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Extended Hormone Therapy for Postmenopausal Breast Cancer

09 June 2016

A study presented at the recent American Society of Clinical Oncology meeting evaluated the use of extended endocrine therapy in post-menopausal women. I’ve covered some of the basics of endocrine therapy for breast cancer in a previous post. In 2012, results of the ATLAS Trial were published, and found that when tamoxifen was given for 10 years instead of the standard 5, improvements were noted in overall and disease free survival.

Up until this point, no study has demonstrated similar findings for post-menopausal women taking aromatase inhibitors. Results of the MA.17R study were reported at the 2016 ASCO meeting, Patients in the study had already completed at least 5 years of endocrine therapy with the aromatase inhibitor letrozole. They were then randomized to receive either an additional 5 years of letrozole or a placebo. Median follow up was 6.3 years.

The key study findings were as follows:
–   Disease free survival was 95% in the treatment group and 91% in the placebo group, a 34% reduction. This was statistically significant.
–  Contralateral breast cancer (a new cancer developing in the opposite breast) occurred in 1.4% of the treatment group, and 3.2% of the placebo group a 58% reduction. This was also statistically significant.
–  Overall survival was the same in both groups.
–  More bone fractures (14% vs. 9%) and new-onset osteoporosis (11% vs. 6%) were seen in the patients undergoing extended endocrine therapy – it is well known that these medications accelerate bone loss. These findings were statistically significant.
– Rate of discontinuing therapy was 5.4% in the letrozole group, and 3.7% in the placebo group.

Several points were brought up in the discussion immediately following the presentation as well as in post-plenary “town hall” style session held later in the day, including:

–  It is not clear what the long-term effects of medications used to treat bone loss will be – if patients are on endocrine therapy for longer periods of time, they likely will need to be on the bone protective medications for longer as well.
–  Reported quality of life was similar in both groups, as reported by Dr. Julie Lemieux. However, as Dr. Don Dizon noted: “without compromising quality of life” isn’t the same as “everything’s peachy.”

– It was noted that the patients enrolled in the study were self-selected which may bias the results. As they had already completed at least 5 years of letrozole therapy, these patients likely had few existing side effects from treatment. Concern was raised in the post-plenary discussion that we may see more of an impact on quality of life if a broader population of women is treated with extended endocrine therapy.
– Dr. Lisa Carey noted that adherence to endocrine therapy remains a significant issue in part due to medication side effects. While the rate of discontinuation of therapy in this study was low, this does not reflect real-world experience.

The disease free survival improvement and contralateral breast cancer reduction were widely reported in the press as percentages (34% disease free survival benefit, 58% reduction in contralateral breast cancer). It is important to realize that the absolute benefits are very small – only a few percentage points. While the results achieved statistical significance, they may or may not be significant to an individual patient. It is important that patients understand the concept of absolute risk vs. relative risk.

Professor Ian Smith, who discussed the abstract during the plenary session, concluded by saying that the MA.17R findings do not justify extended endocrine therapy in all patients. Rather, patients with more aggressive features such as larger tumors, positive lymph nodes, and higher cell grade may benefit. He called for physicians to carefully discuss the study results with their patients, and allow them to participate in the decision for or against extended endocrine therapy.

This conclusion prompted the following Twitter exchange with an oncology colleague:

While it should go without saying that we need to discuss study results as well as advantages and disadvantages of treatment with our patients, this point is not emphasized enough during national presentations. The lead author, Dr. Goss, commented during the post-plenary discussion that he is not specifically recommending extended hormonal therapy. Rather, he acknowledged that this is a decision that needs to be made by an individual patient, in consultation with her physician, after carefully reviewing all of the information. The study received a significant amount of media attention, and the discussion at the conference session was very spirited. At the end of the day, it’s important that patients to realize that we don’t have a definitive answer for the individual.

It is also important not to forget the impact of lifestyle factors in terms of reducing risk of recurrence. Regular exercise, weight maintenance, healthy food choices, and moderation in alcohol intake all will help reduce the risk not only of breast cancer recurrence, but also of cardiovascular disease, which remains the number one killer of women in the United States.

Additional Reading:
ASCO Post Overview of MA.17R
Changing Adjuvant Breast Cancer
Dr. Elaine Schattner in Forbes

 

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New Patient Information Website

 

9 November 2015

The American Society of Breast Surgeons Foundation has just launched a patient information website – Breast360.org. The site was developed by breast surgeons, and patient advocates have had input and oversight during the entire process. Please take a look, and feel free to provide feedback if you have a suggestion for additional content.

 

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Race and Breast Cancer

15 October 2015

A recent study has noted that African American and Hispanic women are more likely to be diagnosed with aggressive forms of breast cancer. Drs. Lu Chen and Christopher Lee published their findings, Racial Disparities in Breast Cancer Diagnosis and Treatment by Hormone Receptor and Her2 Status, in a recent issue of the journal Cancer Epidemiology, Biomarkers and Prevention.

Using information from SEER Registries, they identified 120,000 women, age 20 and over, diagnosed with invasive breast cancer between 2010-2011, with documented information about tumor stage, hormone receptor, and Her2 status. They evaluated the associations between patient race / ethnicity and stage at diagnosis as well as receipt of guideline-appropriate care. Findings included:

  • African American and Hispanic women were 30-60% more likely to be diagnosed with stage II-IV breast cancer compared with non-Hispanic white women
  • African American women had 40-70% risks of being diagnosed with stage IV breast cancer depending on tumor subtype
  • American Indian and Alaska Native women had a 3.9 times higher risk of stage IV triple-negative breast cancer
  • African American and Hispanic women were 30-40% more likely to receive non-guideline concordant care for their breast cancer

The findings reflect those reported earlier this year in the Journal of the National Cancer Institute. It is not news that African American and Hispanic women have worse breast cancer outcomes compared to other populations. They are more likely to be diagnosed at advanced stages, are less likely to receive guideline-appropriate treatment, and have worse overall survival. It is becoming clear that breast cancer is a different disease in women of different racial and ethnic backgrounds – they are more likely to have higher-risk subtypes. This study confirms these points, with the exception of survival, which was not assessed due to the short time period of data analysis (2010-2011). This emphasizes the need for continued research regarding the racial and ethnic variations in tumor subtypes.

Presentation at more advanced stage and lack of guideline-concordant care for African American and Hispanic women should be of concern to us all. This points to racial, ethnic and socioeconomic disparities in education, access to screening, and access to quality care. The authors concluded by stating:  “As contributors to racial / ethnic disparities in breast cancer are complex and multifactorial, continued efforts, especially targeted, culturally appropriate interventions, to address these disparities across different subtypes of breast cancer have the potential to reduce these long-standing disparities and hopefully close the existing survival gaps.”

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Chemotherapy Can Be Avoided in Certain Patients

29 September 2015

One of the most common questions asked by a newly diagnosed cancer patient is “Will I need chemotherapy?”. Almost everyone is aware of the toxicity related to chemotherapy, and the fact that it is a common component of cancer treatment. A recent study sheds some light on which patients can safely avoid chemotherapy.

We have known for many years that not all patients who receive chemotherapy will benefit from it – in some cases, less than 3% of patients benefit. We traditionally used measures such as tumor stage, tumor grade, and receptor status such as ER/ PR and Her2/neu. Since 2004, many of us have relied on the OncotypeDx test. This assay, which is performed on the tumor, analyzes 21 genes (of the cancer – different from genetic testing of the patient) that have to do with cell growth and proliferation. The score, which is reported as low, intermediate, or high, is used to help determine whether or not a patient will benefit from chemotherapy.

The initial studies leading to widespread use of the OncotypeDx test were retrospective. Many of the large national breast cancer trials had tissue saved from the original procedures. The OncotypeDx test was run on these tissue samples, and then was analyzed with respect to patient outcomes. Based on these studies, patients with low risk scores were advised not to undergo chemotherapy; chemotherapy targets rapidly dividing cells, and low-risk tumors simply will not respond. Conversely, patients with high risk scores were advised to undergo chemotherapy treatment. Based on these studies, we discovered that our traditional methods of determining who should receive chemotherapy were not very accurate.

A new study published in the New England Journal of Medicine is the report of the first prospective trial involving OncotypeDx testing. Dr. Joseph Sparano and colleagues reported on the Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. In this study, patients with hormone-receptor positive, Her2/neu negative breast cancers, 1.5 – 5.0 cm in size, had OncotypeDx testing on their tumors. Patients with low-risk tumors received endocrine therapy (tamoxifen or aromatase inhibitors). Patients with high-risk tumors received chemotherapy. Patients with intermediate-risk tumors were randomized to either hormonal therapy or chemotherapy, as prior studies did not demonstrate a clear benefit from either class of treatment.

The current study reports on the low-risk group, which included 1626 women. At 5 years, fewer than 2% of patients experienced a local-regional (breast or lymph nodes) or distant / metastatic (spread to other areas of the body) recurrence.

The authors concluded that endocrine therapy is perfectly appropriate for patients with low-risk tumors, and chemotherapy would not add any significant benefit in terms of recurrence or overall survival. A criticism of the study was that follow up was only 5 years, but the authors note that the primary benefit of chemotherapy is in reducing recurrences within the first 5 years of treatment. Endocrine therapy is recommended for longer-term reduction in recurrence in these patients.

Dr. Clifford Hudis, of the Memorial Sloan Kettering Cancer Center in New York, wrote an accompanying editorial: Biology Before Anatomy in Early Breast Cancer – Precisely the Point. He noted that “this assay is the most rigorously tested option and provides proof of the principle that we can develop reproducible predictive results to select patients who should not receive chemotherapy. In that regard, it is one more step towards precision. There are more steps ahead.”

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Do I Need Surgery for DCIS?

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

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Breast Cancer – Knowledge About Disease

28 January 2015

A study published in the journal Cancer found that many women lack basic knowledge about their breast cancer. Researchers at the Dana Farber Cancer Institute in Boston surveyed 500 women treated between 2010-2011 for Stage 0 – III breast cancer in Northern California. Women were asked about 4 tumor characteristics – estrogen receptor (ER) status, Her2/neu status, tumor grade and disease stage.

They found that overall, 55% reported knowing their ER status, 33% reported knowing their Her2/neu status, 82% reported knowing their disease stage, and 32% reported knowing their tumor grade. 14% reported knowing all characteristics, and 14% reported knowing none.

However, patient perception of knowledge did not reflect actual knowledge. Only 8% answered all questions correctly. They also found that African American and Hispanic women had a lower rate of stated knowledge and correct answers. Differences in education and health literacy were associated with less knowledge about one’s own condition, but controlling for these factors did not eliminate the observed differences for minority participants.

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The findings are important for several reasons. As the authors noted in their manuscript, “having knowledge about one’s health conditions or the risk of developing health conditions can promote healthy behaviors and treatment adherence. Better general knowledge about cancer is associated with cancer screening, earlier stage at presentation and survival, and enhanced satisfaction with care.” “Improving a patient’s understanding about why a particular treatment is important to her individual situation may lead to more informed decisions and better adherence to treatment plans.”

While it is generally felt that breast cancer patients are highly educated about their disease, this study shows that as physicians, we have a long way to go. We need to do a better job assessing a patient’s understanding of their disease and treatment options, and we need to design and participate in research studies that evaluate new and innovative ways to explain complicated information to a newly diagnosed breast cancer patient taking into account education level as well as racial, ethnic and cultural differences. Our discussions need to be tailored to the individual patient. And patients should feel empowered to ask questions and obtain clarification in order to fully understand the treatment recommendations and the rational behind those recommendations.

Reuters News Coverage

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Increasing Mastectomy Rates – Science vs. Personal Choice

19 January 2015

This past weekend, I gave a talk at the Southern California Chapter of the American College of Surgeons Annual Meeting – the title of the talk was Increasing Mastectomy Rates – Science vs. Personal Choice.

There is a tremendous amount of literature documenting the increasing mastectomy rates. The talk focused on women with early stage breast cancer at average risk for developing a recurrence or new cancer – women without a BRCA gene mutation. As has been my practice for several years when giving a talk which includes the patient experience, I asked you for input, and received a lot of information. The following is a summary of the talk, including your perspective.

The use of mastectomy for breast cancer has been documented as early as the 1500s, despite the fact that general anesthesia did not come into use until the 1840s. Sir William Halsted described the radical mastectomy, which involved removal of the breast, all of the overlying skin, the pectoral (chest) muscle, and a significant number of lymph nodes. It was a very aggressive surgery but at the time, many women at the time presented with advanced disease – cancers that grew through the skin or chest muscle. The Halsted theory was that if the breast and lymph nodes could be removed with an extensive “en bloc” surgery, the cancer had a lower likelihood of spreading. However, despite this aggressive approach, the dismal survival rates from breast cancer did not improve.

Halsted died in 1922, but the radical mastectomy remained the surgical procedure of choice until the 1960-70s. The landmark NSABP B04 trial, led by Dr. Bernard Fisher, demonstrated that regardless of surgical decision (radical mastectomy vs. total mastectomy – no removal of the muscle) the survival rates were equivalent, and these results have held up for 25 years(1). The Fisher theory was that cancer may be metastatic from the beginning, and that a more extensive surgical procedure would not be expected to improve survival rates. The NSABP B06 trial demonstrated equivalent survival rates whether women underwent mastectomy, lumpectomy / radiation, or lumpectomy alone. However, if radiation therapy was not performed, the risk of local recurrence (cancer returning in the breast) was 39.2%, compared to 14.3% with radiation(2). This is the basis for our current recommendation of lumpectomy followed by radiation therapy for early stage breast cancer. A 1990 NIH consensus panel stated that “breast conservation treatment is an appropriate method of primary therapy for the majority of women with early-stage breast cancer and is preferable because it provides survival rates equivalent to those of mastectomy while preserving the breast’’(3).

This was seen as a major scientific advance, and one that was embraced by patients – no longer did women need to have a breast removed for early stage disease, and from the early to mid 1990s, lumpectomy rates started increasing while mastectomy rates decreased.

The Women’s Health and Cancer Rights act of 1998 stated that if an insurance company covered the procedure of mastectomy, they were required to cover reconstructive surgery, including procedures performed on the other breast to produce a symmetrical appearance, as well as prosthetics for lymphedema. This set the stage for immediate reconstruction, which prior to this time was generally not performed (or recommended) on a regular basis.

We think of the “Celebrity Effect” when we hear Angelina Jolie, Amy Robach, and others discuss their decisions. But in 1987, Nancy Regan underwent a mastectomy for breast cancer, and she received a significant amount of criticism for her decision, both from the medical community as well as from advocacy groups. Women who underwent breast cancer surgery from the end of 1987 to early 1988 were 25% less likely to undergo lumpectomy compared to earlier in 1987, prior to her diagnosis(4). Lumpectomy rates subsequently increased, but she later wrote “This is a very personal decision, one that each woman must make for herself. This was my choice, and I don’t believe I should have been criticized for it”(5).

Around 2004, it was noted that mastectomy rates started rising(6). This trend was seen nationally as well as in many individual institutions.

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In addition to an increase in mastectomies being performed for early stage breast cancer, an increase has been seen in contralateral prophylactic mastectomy – removal of the other, non-cancerous breast. Many studies have been published confirming this trend, and also evaluating factors associated with an increased mastectomy rate(7,8,9). They include:
– Young age, Caucasian race
– Higher economic status, better insurance, availability of reconstruction
– Family history of breast cancer or genetic testing – even if the genetic testing was negative
– Undergoing an MRI, even if the MRI was normal

Patient factors have also been evaluated. Many studies have cited that women make their decisions out of fear. Interestingly, there seems to be some intellectual disconnect – women report that they understand there is no improvement in survival, yet state that they made their decision “to live longer”. The physician has been identified as a very important source of information, yet only 1/3 of women stated that a desire to follow their physician’s recommendation was important in making their decision. Many women over-estimate their risk of developing a new breast cancer – some reporting they think their risk is as high as 50%. Other studies have reported that women make their decisions to gain a sense of control over cancer, but that many have an exaggerated sense of control, stating that they are making the decision “so I don’t have to go through this again”, while admitting that they are aware that mastectomy does not reduce the rate of metastatic disease. The impact of a family member / friend experience was also noted to be very important. All of us make decisions in our daily lives based on personal experience rather than hard facts – a woman facing a decision about breast cancer surgery is no different. Finally, many woman remain very satisfied with their decision even 20 years after the surgery. However, it is important to note that 10-30% report issues related to self-esteem, body image, sexuality, emotional stability, and overall quality of life (10, 11, 12).

Some facts(10, 13, 14, 15):
– For women at average risk of breast cancer (BRCA negative) the rate of developing a new breast cancer is approximately 0.5 – 0.75% per year. This can be reduced if the women undergoes chemotherapy and/or endocrine therapy
– Mastectomy for early stage breast cancer or contralateral prophylactic mastectomy does not reduce the likelihood that breast cancer will metastasize (spread to other areas of the body)
– The complication rate increases with more surgery – bilateral mastectomy is associated with 30-40% risk of complications including infection, fluid accumulation, and re-operation.

So what did you, the #BCSM Community have to say? Out of those who responded:
– “I knew survival rates were the same” – most patients well informed, had surgeons who presented all sides, supported their decision
– 40% said decisions influenced by family/friend experience
– 15% had lumpectomy initially, then opted for bilateral mastectomy after anxiety of repeat imaging and biopsies.
– 6 patients: lumpectomy and radiation: significant problems with wound healing, fibrosis and later underwent a mastectomy
– 5 patients subsequently developed metastatic disease; no regrets on their decision
– 3 patients required multiple surgeries due to revisions, infection, lost implant – no regrets
– 2 patients felt pushed into their decision, one by family members and another by their physician – both regretted their decision

There are a lot of comments on the original blog post; here are a few I received by email:
– “I wish doctors, researchers and the media understood (some do) – there are many valid reasons for choosing a mastectomy, even with the state-of-science today”
– “The focus is on ‘simple’ surgery – the potential toxicity of radiation therapy is grossly minimized. While serious and long-term side effects of radiation therapy may be rare, they do occur. It is ironic now that patients have a choice in treatment selection, there is so much hand-wringing by the medical establishment in the choices that many women make”
– “We are diligent. We are thoughtful. We have good reasons for choosing the “big surgery”. Our doctors explain the risk factors, we process the information, we understand the full ramifications of our choice, and are still confident that this is the right choice for our set of circumstances.
– It may not fit the medically necessary criteria, but it may fit with the emotionally necessary criteria. I hear your evidence based science and I’ll raise you five intangibles…”

So what is the answer? Clearly physicians have a responsibility to educate our patients not only on the lack of overall survival benefit, on the complication rates. Physicians also need to do a better job of assessing and explaining a patient’s risk of developing a recurrence or a new breast cancer. And patients should be encouraged to take their time, obtain opinions, and carefully consider all options prior to making a decision. But rather than irrational fear, what many of see in our practice is “Reasonable Fear”. Patient’s biases and personal experiences need to be acknowledged. Some bias, but not all, can be overcome with education. But until science advances to allow us to truly predict who will and will not develop a recurrence or a new breast cancer, personal choice should remain an option.

References:
1. Fisher B et al. 25 Year follow up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. NEJM 2002;347 (8)
2. Fisher B et al. 20 Year follow up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer NEJM 2002;347 (16)
3. NIH Consensus Conference: Treatment of Early Stage Breast Cancer. JAMA 1991 265
4. Nattinger AB, et al Effect of Nancy Regan’s mastectomy on choice of surgery for breast cancer by US women. JAMA 1998 (279) 10 762-766
5. Olson, J: “Bathsheba’s Breast: Women, Cancer and History” The Johns Hopkins University Press 2002
6. McGuire KP, et al Are mastectomies on the rise? A 13 year trend analysis of the selection of mastectomy versus breast conservation therapy in 5865 patients. Ann Surg Oncol 2009 16:2682-2690
7. Mahmood U, et al Increasing national mastectomy rates for the treatment of early stage breast cancer. Ann Surg Oncol 2013 20:1436-1443
8. Yao K, et al Trends in contralateral prophylactic mastectomy for unilateral cancer: A report from the national cancer database 1998-2007. Ann Surg Oncol 2010(17) 2554-2562
9. King TA, et al Clinical management factors contribute to the decision for contralateral prophylactic mastectomy. J Clin Oncol 29:2158-2164 97-200
10. Rosenberg SM, et al Perceptions, knowledge and satisfaction with contralateral prophylactic mastectomy among young women with breast cancer Ann Intern Med 2013;159:373-381
11. Covelli AM, et al ‘Taking control of cancer’: Understanding women’s choice for mastectomy.  Ann Surg Oncol DOI 10.1245/s10434-014-4033-7
12. Frost MH, et al Contralateral prophylactic mastectomy: Long term consistency of satisfaction and adverse effects and the significance of informed decision making, quality of life, and personality traits. Ann Surg Oncol 2011 18:3110-3116
13. Fayanju O et al Contralateral prophylactic mastectomy after unilateral breast cancer: a systematic review and meta-analysis. Ann Surg 2014; 260:1000-1010  
14. Roberts A et al Cost effectiveness of contralateral prophylactic mastectomy for prevention of contralateral prophylactic mastectomy. Ann Surg Oncol 2014 21:2209-2217
15. Miller ME et al  Operative risks associated with contralateral prophylactic mastectomy: A single institution experience. Ann Surg Oncol 2013 204113-4120.

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Male Breast Cancer: Facts and a Personal Perspective

23 November 2014

Guest Post by Dr. Oliver Bogler

When thinking about a post on male breast cancer, one person came to mind –  Dr. Oliver Bogler. As a cancer researcher, Dr. Bogler has a very unique perspective on his diagnosis, treatment, and the larger problem of research disparities when it comes to male breast cancer. Here is his guest post: 

My personal encounter with breast cancer started with my diagnosis in September of 2012. My story is very typical. As I have written more extensively about it elsewhere let me be brief: I felt a lump, and after a few months of denial I had it checked out, and then very quickly was diagnosed and treated at MD Anderson Cancer Center in Houston, where I also work. More on that below, but let’s first look at some facts about the male disease.

About Male Breast Cancer
Approximately one in every hundred people diagnosed with breast cancer is a man. That’s about 2,200 new cases a year in the USA. Men have breasts, meaning that they have the same lobular glands and ducts that women have, though they have less tissue and it does not produce milk. Accordingly, male breast cancer is typically ductal carcinoma and hormone receptor positive and Her2 negative, which is also the most common type of breast cancer in women. Men are diagnosed later in life, typically, with a median age at diagnosis of 68, or about 7years older than women. For that reason men also present more often with more advanced forms of breast cancer – stages III and IV are more common, and stage I very rare. One possible explanation is that a lack of awareness results in delayed diagnosis, and so more advanced presentation at a later age.

Treatment regimens for men are essentially identical to those used for women, and outcomes are very similar, as far as we know. Because male breast cancers are typically hormone receptor positive, hormone therapy with the anti-estrogen tamoxifen is commonly an important part of the therapy. It suppresses male estrogen, and thereby other hormones also, which are co-regulated, including testosterone.

Many websites, including those of the American Cancer Society and the National Cancer Institute provide fundamental information about male breast cancer. Interventional clinical trials on breast cancer that men are eligible for can be found here (ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world).

My advice: if you feel a lump, any lump, go see a doctor right away.

My Journey – Our Journey
One of the reasons I hesitated to get my lump checked out was that my wife had been diagnosed and treated for breast cancer about 5 years before me. I couldn’t really grasp the improbability of it hitting our nuclear family twice. Being Irene’s care taker and then a patient allows me to say with confidence that the treatments for men and women are identical: we both had up-front chemotherapy in a two step regimen: 12 rounds of weekly Taxol and then 4 rounds of the combination FAC at three week intervals. MD Anderson physicians prefer to give the chemo first as it provides an opportunity to see how the tumor responds. Then we both had surgery – modified radical mastectomy with axillary lymph node dissection – followed by 6 weeks of radiation to the chest wall. Now we both take hormone therapy – aromatase inhibitors for Irene, good old tamoxifen for me. Evidently we feel that marriage is all about sharing experiences 🙂

What we know about male breast cancer and opportunities to learn more
What do we know? Probably not enough. I do accept that the treatment men receive is effective – there are some relatively small-scale, hospital registry based studies showing this. When adjusted for age and stage at diagnosis, it looks like men do as well as women with today’s approaches. On the other hand, the possibility that a sex-hormone driven cancer may have important differences between men and women cannot be excluded. Very encouraging is a current, larger registry trial in a network of European and US cancer centers with about 1,200 men that will provide a robust baseline outcomes data set and afford the opportunity to collect tissue and study the disease. It is the kind of research that was being done 20+ years ago in women.

An analysis I wrote about on my blog and in Breast Diseases Quarterly [Bogler, O. (2013) Male Breast Cancer: Opportunities for Research and Clinical Trials. Breast Diseases: A Year Book Quarterly 24(3), 216-218] suggests that there is very little primary research on the male disease. There are no laboratory models, cell lines or other tools. Few if any grants supporting this kind of fundamental biology are in evidence, and aside from the inclusion of male breast cancer in the epidemiology of rare cancers it is hard to find any support for research from the National Cancer Institute or foundations. Given that the NCI alone spends $600M on breast cancer research, there is in my mind ample opportunity to dedicate some to this question. Perhaps 1% would be a good start?

On a similar note, men are only eligible for about 30% of breast cancer clinical trials found on clinicaltrials.gov, suggesting that access is a real issue. Of course in some instances our inclusion may not make sense, but I believe that in many instances inertia rather than a biological rationale underlies the exclusion of men. Both of these areas provide significant opportunities to learn more about the male disease and how best to deal with it clinically.

The Awareness Gap
Being a man with what is widely understood to be a women’s cancer leads to some dissonant experiences. To me these are mostly mildly funny, and not an issue – being asked how I get a mammogram for instance (the same way you do…), or filling out a form that asks me whether I am pregnant or when my last period was. Its fine – I get it. Mostly women here, and mostly the men in the waiting room aren’t wearing the medical arm band. But having breast cancer as a man is still (local) news worthy, and has modest shock value – that is surprising. The issue here is that a lack of awareness is probably a contributing factor to the delayed diagnosis in men and that means in some cases in their earlier death. It is certainly contributing to the underfunding of research and exclusion of men from trials. We need to change that.

A key challenge for men with breast cancer is the phenomenal success of the breast cancer awareness community. While the excesses of “pink” are unfortunately common these days, I do acknowledge the amazing work the community has done, and am deeply grateful for it. Alone the fact that we can have frank, open discourse about breast cancer, any cancer, is a tribute to the brave women who came out with their disease in the past 50 years. Then, the mobilization of public and private resources for awareness, screening and research is a tremendous accomplishment. And the US is a clear leader in this – a significant cultural accomplishment. But if this huge silver lining has a tiny, tiny black cloud it is that pink leaves almost no room for awareness about men. Breast cancer actually is not a sex-specific cancer like ovarian, uterine, testicular or prostate – it just appears to be. A great illustration of this phenomenon for me is the NFL players who in October don pink in support of women with breast cancer (hurray!) and completely fail to take the opportunity to also mention that they themselves could be diagnosed with this disease one day (booo!).

I want to close by being clear: I am not advocating for male breast cancer at the expense of other forms of breast cancer. Not at all. I want it to have its place with, and alongside. And in proportion – 1% would be a good start. Perhaps my concerns are not dissimilar from those of the inflammatory, triple negative or metastatic breast cancer communities: being outside the pink mainstream presents awareness challenges, which in turn make it harder to gain the resources needed to change the fate of many women and men with breast cancer.

 Dr. Oliver Bogler is a cancer researcher, male breast cancer patient, and male breast cancer advocate. His blog can be found at Entering a World of Pink.

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Clinical Trials

11 November 2013

One of the first things that might be discussed when you are looking at your cancer treatment options is whether or not there are clinical trials that you might qualify for. While many still view clinical trial participation as being a “guinea pig” in an experiment, it is important to understand that the clinical trial process is designed to protect patients. Any clinical trial needs to be overseen by an Institutional Review Board (IRB), an independent ethics and monitoring body dedicated to protecting human subjects from physical or psychological harm.

If it were not for clinical trials, we would still be performing radical mastectomies on all women with breast cancer – randomized studies have shown us that more aggressive surgery does not lead to improved outcomes. We are able to offer shorter courses of radiation therapy thanks to the data generated from large studies, and medications such as trastuzamab, previously used only in patients with advanced metastatic disease, are now considered first-line therapy in selected patients with early-stage cancer.

The post discussing clinical trials was written by Carmen Gonzalez, Communications Project Manager at Heath Services Advisory Group of California, Inc., and originally appeared on the #BCSM Community Website.

Clinical Trials 101 – Guest Post by Carmen Gonzalez
The world of clinical research can present a hornet’s nest of almost incomprehensible clinical jargon to the average Jane or Joe. Added to that reading burden is finding what study is right for you.  Assuming you have waded through all the public information, there remains the task of asking the right questions so that your experience is productive, worthwhile, and fits your life. In this blog, I will cover “just the basics,” arming you with the essentials to find what you need.

How to Find Them
If you are starting at square one, you probably don’t know how to find clinical studies. First, start by inquiring from trusted sources, including your doctor and other medical professionals with whom you’ve established trust.  If searching for breast cancer-related studies, visit disease-specific sites where patient-centered resources are available which feature clinical studies, e.g. The Susan Love Research Foundation’s Army of Women. Being the empowered patient that you are, expand your knowledge of available studies further by seeking out online clearinghouses, such as BreastCancerTrials.org, a non-profit dedicated to helping breast cancer patients connect with researchers. BreastCancerTrials.org compiles the trials from ClinicalTrials.gov. and Cancer.gov—comprehensive libraries of ongoing studies— into one hub, so it saves you two less searching chores. There’s an added benefit with BreastCancerTrials.org: they use your health history to guide you to the right trial, and they eliminate a lot of clinical jargon that can trip up novices to clinical research. While you can choose to see all the trials available, their screening tools make it easier to find what you need.

If you do decide to explore ClinicalTrials.gov directly to explore clinical studies, be forewarned: technical clinical language lies ahead. Search  trials by inserting general terms, such as “breast cancer,” “stage 2,” and “HER-positive.” To tame what could be a fire hose of responses, insert search terms that narrow your focus, such as the disease topic with your location and other distinctive traits, e.g. “Chicago” AND “breast cancer” AND “metastatic cancer.”

Here are a few rules of the road when considering different categories of studies.  Research trials are either observational or investigational, meaning only as to the latter are patients given a treatment. There are four basic types of investigational studies : Phase I, II, III, and IV studies.

—Phase I refers to studies which are being conducted for the first time in humans, having been successfully tested in animal models. Phase I studies are exploring the safety of the drug or device, and are typically involved with  small number of participants.
—Phase II studies involve a larger group of study volunteers to test if the drug or device is effective, commonly against a placebo. If a drug or device is successful in its phase I and II stages, then a significantly larger study group is involved in a Phase III study.
—Phase III studies help to determine if the drug or device is as good or better than the standard of care. During this phase, issues of safety are also closely watched. While success at the phase III stage poises the drug or device for likely market approval by the FDA, another phase is needed.
—Phase IV is imposed to see if late-breaking safety issues arise in the wider marketplace. What does this boil down to for you? The more phases the drug or device has passed successfully, the safer it  has proven to be. Foolproof? No. Remember Vioxx? That’s why Phase IV is so important.

What to Ask About
Whether you are healthy or sick, an appropriate clinical study has to fit into your life for it to be meaningful and worthwhile. That means that you need to have a full understanding of the study’s implications to your health and full knowledge of the obligations before you. Let’s consider these topics separately. First, dig into whether this study offers you significant personal benefit, and if it advances the science in the field. Start by asking how this study advances scientific knowledge and how it improves your prospects of recovering, improving, living longer, or in better managing your disease.
Ask the study team if the research offers a novel treatment, device, or delivery method.  Once you get answers to these questions, mull them over with your doctor if you’re unsure of its potential benefit to you.

Once the overarching considerations meet with your satisfaction, use the following checklist when asking the clinical study team about the study’s logistics:

  • Are there any anticipated side effects? What are they and their severity?
  • How long is my study obligation? (e.g. number of days, weeks, months, years)
  • How many visits in total will require my in-person presence at research clinic?
    • How many visits per week or month does this mean for me?
  • Are there additional visits to other specialists beside the research clinic? (e.g. imaging tests at a radiology lab)
    • How far away are these office from the research clinic?
  • What other study duties are required of me?
    • Is there a diary I have to keep?
    • Am I required to take study medications at home?
    • Is there a medical device I have to use?
    • Are there dietary or activity restrictions?
  • Are there any post-study activities required of me? (e.g. phone check-ins)
  • What is the stipend offered for my participation? Is my travel compensated?
  • When will the study officially end? When and where can I obtain the study’s results?

Once you inquire about what is involved, now ask about the likely impacts on your family. This is often overlooked and leads to unanticipated conflicts, so tackle them beforehand. While you can walk away from any study at any time, it will save you considerable time and frustration to find the right fit upfront. Consider asking the following:

  • Does the schedule conflict with family vacations or other commitments? Is there a way to accommodate these priorities? For example, if study visits are required at a time of day that is inconvenient, will the team consider other time slots or weekends?
  • Does the study impose obligations that conflict with your religion? Take the fasting periods of Ramadan for example, and some studies conducted during the summer might not work with your requirements.

Be realistic about where you are in your emotional life as well. If you are undergoing grieving for a marriage or loss of a loved one, you might not be ready to be a study volunteer. Acknowledge your own expectations and biases regarding the study and discuss those reservations and hopes with the study team. They can provide able counsel to help you determine if participation makes sense at this moment.

What To Expect
If you are placed in a control group—study volunteers who are not receiving the active study medication or device—then any positive response you experience will be attributed to what is called the “placebo effect.” You won’t know whether you were assigned to a placebo or “active” group, as that would defeat the scientific process. However, sustained dramatic improvement tends to suggest that patients were in the “active” group. For patients to gain answers to which groups they were in and the overall impact of the study, they must wait for the trial’s conclusion. In the U.S., study teams are required to post their results on ClinicalTrials.gov upon completion, but faithful adherence is spotty at best. To ensure you get the answers you need, aside from your personal outcome, request the results from the study team and create a tickler on your calendar to remind those in charge to keep you posted.

If during the course of the study, you experience unwanted side effects, immediately report your symptoms to the study team right away for intervention. Depending on the study, there are some minor  side effects that are anticipated, but in all cases, report your experience no matter what. For patients with multiple pre-existing medical conditions, there may be fewer studies for which they are eligible, but that rarely rules out everything.

In studies that span several months or years, the mere slogging pace of the study can impose a weariness commonly called “study fatigue”—not an ailment, but an acknowledgement of growing impatience. Be honest with yourself if you can endure a long-term study and the duties that come with it. While you can’t predict all the events that might upset your study schedule commitments, understanding and knowing how you manage everyday routines will give you a candid idea of your likely study visit consistency. Armed with these tips, you can make better decisions concerning study involvement.

PBS Need to Know: Dispelling the Myths Surrounding Cancer Trials

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Breast Cancer Overdiagnosis and Overtreatment

3 August 2013

What’s in a name? In the case of cancer, there are myths, fears, and misinformation – more than perhaps any other illness.

Cancer encompasses hundreds of different diseases and each one is complex. Even women diagnosed with exactly the same “type” of breast cancer and who undergo the same treatment can have very different outcomes. Not all cancers are equal and not all cancers are lethal.

While early detection and treatment were once equated with improved survival, we now know that tumor biology (characteristics governing the behavior of spread and response to treatment) plays an extremely important role in the prognosis of an individual cancer. There is an increasing recognition that current screening tests, meant to diagnose cancer in the earliest stages, will often diagnose lesions that have minimal potential to become aggressive or lethal. As our screening technology improves, we are detecting more patients in early stages or with pre-cancerous conditions and we are treating those patients with surgery and other potentially toxic therapies.

In 2012, the National Cancer Institute convened a working group to “evaluate the problem of ‘overdiagnosis’ which occurs when tumors are detected that, if left unattended, would not become clinically apparent or cause death.” Unrecognized overdiagnosis, they stated, “generally leads to overtreatment”1.

The recommendations of this panel were recently published in the Journal of the American Medical Association: Overdiagnosis and Overtreatment in Cancer, An Opportunity for Improvement.  The authors provide five recommendations:
1. Physicians and patients alike need to acknowledge that screening results in overdiagnosis – especially in breast, lung, prostate and thyroid tumors.
2.  The term ‘cancer’ should be reserved for describing lesions with a reasonable likelihood of lethal progression if left untreated.
3.  Create observational registries for low malignant potential lesions in order to better understand prognosis and best treatment options.
4. Mitigate overdiagnosis with an ultimate goal of preferential detection of consequential cancer while avoiding detection of inconsequential disease.
5. Expand the concept of how to approach cancer progression by controlling the environment in which cancerous conditions arise.

While these are certainly laudable goals, some important points should be made, especially in regards to breast cancer and ductal carcinoma in-situ – the most important being that we do not currently have biomarkers or other indicators that can clearly distinguish a potentially lethal cancer from a more indolent one. The field of cancer genomics is rapidly changing, and today more than ever, we can obtain very sophisticated prognostic information regarding an individual’s tumor. Despite that, Dr. Larry Norton, medical director of the Evelyn H. Lauder Breast Center at Memorial Sloan Kettering Cancer Center, stated “Which cases of DCIS will turn into an aggressive cancer and which one’s won’t? I wish I knew that. We don’t have very accurate ways of looking at tissue and looking at tumors under the microscope and knowing with great certainty that it is a slow-growing cancer”2.

Regarding the modern management of DCIS, there are three points to remember:
1. When DCIS lesions diagnosed by needle core biopsy are surgically removed (which involves removal of substantially more tissue from the abnormal area), there is an approximately 15% rate of ‘upstaging’ to invasive ductal cancer 3. Put another way, one cannot always reliably predict the behavior of an entire lesion based on a core biopsy specimen.
2. During surgery for DCIS, axillary lymph node metastases have been demonstrated up to 20% of the time, usually indicating missed microinvasion or invasion 4.
3. Finally, if DCIS recurs, 50% of the time it is invasive 5.

What is important to be aware of is that any woman with breast disease, including DCIS, should be presented with the information necessary so that she may gain an understanding of where her diagnosis stands in the biological spectrum and the wide array of choices she has for treatment. DCIS is far from simple, and it is not to be taken lightly. Clearly there are cases where ‘watchful waiting’ is safe – but we cannot always reliably predict who will truly benefit from treatment. Moving forward, we need to be aware of the facts – what medical technology can provide the patient and the physician now, and we need to ask how we can drive this conversation in the future.

Deanna J. Attai, MD, FACS
Michael S. Cowher, MD

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