By Dalia Deak
This week, a JAMA Oncology article made a splash when it intensified discussion around what ductal carcinoma in situ (DCIS) should be considered – cancer, precursor, or risk factor – and whether current treatment approaches have been effective. The New York Times, The Guardian, and others have picked up the story, and readers have reacted extensively, only amplifying a demand for answers to questions raised.
Often called Stage 0 breast cancer, DCIS is considered to be abnormal cells that are confined inside the milk ducts and, as such, are not considered invasive. Because of the increased risk associated with DCIS, many women who are found to have DCIS (a growing number considering the frequency of and improvements in mammography) undergo lumpectomies or mastectomies often accompanied by radiation therapy.
To study the long-term outcomes associated with DCIS and its treatment, the authors of the JAMA Oncology study conducted a large observational study of more than 100,000 women with a diagnosis of DCIS over 20 years, finding, among other things, that regardless of choice of treatment, a significant difference in breast cancer related mortality has not been achieved, though a decrease in recurrence has. One piece of evidence offered in support of the conclusion regarding treatment and mortality is that women who had mastectomies (removal of the entire breast) did not have a significantly lower death rate due to breast cancer than those who received lumpectomies (removal of the lump), undermining the argument that DCIS is a precursor to or an early stage of cancer. The study did find that some groups had excess risk associated with a DCIS diagnosis, such as women who were under 35 and African American women.
Additionally, if DCIS were a precursor, then, an accompanying editorial on the paper noted, the incidence of breast cancer in the population can be expected to decrease given the increases in identification and treatment. This has not been the case, and stands in stark contrast to the removal of colonic polyps, for example, which is associated with a decrease in the incidence of colon cancer.
The study does have important limitations, not least of which is that it was retrospective and could not control for a number of important factors. Yet, this study does contribute to a growing body of evidence that treatment strategies around DCIS, and even the way we have defined DCIS, may need rethinking. Moreover, it has captured the attention of many in the breast cancer community and the general public.
While certainly more evidence must be developed and concerted exploration must be conducted, particularly around how to more closely align treatment with expected outcomes in high- and low-risk groups, important ethical and policy questions persist, including: How should DCIS and its risks be classified and communicated to patients? How should informed patients balance their concerns regarding overtreatment with the risks of DCIS developing into invasive cancer? How should providers balance the population-level assessment regarding DCIS with the need to act in the best interest of each patient? Given statements that a clinical trial is needed to settle the debate, is it ethical to conduct one and withhold treatment one way or another? These are questions that will demand attention and this will be an important area of research to watch, particularly as patients and other stakeholders wade in and push for answers.
The low but consistent incidence rate of invasive breast cancer deriving from ductal in situ carcinoma (DCIS) justifies that the usual surgical and adjuvant therapy of high grade DCIS is not always capable of ensuring a tumor-free life, while low grade DCIS is perhaps superfluously over treated.
Appropriate estrogen receptor (ER)-signaling is the chief safeguard of genomic stability in strong interplay with DNA-controlling and repairing systems, such as BRCA-genes and their protein products [https://goo.gl/EsB1bK]. Detection of DCIS by mammographic screening may be regarded as an early marker of disturbed hormonal, metabolic and DNA-stabilizer equilibrium, since the female breast is exquisitely sensitive to the defects of estrogen signaling [https://goo.gl/xRh4wL]. The stronger the defect of cellular estrogen surveillance, the higher is the probability of DCIS development with high-risk characteristics.
In women, during aging, progressive weakening of estrogen signaling and the associated gene stabilizer mechanisms are dangerous systemic processes [https://goo.gl/yiYszF], despite any usual, aggressive treatment of DCIS. In patients having increased risk of invasive breast cancer, natural estrogen substitution is the optimal risk-reducing therapy aiming the stabilization of gene regulatory processes and the apoptotic death of accidentally initiated tumor cells [https://dx.doi.org/10.2147/dddt.s89536]. By contrast, antiestrogen treatment against tumor recurrence may be risky, being effective only in such genetically proficient women who are capable of strong, counteractive upregulation of estrogen signaling. Tumor growth may be provoked by de novo or acquired antiestrogen resistance being associated with the missing capacity of patients for the extreme upregulation of estrogen signaling or with the exhaustion of defensive counteractions by excessive antiestrogen administration [https://dx.doi.org/10.2147/dddt.s89536].
In conclusion, in cases of DCIS which have been diagnosed, the most important preventive strategy against invasive breast cancer development is to combine lumpectomy with strict control and maintenance of estrogen signaling over a whole lifetime.
Zsuzsanna Suba