Contrary to what has been assumed, all recurrences of ductal carcinoma in situ (DCIS) are not genetically the same, according to a study presented at the American Association for Cancer Research (AACR) Annual Meeting 2022.¹ Almost 20% of ipsilateral recurrences found in the study were genetically distinct from the primary DCIS (ie, nonclonal) tumor.

The findings call into question the use of the same treatment strategies for all DCIS, because a proportion of recurrences do not share clonality with the primary tumor. “This research suggests that predictive biomarkers may not be useful in this case,” said lead author Tanjina Kader, PhD, a postdoctoral researcher at Peter MacCallum Cancer Centre, Melbourne, Australia.

Tanjina Kader, PhD

About 25% of patients with DCIS will have a recurrence, and about half are invasive breast cancers.

“We assumed that recurrent tumors are all the same and genetically related to the primary DCIS,” Dr. Kader said at a press conference. “Therefore, the treatment options for these patients have been the same. All patients with recurrent DCIS will be treated with further surgery or surgery and radiotherapy. However, the question remains, do we really know the second tumor is related to the primary tumor?”

Study Details

To answer this question, Dr. Kader and coauthors performed a genetic analysis to compare chromosomal changes and gene mutations in nonrecurrent primary DCIS cases (n = 32) and recurrences (ipsilateral, n = 67; contralateral, n = 4). The goal of the analysis was to identify potential biomarkers to distinguish primary DCIS tumors with a high risk of recurrence from those with a low risk of recurrence.

The investigators performed DNA sequencing on 67 paired specimens of DCIS (primary vs ipsilateral recurrent tumors) using high-depth next-generation sequencing to compare mutations and changes in copy number. Paired specimens with shared genetic events indicated common ancestry (ie, clonal), whereas the absence of shared features indicated the recurrent tumor had different ancestry from the primary tumor (ie, nonclonal). They also sequenced specimens of 32 cases of nonrecurrent DCIS, in the hope of identifying potential biomarkers to distinguish high-risk from normal-risk DCIS.

Question of Clonality

The first comparison of paired specimens found that 12 of 67 recurrent tumors (18%) did not have shared common ancestor with the primary DCIS. The likelihood of clonality was not significantly related to the following factors of the primary tumor: tumor grade, hormone receptor status, HER2 status, or type of therapy (surgery alone or surgery plus radiation and or endocrine therapy).

“These [12] tumors were new primaries, and independent tumors suggest there is a high-risk environment or genetic predisposition that makes patients highly susceptible to develop new tumors,” Dr. Kader said. “Therefore, we are proposing that in the future, instead of treating all recurrent patients the same, we have to find out first whether the [recurrences] are nonclonal.”

“This is the first study to document the distinct genetic makeup and clonality of recurrent DCIS. Now we know that nonclonal tumors should be treated differently from clonal tumors.”

— Tanjina Kader, PhD

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“Surgery alone is not going to be sufficient for patients who are highly susceptible to develop new tumors,” she continued. “We should consider preventive therapies, which could include bilateral mastectomy, endocrine therapy, or genetic counseling.”

In a separate interview with The ASCO Post, Dr. Kader said she expects this research will inform the way patients with DCIS are managed at Peter MacCallum Cancer Centre. “We have high-depth next generation sequencing that allows us to do this analysis. Now that we know nonclonal tumors should be treated differently from clonal tumors, this testing most likely will be done at our center,” she said.

Role of Predictive Markers in DCIS

When recurrent and nonrecurrent tumors were compared, five potential genetic markers were identified to distinguish DCIS with a high likelihood of recurrence from normal-risk DCIS. Recurrent clonal DCIS samples were highly enriched for changes in chromosomes 5, 11, 17, and 20, as well as TP53 mutation.

In addition, the investigators found that ­nonclonal, recurrent DCIS had a similar genetic profile to that of nonrecurrent DCIS. “Therefore, this calls into question the clinical value of using these genetic changes as predictive biomarkers, which could lead to undertreatment of patients who develop nonclonal tumors and may be categorized as being at low risk,” Dr. Kader continued. “Even though we can get excited about these biomarkers, this particular finding [about the genetic makeup of nonclonal recurrent DCIS] raises a question as to whether we should actually use predictive markers for DCIS.”

“This is the first study to document the distinct genetic makeup and clonality of recurrent DCIS,” she told listeners.

Dr. Kader noted that a limitation of this study was that the phylogenetic analysis was based on chromosomal changes—the main genetic changes observed in breast cancer. A phylogenetic analysis based on all tumor-specific mutations could not be performed, due to the lack of baseline genetic information from normal cells.

The next steps would be to study the interaction between tumor cells and the tumor microenvironment to analyze changes that occur, as well as the molecular and genetic factors involved in the interaction. 

DISCLOSURE: Dr. Kader reported no conflicts of interest.

REFERENCE

1. Kader T, Mahale S, Zethoven M, et al: Predictive biomarkers of recurrence may not be useful for de-escalating treatment of ductal carcinoma in situ due to de novo ipsilateral invasive carcinoma development. AACR Annual Meeting 2022. Abstract 43. Presented April 10, 2022.