional because I would argue that for breast radiation, hypofractionation is standard as well,” Salerno said. The recommendation is to deliver a total of 40 to 42 Gy in daily fractions for whole-breast radiotherapy or 34 to 38.⁵Gy given in twice-daily fractions for accelerated PBI (APBI).

The guidelines for suitability of APBI accept the updated American Society for Radiation Oncology criteria,³which stipulate that patients ≥50 years with invasive DCIS measuring ≤2 cm (T1 disease) with negative margin widths of ≥2 mm, no lymphovascular invasion, ER-positive status, and negative for a BRCA mutation, and patients with a low or intermediate nuclear grade screen-detected DCIS measuring ≤2.5 cm with negative margin widths of ≥3 mm, are both eligible for APBI.

Whether or not to treat with RNI is based on assessment of an individual’s risk for recurrence using nomograms or recurrence scores, said Salerno. RNI was found to improve locoregional disease-free survival (DFS), distant DFS, and breast cancer mortality, with 10 years’ median follow-up in women who underwent breast conservation surgery in the MA.²⁰and EORTC22922 studies. The rate of regional and distant recurrences was reduced in both studies; however, an improvement was not seen in overall survival.

In general, RNI is recommended for patients with ≥4 positive nodes or locally advanced disease and should be strongly con- sidered for patients with 1 to 3 positive nodes.

INCORPORATING MULTIGENE ASSAYS

The latest version of the NCCN breast cancer guidelines incorporates the use of genomic expression profiling to assist in adjuvant treatment decision making in women with hormone receptor (HR)— positive, HER2-negative breast cancer.

Genomic profiling has been found to successfully predict the benefit of endocrine therapy, as was demonstrated in the TAILORx study, said Lee S. Schwartzberg, MD. The study utilized the 21-gene recurrence score (Oncotype DX) to determine the risk of recurrence.⁴Patients with a score ≤11 had a lower risk of their breast cancer returning. The study found that patients with breast cancer whose tumors had a favorable gene-expression profile had very low rates of recurrence at 5 years following treatment with endocrine therapy.

The 21-gene recurrence score has also been found to be prognostic in women with node-positive cancer, although its predictive value in this group remains uncertain, said Schwartzberg, executive director, West Cancer Center and chief, Division of Hematology/Oncology, University of Tennessee Health Science Center.

Genomic profiling can also be used to select candidates for chemotherapy. In the MINDACT study of patients with node-negative breast cancer, those with a high clinical risk and low genomic risk, per the 70-gene signature (MammaPrint), who did not receive adjuvant chemotherapy had a rate of distant metastasis-free survival of 94.7%.⁵

Evidence also points to genomic classifiers being prognostic for late relapse, which is common in ER-positive patients, Schwartzberg added. The EBCTCG group found that distant recurrence rates kept increasing after 5 years of tamoxifen exposure.

The updated guidelines state that for patients with HR-positive, HER2-negative, node-negative breast cancer whose tumors are >0.5 cm, the 21-gene recurrence score assay should be considered. For a low recurrence score (<18), adjuvant endocrine therapy alone is recommended. For an intermediate recurrence score (18 to 30), adjuvant endocrine therapy or chemotherapy followed by endocrine therapy is acceptable. A high recurrence score (&ge;31) merits both adjuvant endocrine therapy and chemotherapy. The guidelines mention in the footnotes that the 21-gene recurrence assay can be considered in select patients with 1 to 3 positive nodes, and that other genomic expression profiling assays are prognostic, but are supported by less evidence to predict response to chemotherapy.¹

NEW APPROACHES TO ENDOCRINE THERAPY

Overcoming resistance to endocrine therapy has been an emphasis of clinical research. The NCCN guidelines have adopted partnering strategies in which targeted agents are added to endocrine therapy in an effort to combat resistance, said William J. Gradishar, MD.

The recognition that breast cancer is cyclin-dependent has led to the development of agents that act on the cyclin D/CDK4/6/INK4-Rb pathway. With the advent of CDK4/6 inhibitors, everolimus (Afinitor) has now been shifted to a later line of therapy.

Biomarker development is essential to help determine which patients stand to benefit from CDK4/6 inhibition and everolimus, said Gradishar, deputy director, Robert H. Lurie Comprehensive Cancer Center and interim chief, Division of Hematology/Oncology, Northwestern University&rsquo;s Feinberg School of Medicine. However, the various CDK4/6 inhibitors &ldquo;should not be assumed to be exactly the same—clinically, pharmacodynamically, or kinetically,&rdquo; he said.

Findings from the PALOMA trials showed consistent clinical bene t across all 3 trials with palbociclib (Ibrance). Based on these findings, the updated guidelines now include palbociclib/letrozole and palbociclib/fulvestrant (Faslodex) as options for endocrine therapy for postmenopausal women with recurrent or stage IV disease, with a category 1 recommendation for the palbociclib/letrozole regimen in HER2-negative patients.

The guideline updates also noted that women who are postmenopausal at diagnosis can be considered for an additional 5 years of an aromatase inhibitor, for a total treatment duration of 10 years. This consideration lies in the observation of very late recurrences of ER-positive disease. &ldquo;Even out to 20 years, you see a progressive increase in recurrence rates,&rdquo; Gradishar said. Yet due to the conflicting nature of the data, the recommendation was not quali ed as category 1 in the updated guidelines.

References:

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V.2.2017. NCCN website. https://www.nccn.org/professionals/physician_gls/ pdf/breast.pdf. Accessed April 10, 2017.
2. Correa C, Harris EE, Leonardi MC, et al. Accelerated partial breast irradiation: Executive sum- mary for the update of an ASTRO evidence-based consensus statement. Pract Radiat Oncol. 2017;7(2):73-79. doi: 10.1016/j.prro.2016.09.007.
3. Whelan TJ, Olivotto IA, Parulekar WR, et al; MA.20 study investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373(4):307-316. doi: 10.1056/NEJMoa1415340.
4. Sparano JA, Gray RJ, Makower DF, et al. Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med. 2015;373(21):2005-2014. doi: 10.1056/NEJMoa1510764.
5. Cardoso F, van&rsquo;t Veer LJ, Bogaerts J, et al; MINDACT Investigators. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;375(8):717-729. doi: 10.1056/NEJMoa1602253.