According to GLOBOCAN data, over 2 million women are diagnosed with breast cancer annually [1], making it one of the primary global oncological challenges. Recently, an increasing number of countries have implemented organized mammographic screening programs; consequently, the proportion of breast cancer cases diagnosed at early, invasive stages is consistently rising. Since the 1980s, screening has also increased the diagnosis of non-invasive tumors by approximately 4–5 times [2]: today, DCIS (ductal carcinoma in situ, Tis) accounts for approximately 20–25% of all screen-detected breast pathologies.
How do we treat early-stage invasive breast cancer and non-invasive carcinoma?
For non-aggressive biological types of early-stage invasive breast cancer without regional spread, as well as for DCIS, the primary treatment modalities are surgery and radiation therapy. Surgical intervention is focused on the excision of the tumor mass, while radiation therapy ensures the destruction of residual cells within the postoperative bed and surrounding tissue.
Why is radiation therapy necessary?
Clinical trials conducted from the 20th century to the present—including NSABP B-17, EORTC 10853, SweDCIS, and UK/ANZ DCIS (conducted in the U.S., Europe, and the UK) [3–6]—provide a clear answer:
For patients with non-invasive carcinoma (DCIS) following breast-conserving surgery, the addition of radiation therapy reduces the risk of local recurrence by 50%.
In cases of early-stage invasive carcinoma, radiation therapy reduces the risk of local recurrence by approximately threefold.
If this is the case, why and for whom do we consider the possibility of avoiding radiation therapy?
Interest in avoiding radiation therapy has grown over time. The reason is straightforward: the patient population described above often has a favorable long-term prognosis, and in most cases, early-stage breast cancer (when treated appropriately) does not significantly impact overall mortality. Therefore, the risk of “overtreatment” is a constant consideration.
The logical next step was to conduct trials in which patients at a relatively low risk did not receive radiation, with careful observation of the outcomes. We will consider DCIS first, followed by early-stage invasive tumors.
DCIS: What is the prognosis for patients without radiation?
In total, a 20-year observation period (DCIS: ECOG 5194 [7]) demonstrated that without radiation therapy, the risk of local recurrence increases incrementally over the first 15 years: by 1.5% annually in the high-risk group (poorly differentiated DCIS, cm) and by 1% in the low-risk group (well to moderately differentiated DCIS, cm). It is important to emphasize that in approximately half of the recurrence cases, patients who initially had non-invasive disease developed invasive breast cancer upon recurrence. Statistical analysis showed that the risk of recurrence depends on the patient’s cohort (the 20-year recurrence risk for the low-risk group is 17.8%, compared to 28.7% for the high-risk group) and tumor size. Age and menopausal status did not influence this risk.
Subsequently, a randomized trial (DCIS RTOG 9804 [8]) conducted on low-risk patients yielded the same result: radiation halves the risk of local recurrence (from 15% to 7% over 15 years of observation). Notably, 50% of these recurrences were invasive in nature.
DCIS: Can we identify who will benefit particularly from radiation?
As noted above, categorizing patients solely by tumor grade and size proved insufficient, as the prognosis remained significantly worse without radiation therapy. To better categorize patients, genomic tests such as Oncotype DCIS [9] and DCISionRT [10] were developed, which utilize tumor-associated genes and molecular markers to stratify patients into risk groups.
Oncotype DCIS is prognostic: it can accurately determine the risk of recurrence.
DCISionRT is both prognostic and predictive: it can additionally determine the extent to which a patient will respond to radiation. For example, patients categorized as low-risk by DCISionRT gain only a 1% absolute benefit from radiation therapy (the 10-year recurrence risk is reduced by 1%); therefore, for them, avoiding radiation is relatively safe.
DCIS: Final recommendations—What do the guidelines suggest?
Given that the reliability of genomic tests has not yet been fully evaluated in prospective trials, and their availability is limited in most regions of the world (including Georgia), guidelines do not unequivocally recommend omitting radiation. For example, the NCCN recommends whole or partial breast irradiation for patients with DCIS (Category 1), while classifying the tactic of radiation omission as Category 2B [11].
Early-stage invasive carcinomas: What is the prognosis for patients without radiation?
It should be noted from the outset that the trials described below involved patients with particularly low-risk, early-stage invasive carcinoma: T1–T2 and Luminal A type. Applying these data to patients with early or late-stage HER2/neu positive, hormone-negative, or node-positive disease is inappropriate.
The possibility of avoiding radiation in invasive carcinomas was investigated in the CALGB 9343 [12] ( years old, ER+ patients) and PRIME II [13] ( years old, ER+ patients) trials. These studies evaluated the frequency of loco-regional recurrence, the need for subsequent mastectomy upon recurrence, overall survival, and the risk of distant metastasis in patients who received radiation versus those treated only with surgery and anti-estrogen therapy. After 9–12 years of observation, it was found that 90–91% of patients in the anti-estrogen-only group were disease-free, while the figure for the anti-estrogen + radiation group was 98–99%. No significant differences were recorded in other study parameters.
Early-stage invasive carcinomas: Can we identify who will benefit particularly from radiation?
It is possible: for these cases, the Oncotype DX 21-gene assay exists [14]. The IDEA trial [15] demonstrated that patients who scored <18 on the Oncotype DX 21 test achieved 100% overall survival and 99% disease-free survival after 5 years, even without radiation therapy.
Early-stage invasive carcinomas: Final recommendations—What do the guidelines suggest?
The NCCN provides a Category 1 recommendation: consider avoiding radiation only if the patient meets the criteria of the CALGB 9343 (aged , HR+, HER2-negative, cN0 pT1 cm) or PRIME II (aged , HR+, HER2-negative, pN0, pT cm) trials [11].
From a practical standpoint, only a relatively small portion of patients seen in routine clinical practice meet all these criteria.
Finally, it should be noted that the transition from conventional fractionation to ultra-hypofractionated (5-day) regimens has significantly reduced the treatment burden without compromising local control rates or increasing clinically significant acute or late toxicity. In other words, parallel to developments in surgery and chemotherapy, the technique and fractionation of radiation therapy have also improved. As we have sought to identify individuals who derive less benefit from radiation, the discomfort caused to patients by radiation therapy has simultaneously decreased. As a result, the issue of omitting radiotherapy today is based less on the desire to avoid treatment toxicity and more on an individualized assessment of the expected absolute benefit for each patient.
Sources:
[1] {GLOBOCAN 2020 World Fact Sheet, https://gco.iarc.who.int/media/globocan/factsheets/populations/900-world-fact-sheet.pdf}
[2] {Overview of breast cancer epidemiology (PMC6697179), https://pmc.ncbi.nlm.nih.gov/articles/PMC6697179/}
[3] {NSABP B-17 trial (DCIS radiotherapy after lumpectomy), https://pubmed.ncbi.nlm.nih.gov/?term=NSABP+B-17+DCIS}
[4] {EORTC 10853 trial (DCIS radiotherapy vs observation), https://pubmed.ncbi.nlm.nih.gov/?term=EORTC+10853+DCIS}
[5] {SweDCIS randomized trial, https://pubmed.ncbi.nlm.nih.gov/?term=SweDCIS+trial}
[6] {UK/ANZ DCIS trial (radiotherapy outcomes), https://pubmed.ncbi.nlm.nih.gov/?term=UK+ANZ+DCIS+trial}
[7] {ECOG 5194 study (low-risk DCIS without RT), https://pubmed.ncbi.nlm.nih.gov/?term=ECOG+5194+DCIS}
[8] {RTOG 9804 trial (low-risk DCIS radiotherapy), https://pubmed.ncbi.nlm.nih.gov/?term=RTOG+9804+DCIS}
[9] {Oncotype DX DCIS Score assay, https://www.oncotypedx.com/en-US/breast-cancer/patients/dcis-score}
[10] {DCISionRT genomic assay (PreludeDx), https://preludedx.com/dcisionrt/}
[11] {NCCN Clinical Practice Guidelines in Oncology – Breast Cancer, https://www.nccn.org/guidelines/category_1}
[12] {CALGB 9343 trial (elderly breast cancer, RT omission), https://pubmed.ncbi.nlm.nih.gov/?term=CALGB+9343+breast+cancer}
[13] {PRIME II trial (radiotherapy omission in low-risk elderly), https://pubmed.ncbi.nlm.nih.gov/?term=PRIME+II+breast+radiotherapy}
[14] {Oncotype DX 21-gene assay in breast cancer, https://pubmed.ncbi.nlm.nih.gov/?term=Oncotype+DX+21-gene+breast+cancer}
[15] {IDEA trial (radiotherapy de-escalation/omission study), https://pubmed.ncbi.nlm.nih.gov/?term=IDEA+trial+breast+radiotherapy}
[16] {SEER Cancer Stat Facts – Female Breast Cancer, https://seer.cancer.gov/statfacts/html/breast.html [1]}
[17] {Breast Cancer PDQ – NCI (Incidence and Mortality section), https://www.cancer.gov/types/breast/hp/breast-treatment-pdq [2]}
