14 August 2018
I was honored to participate in a Sharsheret national webinar, where breast cancer research that had been presented at the June 2018 meeting of the American Society of Clinical Oncology was reviewed. The webinar video and transcript are linked below. Dr. Sharyn Lewin, a gynecologic oncologist, presented ovarian cancer research updates.
Additional Sharsheret Symposia Transcripts
This post has not been endorsed by the American Society of Clinical Oncology
4 June 2018
The American Society of Clinical Oncology (ASCO) annual meeting, a gathering of over 40,000 oncology specialists, was held this past weekend in Chicago. One of the studies that received a significant amount of press attention was the TAILORx study.
There are several genomic tests which evaluate a tumor’s DNA to better determine how aggressive that tumor is, and how likely it is to recur without chemotherapy. The Oncotype Dx test was the first commercially available one. A sample of tumor is sent for analysis and the result is reported as a “score” which is then assigned to one of 3 categories – low, intermediate and high risk of recurrence. A sample of the report generated from the test is shown below. It is important to note that the Oncotype Dx test was validated in patients who received endocrine therapy, so the results assume treatment with tamoxifen or an aromatase inhibitor. It is appropriately used in patients with Stage I or II breast cancer, with spread to 1-3 underarm lymph nodes, if the tumors are estrogen receptor positive (ER+) and Her2/neu negative (Her2-). The results of the low risk cohort were published in 2015, which confirmed that patients with low scores receive little benefit from chemotherapy.
Sample Oncotype Dx Report
The study presented at ASCO reported on the results of the intermediate risk group. For the purposes of the study, intermediate risk was defined as a score of 11-26. It is important to note that in patients outside of the study, intermediate risk is a score of 18-31. However, as patients in the lowest risk category did not receive chemotherapy as part of this study, the categories were shifted to the left to be more cautious. Patients enrolled in the study were women between the ages of 18-75, with a median age of 55-58. Eligibility criteria included patients who had tumors smaller than 5 cm, ER+, Her2-, and with negative underarm lymph nodes (as determined by surgical pathology – all patients in this study underwent surgery). Patients with an Oncotype Dx score of 11-26 (69% of the total study population, about 6700 patients) were then randomized to chemotherapy followed by endocrine therapy, or endocrine therapy alone. Median follow up was 7.5 years.
The study showed that there was no significant difference in the overall survival (~94%), invasive cancer disease free survival (~84%) or distant disease free survival (~95%) between the 2 groups. However, in women under the age of 50, it was found that those with scores of 16-25 did receive some benefit from chemotherapy. It is unclear from the study if the benefit in these patients was specifically from the chemotherapy, or if it was that menstrual cycles and ovarian function are suppressed with chemotherapy, which then lowers estrogen levels. The authors raised the question of whether or not similar results in this group of patients could be achieved using medications to suppress the ovaries (which would induce menopause) and an aromatase inhibitor instead of chemotherapy.
It is important to note that a low risk score does not mean the patient will not develop a recurrence or metastatic disease – it simply means that the risk of recurrence is extremely low and that chemotherapy will not significantly improve on that low risk. It is also important to keep in mind that this study did not include patients with triple negative or Her2/neu positive breast cancer, or patients where the cancer had spread to the lymph nodes.
There are several commercially available genomic tests, and which test is used for a particular patient is often related to guideline recommendations and physician preference. Most of these tests are covered by insurance but the costs are high (~$4500.00) and patients should check with their insurance to determine if they have a share of cost. Most of the testing companies have payment assistance programs. For patients right on the edge of one of the risk categories, treatment decisions are not always as clear cut, and should be made in the context of the patient’s other disease factors and as part of a balanced discussion of the risks and benefits of treatment as well as patient preferences.
There has been a lot of focus on de-escalaton of therapy, and rightly so. While chemotherapy and other toxic treatments have their place, there are significant short term and long term side effects, so determining which patients have the best likelihood of benefit from these treatments is important. Not all cancers will respond to chemotherapy, and in those cases, the patient is subjected to all of the harms and receives none of the benefit.
10 May 2018
The American Society of Breast Surgeons held their Annual Meeting in Orlando, FL from May 2nd – 6th. As usual, it was well attended – the meeting is known for being very practical and full of information that breast surgeons can bring back to their practices to help improve patient care.
I’ve picked a few topics to highlight in this post: Genetics, Imaging, Local Therapy, Systemic Therapy, Immunotherapy, Liquid Biopsy, Diet and Hormone Therapy, and Changing Paradigms. The following are comments expressed by the meeting speakers. My own comments will be noted in bold italics.
Genetics:
Breast Imaging:
Loco-Regional (breast and underarm lymph nodes) Therapy:
Systemic Therapy:
Immunotherapy / Liquid Biopsy:
Diet and Hormone Replacement Therapy:
Changing Paradigms – Avoiding Surgery for DCIS and Neoadjuvant Patients
Lifetime Achievement Award
Dr. Ernie Bodai, the breast surgeon who spearheaded the Breast Cancer Research Stamp, was honored with a lifetime achievement award. It was fascinating to hear his story and how one man (with a little help) got congress to change a law.
This post has not been endorsed by the American Society of Breast Surgeons
9 November 2017
In patients with a common form of breast cancer, known as estrogen receptor (ER) “positive”, endocrine therapy is often recommended after other treatments such as surgery, chemotherapy, and radiation are complete. Tamoxifen, most commonly used in pre-menopausal women, blocks the estrogen receptor on the breast cell, so estrogen cannot impact cell growth. In post-menopausal women, aromatase inhibitors (AI) are commonly used – these medications block the production of estrogen in the fat cells – a primary source of estrogen after menopause. Historically, these medications have been used for 5 years after completion of other treatment, although there are some studies suggesting longer courses may benefit certain patients. However, longer courses of therapy are associated with a higher incidence of side effects.
A study just published in the New England Journal of Medicine demonstrated that after 5 years of endocrine therapy, patients have an increasing risk of breast cancer recurrence with long term follow up. The authors evaluated individual patient data from a large database of randomized trials. They found that in patients with stage I tumors (tumor less than 2 centimeters and no lymph node involvement) the 20 year risk of recurrence was approximately 13%. In patients with 4-9 involved nodes, the risk ranged from 34-41% depending on the size of the main tumor.
This study is important as it confirms what many of us see in our practices – that breast cancer can and does recur, even many years after therapy. However, it also raises an important discussion point about our treatments. Studies have estimated that as many as 30% of women prescribed endocrine therapy stop treatment due to side effects which significantly interfere with quality of life such as menopausal symptoms, bone and joint pains, bone loss (osteoporosis) and fracture, and mental status changes (“chemobrain”). Patients should discuss any of these symptoms, especially if they are considering stopping their medication, with their physicians. Lifestyle changes, exercise programs, and medications may be of benefit. It is also important to understand that despite all appropriate treatment, cancer can and does come back – so health maintenance and surveillance are important even long after cancer therapy has ended.
27 September 2017
3D mammography, also known as tomosynthesis, is becoming more widely available. The thin “slices” (images) make it easier to spot cancers in patients with dense breast tissue. In addition, the use of 3D mammography can decrease the rate of “callbacks” – additional images that are often recommended after a screening mammogram due to uncertainty about the findings. Callbacks are more common in women with dense breast tissue. One concern about tomosynthesis is that it might find too much – not everything that is found will be dangerous, and this can result in over diagnosis and over treatment. In addition, a slightly higher dose of radiation exposure is required with 3D imaging in some facilities.
In 2005, the DMIST trial results were published in the New England Journal of Medicine – this study compared the older film screen mammography to digital mammography and found that digital mammograms were more accurate for women under the age of 50, women with dense breast tissue, and those who were pre- or peri-menopausal. Digital mammograms are now standard across most of the country.
The TMIST (Tomosynthesis Mammographic Imaging Screening Trial) trial will compare 3D mammography 2D digital mammography. Rates of cancer detection, callbacks, and procedures (such as biopsies) will be monitored. In addition to evaluating the performance of the imaging technology, the study will attempt to identify biological factors associated with breast cancer risk – patients who participate in the study will be asked to provide a buccal (cheek) swab and blood sample.
The study plans to enroll approximately 165,000 women at approximately 100 centers across the country. Additional information about the study and participating centers is available at the following sites:
National Cancer Institute
ECOG-ACRIN (cooperative group sponsoring the trial)
ClinicalTrials.gov
12 September 2017
A common misconception among patients is that more aggressive surgery for breast cancer leads to better outcomes. In fact, nothing could be further from the truth. The standard operation for breast cancer for years (up until the 1960-70s) was the Halsted radical mastectomy, during which the breast, pectoralis muscle of the chest, and underarm lymph nodes were all removed. Randomized trials then showed that less aggressive surgery, including lumpectomy, resulted in similar survival rates as the more extensive procedure. Axillary lymph node dissection, or removal of a large number of underarm lymph nodes, was also a standard procedure for any patient with breast cancer. Studies performed in the late 1980s reported on the accuracy of the sentinel node biopsy technique, which involves removal of only a few targeted underarm lymph nodes. Adoption of that procedure resulted in decreased rates of arm swelling (lymphedema) and did not negatively impact recurrence or survival rates.
Up until about 10 years ago, it was standard practice to test the sentinel nodes in the operating room and if cancer cells were found, complete axillary dissection would be performed. Published in 2011, the American College of Surgeons Oncology Group Z11 study showed that the addition of axillary dissection did not impact local recurrence (cancer coming back in the underarm) or survival rates. This changed practice immediately – and many more women were spared from undergoing full lymph node removal. The 10 year follow up results to Z11 were just published, and confirm the earlier studies noting similar disease-free and overall survival in patients undergoing sentinel node biopsy alone.
It is important to note that the “Z11 criteria” do not include all patients. Women in the study had early stage breast cancers, were “clinically node negative” (not able to feel any underarm lymph nodes), and only had 1 or 2 involved sentinel nodes. All patients in the study had lumpectomy, followed by chemotherapy and radiation. Patients with more than 2 involved lymph nodes, patients who are being treated by mastectomy, or those who receive chemotherapy or hormonal therapy prior to surgery still may need to undergo the more extensive axillary node dissection. Studies are ongoing to see if we can minimize surgical therapy in these patient populations, because over the years, we have found that more aggressive surgery only leads to more complications, not better outcomes.
Additional Information:
The Atlantic – How Clinical Trials Saved Women With Breast Cancer From Disfiguring Surgery (2013)
8 May 2017
As a past-president of the American Society of Breast Surgeons I am probably more than a little biased. However, as always, the annual meeting held April 26-30th in Las Vegas was terrific. Topics including the full spectrum of breast disease, including benign and high risk lesions, genetic testing, breast cancer diagnosis and treatment including medical and radiation oncology updates, and metastatic disease.
The press briefing highlighted 3 abstracts which showed that:
Dr. Nathalie Johnson moderated a pre-meeting course on Building a Breast Cancer Survivorship Program. I was invited to speak on Traditional Versus Virtual – Options for Patient Support and Education. Just as it can be challenging to choose between cake and ice cream (2 really good things), patients note advantages to both in person and online support and education. It doesn’t have to be one or the other – do what works for YOU! My slides are posted on SlideShare.
During the general sessions, a few topics stood out to me:
Dr. Shelley Hwang from Duke University spoke on DCIS subtyping and overtreatment. She noted that DCIS now comprises over 20% of all mammographically detected breast cancer. It is considered a “non-obligate precursor” of invasive cancer – the rate and likelihood of progression to invasive cancer are not clearly known. However, it is clear that some patients will never exhibit progression to invasive disease, and she discussed this in the context of thyroid and prostate cancer – two situations where we know that treatment in some patients will not provide the patient any benefit. The challenge is to sort out which patients will benefit from treatment and which ones will not. The COMET study is currently enrolling patients with low grade DCIS to in an attempt to help answer these questions.
Dr. Virginia Herrmann from Washington University in St. Louis spoke on non-genetic breast cancer risk factors. This is an important topic and I believe one that doesn’t get covered enough. She noted that hormone replacement therapy does increase risk – although the incremental risk is small and is seen only after about 5 years of use. However, longer term use does result in higher risk. Increased body mass index (BMI) is associated with risk – the risk of breast cancer is 30% higher in patients with a BMI greater than 31 kg/m2 compared to a BMI of 20 kg/m2. She noted that there is a linear relationship between alcohol intake and cancer risk, noting a 10% increase in risk for each 10 gm/day (for wine this is a little over 3 oz) increment in alcohol consumption. The risk is most associated with post-menopausal breast cancer, although in the study she quoted, only alcohol intake during age 50s was associated with an increased risk of postmenopausal breast cancer. She noted the association of ionizing radiation and breast cancer, and young women who received mantle (chest area) radiation for Hodgkin’s lymphoma have a markedly increased risk for developing breast cancer. She noted that breast cancer risk is increased in smokers, correlated with smoking intensity and duration. Finally, she noted the increased risk of breast cancer among soldiers stationed at Camp LeJune related to contaminated drinking water (tetrachloroethylene and trichloroethylene).
Dr. Tiffany Traina, a Memorial Sloan Kettering medical oncologist, gave a brief presentation about triple negative breast cancer: Searching For the Magic Bullet. There are several promising treatment strategies including targeting androgen receptors, the use of PARP-inhibitors in patients who have BRCA gene mutations, antibody-drug conjugates, immune modulating approaches, and targeted therapies based on tumor genomic profiles. Stay tuned – much more to come over the next few years related to this aggressive breast cancer subtype.
Dr. Lisa Newman, from the Henry Ford Health System in Detroit, spoke on Breast Cancer Outcomes: Disparities versus Biology. I have heard her speak on this topic multiple times over the years and always enjoy her excellent presentations. She noted that the incidence of breast cancer in black women is increasing, now close to that in white women. However, mortality rates for black women are higher than those for white women. There is an increased frequency of triple negative breast cancer in black women. She is involved in a research initiative evaluating the association between African ancestry and high risk breast cancer in white American women, African American women, and women in Ghana, including studying novel aspects of tumor biology and breast cancer stem cells – she is asking the question “are there differences in the oncogenic potential of mammary tissue that are associated with ancestry”? She concluded with what I felt was a powerful slide – 60% – 43% – 20%. Those were the survival rates for passengers on the Titanic who were in 1st – 2nd – 3rd class. She noted that healthcare outcomes are often dependent on access to care, and ended with a quote from Dr. Martin Luther King, Jr.: “Of all the forms of injustice, inequality in health care is the most shocking and inhumane”.
Dr. Stephen Edge, from the Roswell Park Cancer Institute, gave an update on the new American Joint Commission on Cancer staging system (AJCC 8th edition). Currently we stage breast cancer based on tumor size and lymph node status. However, it is recognized that that tumor biology plays an important role in prognosis and in some patients it may be more important that tumor size. The new staging system will incorporate tumor grade, Her2/neu status, ER/PR status, and Oncotype Dx status (if available) and should more accurately reflect prognosis. There are 422 lines in the new staging system – it will be impossible to memorize! Thankfully, he noted that the AJCC is working on a staging app.
The last day of the meeting held some great sessions, and the meeting room remained packed up until the very last minute. Dr. Ann Partridge from Dana Farber discussed special considerations in the young breast cancer patient. She noted that the disease is different, the patients are different, and the treatments should be different. Younger women have a higher likelihood to have more aggressive subtypes such as Her2/neu over-expressed and triple negative, and have lower survival rates than older women – even in those with the ER positive breast cancer. However, she cautioned not to over-treat patients based only on age. She noted that young age is not a contraindication for breast conservation, and that there is no clear improvement in mortality in patients who undergo more extensive surgery. She noted the need for improvements in treatment and support, including focused research and guidelines, which should lead to better outcomes.
Dr. Irene Wapnir from Stanford spoke on fertility preservation issues. She noted the various fertility options including medications and procedures. She also reviewed the POSITIVE trial, which will be assessing the risk of breast cancer relapse in patients who temporarily stop endocrine therapy to permit pregnancy, as well as to evaluate factors associated with successful pregnancy after interruption of endocrine therapy. She also stressed that fertility preservation should be discussed with any woman of childbearing age, whether or not she has had a prior pregnancy or a child – physicians won’t know what is important to their patients unless we ask!
Dr. Katherina Zabicki Calvillo from Dana Farber discussed breast cancer in pregnancy. She noted that 0.2-4.0% of breast cancers are diagnosed in pregnant patients – about 1 in 3000 pregnancies. She also noted that given the overall delay in childbearing (and the association of increasing age with breast cancer), the incidence of pregnancy-associated breast cancer will increase. Delays in diagnosis are related to hormonal changes which affect breast tissue making the exam more challenging, and that many patients and physicians assume that masses are related to pregnancy. She stressed that pregnancy termination is usually NOT required, but a multidisciplinary team approach is required. Many of these patients present in more advanced stages, but stage-for-stage, the prognosis is similar to non-pregnant patients with breast cancer. Chemotherapy can be given after the first trimester, but hormonal and Her2/neu targeted therapy should be avoided. She noted that mastectomy should be performed in the first and early 2nd trimester, and discussed the challenges of immediate reconstruction. Breast conservation could be considered in the late 2nd or 3rd trimester with post-lumpectomy radiation planned for after delivery.
Dr. Kevin Hughes from the Massachusetts General Hospital reviewed research studies that have found that in women over the age of 70 with early stage breast cancer, radiation therapy after lumpectomy may not be necessary. The CALGB 9343 study showed that survival rates were the same whether women received radiation therapy or not. Radiation therapy did reduce the likelihood of cancer returning in the breast (local recurrence) from about 4% in the untreated patients to about 1% in the treated patients (after 5 years of follow up). However it is important to realize that the majority of women in that study were treated with endocrine therapy, which can help reduce the risk of local recurrence. As with many decisions regarding breast cancer treatment, a careful discussion of the risks and benefits of each option is necessary.
Dr. Tina Hieken from the Mayo Clinic gave a very interesting talk on the microbiome and the impact on breast cancer. We normally co-exist with many bacteria – we have ten times the more microbial cells compared to human cells. These microbes carry out metabolic reactions that can be essential to human health. The genetic material (genome) of our microorganisms is called the microbiome. She and her colleagues studied breast tissue from women with and without breast cancer and found that the background breast microbiome is different in women with breast cancer compared to those with benign conditions. She concluded by noting that the future may involve using a microbial pattern to predict breast cancer risk, exploiting the microbiome to enhance treatment response, and that there may also be implications for a cancer prevention vaccine. The Washington Post recently covered her research – definitely worth a read for more information.
Dr. Anthony Lucci from MD Anderson discussed the “Ongoing Saga of Circulating Tumor Cells”. We would all like to see the day when a blood test can tell us with certainty if cancer has developed or returned – but we’re not there yet. After reviewing several studies evaluating both circulating tumor cells (CTC) and circulating “cell free” DNA, he concluded that this information does provide prognostic information in both metastatic and non-metastatic patients, but is not in the current ASCO or NCCN guidelines for guiding treatment. Combining the CTC status with response to preoperative chemotherapy may identify a low risk subset of patients, but noted that additional studies are needed before we can reach the ultimate goal which is improving outcomes by monitoring and responding to CTC and cell free DNA levels.
Dr. Manjeet Chadha from Mount Sinai spoke on repeat lumpectomy after prior lumpectomy and breast radiation. Traditionally, mastectomy has been recommended if cancer returns after lumpectomy and radiation therapy. On average, there is about a 10% risk of “in breast” recurrence after lumpectomy and radiation, but this will vary based on tumor and treatment type. She reviewed several studies evaluating the different types of focused or partial breast radiation that may be used in selected patients who experience recurrence of their breast cancer. She also called for additional studies in this area.
One of the last talks was by Dr. Mehra Golshan from Dana Farber. He spoke about the decision whether or not to operate on patients with breast cancer who present with Stage IV (metastatic) disease. Traditionally, we have not recommended surgery for patients with metastatic breast cancer as these patients were not expected to have long survival, and it was not felt that removal of the main tumor would impact survival. Evaluating existing studies has also been challenging because while some have shown a benefit to removal of the main tumor, the patients who underwent surgery in those studies tended to be younger and healthier. He concluded by noting that surgery in patients with Stage IV breast cancer is not standard of care, but some studies do support this practice. It is recommended that these patients be evaluated in a multidisciplinary forum and that treatment choices be individualized.
I returned from the meeting exhausted but energized. In addition to the scientific content, the meeting is an opportunity to connect with friends and colleagues across the country. I’m already looking forward to ASBrS 2018!
This post has not been endorsed by the American Society of Breast Surgeons.
20 March 2017
Over 50,000 women in the US are diagnosed every year with ductal carcinoma in-situ (DCIS), also known as Stage 0 breast cancer. DCIS is most often diagnosed on screening mammography and usually presents as a cluster of calcium deposits rather than a lump. In cases of DCIS, malignant appearing cells grow within the milk duct, but do not invade through the wall of the milk duct. DCIS is considered to be a “non-obligate precursor” to invasive breast cancer – it has the potential to develop into invasive disease, but this does not happen in all cases. However, we traditionally have treated DCIS and invasive cancer in a similar fashion – with surgery, radiation therapy and endocrine therapy. It has become clear over the past several years that low grade DCIS is likely a different disease compared to high grade DCIS. Aggressive treatment of low grade DCIS may not improve outcomes but has the potential to cause significant harms.
A new clinical trial has opened for patients with low risk DCIS. The COMET Trial (Comparison of Operative to Monitoring and Endocrine Therapy) is currently enrolling patients under the direction of Dr. Shelley Hwang, a breast surgical oncologist at Duke University. Eligible patients will be randomized to guideline concordant care (standard therapy) versus active surveillance. The primary objective is to evaluate the rate of invasive breast cancer development in the active surveillance group. Secondary objectives include assessments of quality of life and anxiety. In addition, clinical outcomes including mastectomy and breast conservation rates, overall survival and breast cancer specific survival, and ipsilateral (same side) invasive breast cancer rates will be assessed.
The COMET study is not the first to evaluate non-operative therapy for DCIS. The LORIS and LORD trials are already enrolling patients in Europe. A UK-funded initiative known as PRECISION (Prevent Ductal Carcinoma In Situ Invasive Overtreatment Now), headed by the Netherlands Cancer Institute, will collaborate with all three trials.
It is always challenging to go against standard treatment, especially when that means less treatment. It took almost 50 years after the death of Sir William Halsted (“Halsted Radical” mastectomy) for surgeons to accept less invasive surgical procedures. Many patients (and physicians) may feel uncomfortable not removing cells that have been labeled “cancer”. It is important to recognize that lack of surgery does not mean no care – “active surveillance” is now an accepted management strategy for some cases of low grade prostate cancer. Our treatments come with real long term side effects and toxicity. The COMET study is a step in the right direction to help determine which patients may safely avoid aggressive treatment.
Additional Information:
DCISOptions.org
DCIS, Continued…
Slideshare – Are We Overtreating DCIS?
CBS News: Dr. Laura Esserman – When is it OK Not to Treat Cancer?
HealthNews Review Podcast: Dr. Laura Esserman – The DCIS Dilemma
HealthNews Review Podcast: Active Surveillance for Prostate Cancer
26 December 2016
Approximately 75% of breast cancers express the estrogen receptor – we term these breast cancers ER positive (ER+) or hormone-sensitive. Endocrine therapy refers to using medications to exploit this cancer cell property. Tamoxifen is used in premenopausal women and it blocks the estrogen receptor. In post-menopausal women, aromatase inhibitors (AI) are used which prevent estrogen from being produced (primarily in the fat cells after menopause).
In June, a study was presented which suggested that 10 years of endocrine therapy in post-menopausal women might be superior to 5 years of treatment, which had been the standard. The study noted that disease free survival was improved and development of new breast cancers were reduced in the extended therapy patients, but there were more side effects. A conclusion was that extended therapy might be appropriate for higher risk patients – those who based on certain tumor factors we suspect might have a higher risk of recurrence. A challenge has been that we do not have good tests to tell us with certainty which patients will truly benefit from a longer course of therapy.
At the 2016 San Antonio Breast Cancer Symposium, 3 studies were presented which addressed the issue of extended endocrine therapy in post-menopausal women. In all 3 studies, extended endocrine therapy with an AI did not improve disease free survival, in contrast to the study presented in June. A lack of survival benefit does not mean that extended therapy is not worthwhile, as noted in this ASCO Post article, and one of the studies did show improvements in distant metastases and contralateral (other side) breast cancers. Dr. Michael Gnant, who discussed the studies at the meeting, noted that “The trials did not reach the necessary statistical levels to demonstrate a clear benefit for aromatase inhibition extension. Extending aromatase inhibitor therapy may be a good idea for many patients after 2 to 5 years of tamoxifen, but after initial treatment with an aromatase inhibitor, the benefits and risks must be carefully balanced on an individual basis. We are going to need the ‘art of medicine’ here.”
While ER+ breast cancers tend to be “better behaved”, we know that these patients are at risk for relapse many years after initial treatment. This knowledge has to be balanced with the real side effects women experience from taking the medications. Common side effects of the AIs include joint and bone pains, vaginal dryness, hot flashes, and bone loss. Deciding whether or not to continue on the medications in the setting of significant side effects is also difficult for patients, who then have concerns about “not doing enough” to reduce the risk of cancer recurrence. More research is needed to develop both tests to help predict which patients will actually benefit from extended therapy, and treatments with fewer side effects,
25 August 2016
A study published today in the New England Journal of Medicine reports on the 5 year results of the MINDACT (Microarray In Node-negative and 1 to 3 positive lymph node Disease may Avoid ChemoTherapy) trial. This study was designed to evaluate the use of a tumor gene signature test (MammaPrint) compared with standard factors to assess the need for chemotherapy.
This study enrolled 6693 women in 112 countries who had undergone surgery for Stage I and II breast cancer. Once patients were registered, they were stratified based on risk. Risk was assessed both by the MammaPrint (MP) score as well as standard clinical – pathological markers (CP) such as tumor size, grade, ER/PR status, and Her2/neu expression calculated using the Adjuvant! Online tool.
2745 patients who had low risk MP and CP scores did not receive chemotherapy; 5 year metastasis-free survival in this group was approximately 97.6%. These findings were consistent with those reported using a different genomic test, the Oncotype Dx test, which also demonstrated good results without chemotherapy in low risk patients. 1806 patients who were high risk by both assessments received chemotherapy and 5 year metastasis-free survival in this group was approximately 90.6%.
The other 2 groups were those with discordant results, and these patients were randomized to either chemotherapy / endocrine therapy or endocrine therapy. The results for the 592 patients with high risk MP scores but low risk CP assessment are pending. The recently published study focuses on the 1550 patients with low risk MP scores but were high risk based on CP assessment.
The study demonstrated that in these patients, chemotherapy provided a slight benefit: 1.5% improvement in survival without metastatic disease, 1.4% improvement in overall survival, and 2.8% improvement in disease free survival. The study was not powered or designed to determine if these differences were statistically significant.
On the surface, the study seems to indicate that chemotherapy is of little to no benefit for those patients with low risk MP scores and high risk CP features. There is no question that genomic tests such as the MammaPrint have revolutionized our treatment recommendations. We now have the ability to obtain more detailed information about an individual patient’s tumor biology, which can help us guide treatment decisions. It is clear that our traditional methods of assigning risk such as tumor size, grade, and node status, do not always tell the whole story, and it is no longer acceptable to recommend chemotherapy “just to be sure”. The use of genomic tests in appropriate patients is very important to avoid the real dangers of over treatment. But as this study was not designed to assess statistical significance (rather, “non inferiority“), can we say that the benefits demonstrated from chemotherapy may not be important for an individual patient?
Median follow up in this study was was 5 years. 48% of patients were lymph node positive, 93% had grade 2 or 3 disease, and 34% were age 50 or younger. These factors are more often associated with an earlier risk of recurrence, so 5 years may be sufficient to note a difference in survival rates. It was also stated by the authors that “adjuvant chemotherapy exerts most of its beneficial effects early in the course of the disease”. However, they also noted that many of the tumors were ER+, which may recur well past 5 years. 10 year follow up is planned.
In an accompanying editorial, Drs. Hudis and Dickler point out that “although we may all agree that a 1% risk of distant metastasis at 5 years on the basis of genomic testing eliminates any potential benefit of chemotherapy, at what point would we begin to have differing opinions and perhaps mixed results from clinical trials? Answering this question is even more challenging, given that all chemotherapy is not the same in terms of efficacy or toxicity and that patients and health care providers bring subjectivity and personal values to their treatment decisions.”
As was pointed out during a recent online exchange (by a woman who had a low recurrence score and now has metastatic disease), these tests are not guarantees. While the numbers are low, some women in the low risk group developed metastatic disease. It is not known if chemotherapy would have been of benefit, but it does demonstrate how percentages are applicable to populations, not necessarily to individuals. We do not yet have a test that will predict the outcome with 100% certainty. The test results should be presented as part of a discussion which includes the patient’s preferences, values and concerns – concerns regarding cancer recurrence as well as potential side effects of therapy.