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15 March 2020

Ductal carcinoma in-situ, also known as DCIS or stage 0 breast cancer, is traditionally treated with surgical excision (lumpectomy or mastectomy). Treatment may also include radiation therapy, as well as endocrine therapy (tamoxifen or an aromatase inhibitor) if the disease is estrogen receptor positive (ER+).

For invasive cancer, we sometimes take a neoadjuvant approach, treating with chemotherapy or endocrine therapy prior to surgery. This has the advantage of confirming that the tumor will actually respond to treatment. In addition, in cases where the tumor does not completely resolve with treatment (based on pathology assessment of the tissue that is removed), additional chemotherapy or targeted treatments may be recommended.

We have not traditionally used a neoadjuvant approach for DCIS. While invasive cancers may shrink in response to treatment, it is unclear if that reliably happens with DCIS. A study recently published used letrozole (Femara – an aromatase inhibitor) in patients with ER+ DCIS. Patients were treated for 6 months, had MRIs at baseline, 3 and 6 months, and then underwent surgery. The size of abnormality on MRI (which often, but not always correlates with the amount of disease) was measured, and ER, PR (progesterone receptor) and Ki67 (a measure of cellular proliferative activity) was assessed on the pre-treatment needle biopsy and on the surgical specimen. 79 patients were enrolled, 70 completed 6 months of letrozole, and MRI data for all 3 time points was available for 67 patients.

The study found that:

  • Median volume of disease as measured by MRI declined by 0.8cm 
  • ER and PR H-scores decreased by a median of 15 and 85 points, respectively
  • Ki67 decreased by a median of 6.3%

Of the 59 patients who underwent surgery, findings included:

  • Persistence of residual disease in 50 patients (85%)
  • Invasive cancer in 6 patients (10%)
  • No residual DCIS and no invasive cancer found in 9 patients (15%)

As mentioned above, the finding of residual disease is not unexpected. DCIS does not often resolve after neoadjuvant therapy, and endocrine therapy works very slowly. In addition, several patients were found to have invasive cancer – the authors suspect that most likely this was not picked up on the initial biopsy as we know the “upstaging” rate for DCIS at surgery can approach 25%. However, despite these limitations, the finding of decreased volume of disease by MRI and changes in biomarkers (ER, PR and Ki67) indicate treatment response and suggest that extended neoadjuvant endocrine therapy may eventually play a role in the treatment of ER+ DCIS and may possible replace surgery in selected patients. This was a relatively small Phase II trial, so more study certainly is needed. 

*If you are not able to access the full study and would like a copy, please email me: contact at drattai dot com

14 October 2015

The discussion on whether or not DCIS is cancer, and how best to treat it, continues.

A study published recently in the Journal of Clinical Oncology by Dr. Lawrence Solin and colleagues evaluated the risk of developing an invasive cancer if radiation therapy was not performed after lumpectomy for DCIS. This was a prospective non-randomized trial. Patients were enrolled from 1997 – 2002. Patients were divided into 2 groups: 1.) low or intermediate grade DCIS, tumor size 2.5cm or smaller (561 patients), and 2.) high-grade DCIS, tumor size 1cm or smaller (104 patients). All patients underwent lumpectomy but none received radiation therapy.

The study reports 12 year results. There were 99 “in-breast events” (IBE – a new DCIS or invasive cancer), 51 (52%) were invasive. The rates of all IBE and invasive IBE continued to increase during the surveillance period. The 12 year rates of developing an IBE were 14.4% for the low-risk group and 24.6% for the high-risk group. The 12 year rates of developing an invasive IBE were 7.5% for the low-risk group and 14.3% for the high-risk group. In addition to low or high-risk category, tumor size was correlated with risk of recurrence. Patient age, menopausal status, size of surgical margin, use of tamoxifen, or prior use of hormone replacement therapy were not associated with risk of developing an IBE.

The authors concluded that “individual patients and their physicians will need to decide if these 12-year risks are acceptable, and to judge whether or not to add adjuvant treatment [radiation and/or hormonal therapy such as tamoxifen] after surgical excision. Not all patients and their physicians will agree on what is considered too high a risk of developing an IBE or an invasive IBE to recommend observation after surgical excision, or what risk is considered too low to justify adding radiation treatment.” While this may lead to more confusion on the part of patients, it points out the need for careful discussion of the risks and benefits of treatment and observation, as well as an assessment of an individual’s risk tolerance.

Adding to the DCIS discussion, was an abstract presented at the 2015 American Society of Clinical Oncology Breast Cancer Symposium. Dr. Kimberly VanZee and colleagues presented an abstract on recurrence rates of DCIS. They retrospectively reviewed a database of DCIS cases between 1978 – 2010 at the Memorial Sloan Kettering Cancer Center in New York. There were 363 (12%) recurrences in 2996 cases. The 5-year recurrence rate from 1978 – 1998 was 13.6% versus 6.6% between 1999 – 2010. Interestingly, the decrease in recurrence rates were limited to patients who did not undergo postoperative radiation therapy. There was no decline in recurrence rates during the 2 time periods in patients who received radiation therapy. They concluded that the rates of recurrence after treatment for DCIS are declining over time, possibly due to improvements in detection and pathologic assessment. The authors felt that it was important to stress to women with DCIS that are considering mastectomy, that while recurrence is a possibility after treatment for DCIS, the rates are very low. This was presented as an abstract and not a full manuscript – I am looking forward to more detailed analysis and discussion when the full paper is published.

The Breast Cancer Symposium also featured a pro-con debate between Dr. Ben Smith (radiation oncologist from MD Anderson) and Dr. Shelley Hwang (surgical oncologist from Duke University). The topic – “Is DCIS Cancer?”. Dr. Smith took the pro / yes position, and Dr. Hwang took the con / no position. Both gave excellent presentations, citing compelling studies and statistics. They both gave a similar analogy, presenting progression of DCIS to invasive cancer as a “crime”. Dr. Smith took the position of wanting to stop the crime before it happened:

While Dr. Hwang noted “should everyone be punished as if they would commit a crime?”

It was definitely an entertaining and spirited debate, but unfortunately we still don’t have the answers for an individual patient faced with this diagnosis.

This isn’t just a discussion that breast cancer specialists are having. A TIME Magazine story: Why Doctors are Re-Thinking Breast Cancer Treatment also addressed the concerns about over-diagnosis and over-treatment, especially for low-grade DCIS. I think the story did a good job covering the controversy over screening mammograms and it raised some good points about cancer treatment and medical progress. It’s worth a read.

NPR discussed a study recently published in the Journal of the National Cancer Institute – Trends in Treatment Patterns and Outcomes for Ductal Carcinoma In-Situ. This was a study using the SEER Registry. 128,080 patients treated for DCIS between 1991-2010. They found that over time, the number of women treated by lumpectomy and radiation increased, while the number of women treated by mastectomy decreased. However, there was an increase in the rate of bilateral mastectomy for DCIS – 0% in 1991 and 8.5% in 2010. The rate of women opting for no treatment increased from 1% to 3% during the study period.

Overall survival was 89.6% in women who underwent lumpectomy and radiation, 86% for those who underwent mastectomy, and 80% for those who underwent a lumpectomy without radiation. However, only 9% of overall deaths were due to breast cancer – the majority of deaths were due to cardiovascular disease. It is well known that more women in this country die due to cardiovascular disease than from breast cancer. Deaths specifically from breast cancer (more relevant than overall survival) were identical for the lumpectomy-radiation, mastectomy, and lumpectomy alone groups. This again raises the need for additional research into which women will truly benefit from treatment for DCIS.

And finally (for now, anyway), Dr. Laura Esserman and others were quoted in an ASCO Post article: Where We Have Been and Where We Can Be. The authors elaborated on points that were made in an August 2015 JAMA Oncology editorial: Re-Thinking the Standard for Ductal Carcinoma In-Situ Treatment. The authors suggested that radiation therapy not be routinely recommended after lumpectomy when the DCIS is not high-grade, as there has been no demonstrated survival advantage. They also suggested that low- and intermediate-grade DCIS should not be a target of screening and early detection. They noted significant challenges in abandoning the use of radiation and decreasing the number of biopsies performed for calcifications that likely represent low grade disease. They also called for more research to be performed to understand the biology of the highest-risk lesions and patient populations.

To be continued…

24 August 2015

A study published in JAMA Oncology raises more questions regarding appropriate treatments for ductal carcinoma in-situ (DCIS). I wrote about surgery for DCIS about a month ago. The controversy continues.

The JAMA Oncology study by Dr. Steven Narod and colleagues used the SEER Database to try to determine if treatment for DCIS improves the death rate. They found that breast cancer-specific mortality was approximately 3.3% over a 20 year period, a very low rate. Certain patient populations such as women under the age of 40, African Americans, and patients with ER-negative and more aggressive subtypes of DCIS had higher mortality rates.

This study has led to headlines including Doubt is Raised over the Value of Surgery for Breast Lesion at Earliest Stage (New York Times, New Breast Cancer Study Raises Questions, Delivers Few Answers (NBC News), Study Sparks Debate on Treatment for Early Stage Breast Cancer (USA Today) and Early Stage Breast Cancer Not a Death Sentence (WebMD). Evaluation of the news coverage by Health News Review provided some context. Linked below are the comments of several experts.

The scope of the problem is huge. DCIS represents approximately 20-25% of all breast cancers, and about 60,000 women in the US will be diagnosed every year. It is most commonly diagnosed by mammography, as it usually does not form a lump. DCIS is known as “Stage 0” breast cancer – under the microscope, the cells look the same as invasive cancer cells, but they are contained within the milk ducts. DCIS has been considered a non-obligate precursor to invasive cancer (may turn into but doesn’t always). A less common point of view considers DCIS to be a “high risk” lesion indicating an increased risk of developing breast cancer in the future. Since we don’t have a good way to determine which lesions simply indicate high risk and which ones will progress, we generally recommend surgery, radiation therapy, and hormonal therapy (such as tamoxifen or aromatase inhibitors, if the DCIS is hormone-receptor positive) with the goal of reducing the risk of invasive cancer and death. The Narod study is notable in that the researchers found that regardless of whether or not women received radiation therapy, survival rates did not change. If DCIS is a direct precursor to invasive cancer, treatment that reduces recurrence rates should result in improved survival.

What is very clear is that DCIS is not one disease, and we haven’t yet gotten to the point of being able to pin this down for the individual woman. Some forms of DCIS may indeed simply be markers of increased risk. Lifestyle changes, hormonal, or immunological therapies could potentially be used to reduce the risk of invasive cancer in these cases, a point raised by Drs. Laura Esserman and Catherine Yau in their JAMA Oncology editorial: Rethinking the Standard for Ductal Carcinoma In Situ Treatment. Some women may ask, “what is the harm in treatment?” or “isn’t it better to be sure?”. But surgery, radiation therapy and hormonal therapy are associated with long term side effects such as pain, breast fibrosis and scarring, lymphedema, osteoporosis and more.

There are some limitations of the study. It was a database review, not a prospective randomized trial, which is considered the “gold standard” for research. While the researchers report on 20-year mortality rates, these are projected, not actual rates – women were followed for variable amounts of time, depending on when they were diagnosed and entered into the database. Other factors such as family history and presence or absence of a genetic mutation were not evaluated.

Research is clearly needed in multiple areas including the biologic behavior of the various subtypes of DCIS as well as racial, ethnic and age-related differences related to tumor behavior. In the meantime, women newly diagnosed should keep in mind that we do not have all the answers. A careful case-by-case evaluation is necessary to help come up with the most appropriate treatment plan, based on our current knowledge and an individual woman’s preferences. A diagnosis of DCIS is not an emergency. Take your time to become informed before making your decisions.

To be continued…

Expert Opinions:
How Should we Treat Stage 0 Breast Cancer Dr. David Gorsky
Why Women and Doctors Need to Know More About DCIS Dr. Elaine Schattner
Treatment for Early Breast Cancer will Benefit Some Dr. Otis Brawley
Are All Appearances What They Seem? New Insights into DCIS Dr. Susan Love
What the Headlines Got Wrong About The New DCIS Study Oncology Times
How Do We Treat Early Stage Breast Cancer The Diane Rehm Show (NPR) with Drs. Barnett Kramer, Shawna Willey, Vinay Prasad and Daniel Kopans

9 June 2015

Surgery doesn’t help women with early-stage breast cancer – that’s certainly a headline that will get attention. The recent NPR article referred to a study published in JAMA Surgery: Survival Benefit of Breast Surgery for Low Risk Ductal Carcinoma In Situ – A Population-Based Cohort Study(1). The study raises some very interesting points, but the NPR headline is misleading. Early stage breast cancer can refer to Stages 0, I, and 2, and the study cited only refers to low grade ductal carcinoma in situ.

In this study, researchers used the SEER database to identify fifty seven thousand cases of DCIS treated in the United States from 1988-2011. 2% of that group did not undergo surgery. The researchers evaluated breast cancer specific survival in the patients treated with and without surgery in relation to tumor grade. They concluded that there was no survival advantage to undergoing surgery in cases of low grade DCIS. For patients with intermediate grade DCIS, 10 year breast cancer specific survival rates were 98.6% in the group who underwent surgery vs 94.6% in the non-surgical group. For patients with high-grade DCIS, 10 year breast cancer specific survival was 98.4% in the surgical patients vs. 90.5% in the non-surgical group.

Ductal carcinoma in-situ is also referred to as noninvasive, or Stage 0 breast cancer. It is primarily diagnosed by screening mammogram, as it often does not form a palpable lump. DCIS accounts for approximately 20% of all breast cancers detected by mammography. As screening mammography has become more prevalent, the rate of DCIS detection has increased. Since DCIS does not always progress to invasive cancer, it is a very reasonable for a newly diagnosed woman to ask “Do I need surgery?”.

A hallmark of cancer is the ability to invade surrounding organs and metastasize, and whether or not DCIS should even be considered “cancer” has been the subject of much debate. Dr. Laura Esserman and others have suggested that DCIS be re-classified as an Indolent Lesion of Epithelial Origin(2). The traditional therapy for DCIS is surgical excision (lumpectomy or mastectomy depending on the extent of disease), radiation therapy, and hormonal therapy such as tamoxifen if the DCIS is estrogen receptor positive. The concern of Dr. Esserman and many others is that we are overdiagnosing and overtreating many women. It is estimated that approximately 25-50% of cases of DCIS will likely progress to invasive disease – 60% over 10 years for high grade vs 16% for low grade (1). Preventing invasive disease, which carries a possibility for metastasis, is the primary goal when treating DCIS.

Unfortunately, we are not yet in a position to accurately predict which cases of DCIS will progress and which will not. The study by Sagara et al categorized the DCIS by tumor grade, and this is an important factor in predicting biologic behavior. However, as was pointed out by Margenthaler and Vaughan in their commentary No Surgery for Low Grade Ductal Carcinoma In Situ? (3), a detailed tumor genomic analysis such as the 12-gene assay provides more comprehensive information about tumor behavior and prognosis. Currently this assay is being used in selected cases to classify DCIS as low, intermediate and high risk and to guide treatment. Another limitation of the Sagara study is the retrospective nature, so that information regarding surgical margins and other factors known to be important in recurrence rates is not known. In addition, only 2% of the patients with DCIS underwent non-operative therapy, so the sample size is very small. It is also not known why some women did not undergo surgery.

An additional concern regarding nonoperative therapy is that if surgery is not performed, the diagnosis depends on the accuracy of the core biopsy. In approximately 15-20% of cases when DCIS is found on core biopsy, the surgical pathology actually demonstrates invasive cancer (4). As the entire lesion cannot be sampled with needle biopsy, we don’t know if we are actually observing an invasive cancer.

So can surgery be avoided in women with early stage breast cancer? My answer is in selected cases possibly, but more information is needed. Several ongoing trials will hopefully provide some answers. In the United States, the ALLIANCE trial involves treating patients with letrozole for 3-6 months prior to surgery with tumor assessment by biopsy and MRI. A similar study is being performed at the University of California San Francisco using either tamoxifen or letrozole prior to surgery. Both studies are evaluating tumor biomarkers to help determine if response can be predicted based on specific tumor factors.

In Europe, 2 non-operative trials are opening – LORD and LORIS. Both will include patients with low-grade DCIS and randomize them to either active surveillance or treatment.

We are anxiously awaiting the results of these studies. Identifying women who do not benefit from treatment is an important question that needs to be answered. However at this time, we do not have enough information to make the general recommendation of active surveillance for all women with low grade DCIS.

References:
1. Sagara Y, et al. Survival Benefit of Breast Surgery for Low Grade Ductal Carcinoma In Situ: A Population-Based Cohort Study. JAMA Surg Published online June 03, 2015.;():. doi:10.1001/jamasurg.2015.0895.
2. Esserman LJ, et al. Overdiagnosis and Overtreatment in Cancer: An Opportunity for Improvement. JAMA 2013:310(8)797-798
3. Margenthaler JA, Vaughan A. No Surgery For Low-Grade Ductal Carcinoma In Situ? JAMA Surg Published online June 03, 2015. doi:10.1001/jamasurg.2015.0895
4. Kumiawan ED et al. Risk Factors for Invasive Breast Cancer when Core Needle Biopsy Shows Ductal Carcinoma In Situ.
Arch Surg 2010;145(11)1098-1104