Neoadjuvant Therapy for Breast Cancer:
Dr. Elizabeth Mittendorf started the session with an overview of neoadjuvant therapy. Neoadjuvant therapy refers to treatment prior to surgery. While traditionally this has been reserved for patients who have inflammatory breast cancer, inoperable breast cancer (invading muscle, skin ulceration, or very bulky disease) or for those who want to try to shrink the tumor to avoid mastectomy, neoadjuvant chemotherapy and endocrine (tamoxifen or aromatase inhibitor) therapy is becoming more common for several reasons. There is no difference in local recurrence rates or overall survival in patients who undergo neoadjuvant therapy, and studies have shown that the mastectomy rate can be decreased by approximately 20% in patients undergoing neoadjuvant chemotherapy and by approximately 50% in patients undergoing neoadjuvant endocrine therapy. Neoadjuvant therapy can also provide prognostic information – patients who experience a complete pathologic response (pCR – finding no invasive cancer in the breast or axilla at the time of surgery) have an improved event-free and overall survival compared to those with residual disease. The outcomes do vary with response to tumor subtype – the improved outcomes are greater in patients with triple negative (TN) or Her2+ disease versus those with ER+/Her2- breast cancer. A small study showed that patients with Her2+ breast cancer who obtain a pCR may do well with 6 months compared to one year of herceptin – more trials are required to fully answer this question. Ongoing trials are also evaluating immunotherapy in the subset of patients with Her2+ breast cancer who have residual cancer after neoadjuvant therapy. Patients with TN breast cancer who obtain a pCR have a good prognosis, but the ongoing challenge is the cancers that do not respond to chemotherapy. Dr. Mittendorf described a trial looking at this – patients with TN breast cancer first receive standard chemotherapy. Those who do not demonstrate tumor response will then be randomized to a Phase 2 Clinical Trial based on molecular profiling of the tumor – this reflects a growing trend of focusing on the biology of the individual tumor.
Dr. Marilyn Leitch discussed neoadjuvant endocrine therapy for patients with estrogen receptor positive (ER+) breast cancer. The majority (~80%) of breast cancers are ER+, and it’s important to avoid overtreating patients – neoadjuvant endocrine therapy can help select patients who do not need chemotherapy. Neoadjuvant endocrine therapy can also provide insight into those who are or may become resistant to endocrine therapy. While patients receiving neoadjuvant endocrine therapy often do not demonstrate a pCR, they do usually experience good outcomes with tumor response to treatment. When the tumor responds to therapy, there is a higher rate of successful breast conserving surgery.
Dr. Jennie Chang discussed tumor heterogeneity – the concept that a single cancer mass is more than one cell type – there can be multiple cell clones within a given tumor. This topic was also covered at the Miami Breast Cancer Conference in February 2015. Dr. Chang noted that the different cell clones that make up a tumor will respond differently to treatment, and that cell clones develop mutations and evolve over time, often in response to treatment and the tumor microenvironment. Different cell clones within a tumor might also have different patterns of metastatic spread. Triple negative breast cancer is at least 5 cancers, and each subset may respond differently to different chemotherapy regimens. Dr. Chang covered some newer clinical trials for TN breast cancer including platinum-based chemotherapy (carboplatin or cisplatin) but she cautioned against using these agents for all TN breast cancers, noting that due to tumor heterogeneity, biomarkers of tumor sensitivity need to be identified so that we can more appropriately use these agents for the tumors most likely to respond. She reviewed some of her research identifying the cancer stem cells most likely to be resistant to therapy, finding the genes most responsible, and “silencing” those genes. This research is being performed in mice, but is very promising.
Dr. Henry Kuerer discussed surgical decision making in response to neoadjuvant therapy response. Currently, we recommend the same surgical therapy in patients with a tumor pCR compared to those with residual disease. Noting that there are “exceptional responders” – tumors that seem to completely melt away in response to preoperative therapy – he noted that this may be the time to re-think our surgical approach, and called for surgical oncologists to “step up”. He noted that we may be able to limit the extent of surgery or avoid surgery altogether in selected patients. An area of much interest to both patients and surgeons!
Quality of Life:
Dr. Jennifer Gass (@jengass) presented her research: Sexual function in breast cancer survivors: what does surgery have to do with it? She noted that with contralateral prophylactic mastectomy (CPM – removal of the unaffected breast at the time of breast cancer surgery), there is a 2.7-fold increase in major surgical complications compared to unilateral (one-side) mastectomy, including additional unplanned surgery and a 5-10% of nipple necrosis (for nipple-sparing mastectomy). Studies have demonstrated that as a result of breast cancer treatment, women may experience decreased sexual interest and arousal, difficulty achieving orgasm or sexual pleasure, and numbness in previously sensitive breasts. In her survey, she noted that there was a significant decrease in the role a woman’s breast plays in intimacy after breast cancer surgery, regardless of whether that surgery is lumpectomy or mastectomy – the rates were about the same. There was a statistically significant decrease in how pleasurable breast stimulation was in mastectomy compared to lumpectomy patients. Women being treated with lumpectomy had a higher rate of satisfaction with the appearance of their breasts after lumpectomy compared to mastectomy and reconstruction; satisfaction with the breast appearance was shown to have the greatest impact on sexual function after breast cancer surgery. She noted that a greater understanding of the role a woman’s breast plays in sexual function and intimacy should help surgeons discuss options and treatment effects before surgical intervention.
Dr. Sarah McLaughlin presented her research: Peace of mind after contralateral prophylactic mastectomy: does it really happen? She noted that the increase in CPM has occurred in spite of the fact that CPM does not improve survival rates and is associated with an increase in the rate of complications. Studies show that patients cite risk reduction, desire for symmetry, and peace of mind as factors influencing their decision. Using a validated survey, she and her colleagues assessed baseline and follow up worry and fear of recurrence in breast cancer patients, and looked at whether or not CPM resulted in less worry than lumpectomy or unilateral (one-side) mastectomy. 305 women were evaluated and followed for a median of 13 years. Those women undergoing CPM were younger, but there was no difference based on tumor type or lymph node status / stage. There was also no difference in recommendations for chemotherapy, hormonal therapy or radiation. At baseline, 50% of patients had clinically significant worry at baseline – only younger patient age (<62) was associated with significant worry. Factors predicting worry at follow up were younger age (<62), larger tumor size, triple negative breast cancer, and recommendation for chemotherapy. She found that CPM did not significantly decrease worry in those patients who underwent the surgery. So while patients may choose CPM for peace of mind, the number of patients experiencing clinically significant worry is reduced from 50% at baseline to 33% after surgery, regardless of the type of surgery performed. She called for interventions prior to surgery to address cancer worry and assist in surgical decision making, as well as more research to develop targeted intervention strategies.
Personalized Therapy for Early Stage Breast Cancer:
Dr. Laura Esserman (@DrLauraEsserman) spoke on predicting cancer behavior with imaging studies and biomarkers. She noted that screening and prevention efforts are still being applied as if cancer is one disease. Our knowledge of breast cancer has evolved over time, recognizing that breast cancer is in fact multiple diseases – our screening and clinical trial approach needs to evolve as well. Improvements in every specialty have been made by tailoring treatment and limiting toxicity. She suggested that screening and treatment will not benefit all breast cancers – she describes the “ultra low (risk)” breast cancers – those that may not need to be detected or treated at all. And in her usual animated way, she stated “My goodness people – let’s make some change!”. She noted that we need data to keep doing what we are doing – what is the failure to adopt (early) the results of clinical trials? [it’s called being stuck in a rut]. We need to do a better job identifying who will actually benefit from surgery, chemotherapy and radiation. Success will depend on collaborative research. Tumor biomarkers can be used to identify lesions of extremely low metastatic potential. When we get to that point, we will be able to do a better job at treating the patients who truly need it, and avoiding toxicity in patients with “ultra-low” risk of disease progression.
Dr. Shelly Hwang spoke about the “less is more” approach to surgery, a topic also covered in great detail at the Miami Breast Cancer Conference. Aggressive surgery does not make up for aggressive tumor biology. Especially in patients who are at higher risk for metastatic disease compared to local recurrence, avoidance of more aggressive surgery (which is associated with a higher complication rate) is recommended. In addition, less surgery may be more than adequate for low-risk disease; she described an ongoing ALLIANCE clinical trial evaluating aromatase inhibitors prior to surgery in patients with DCIS – studies such as these may help us sort out which patients may be candidates for active surveillance alone.
Dr. Debu Tripathy discussed personalized therapy from the medical oncology perspective. One large problem is that many clinical trials were not designed to evaluate long-term side effects of treatment. He posed the question “What is the long-term incidence of neuropathy after taxane therapy?”. His answer – we don’t know – we never studied it. He commented that shared decision-making should be based on individualized absolute benefits balanced with risks.
A highlight of the meeting was the “Great Debate” session. Drs. Laura Esserman and Monica Morrow debated the use of breast MRI in the preoperative evaluation of breast cancer. Dr. Esserman pointed out that MRI has high sensitivity, but lower specificity. It provides excellent 3D detail, but it only incrementally increases the cancer detection rate, does not improve outcomes and should not be used for screening or routine preoperative staging. [note – this session was discussing the routine use of MRI for preoperative patients, assuming otherwise “average” risk – not BRCA patients]
However, she focused on 3 situations where preoperative MRI is beneficial – invasive lobular cancer, evaluating the response to neoadjuvant chemotherapy, and in “occult primary” cases – breast cancer that presents as metastatic disease in the axilla without an obvious lesion in the breast. She specifically recommended against using it in postoperative cancer surveillance. Her closing comment: “use your technology wisely” – tailor the use to where it adds the most value, and support clinical trials assessing the role of MRI.
As expected, Dr. Morrow had a spirited response. She noted that occult breast cancer accounts for <1% of all breast cancers, and that neoadjuvant therapy is used for only 3.8% of breast cancers – she stated that if you want to use MRI for these patients who account for 5% of all breast cancers, “I have no problem with that”. She then went on to discuss why she feels that MRI should not be performed for the remaining 95% of breast cancer patients. “The purpose of any test is to improve outcomes”, yet MRI does not improve survival, local failure (recurrence in the breast), contralateral (opposite side) cancer or surgical outcomes.”MRI is finding and treating stuff that would never become clinically evident”. Countering the point that MRI is useful in finding contralateral (opposite breast) cancers, she noted that the studies have demonstrated that the rate of contralateral breast cancer identified by MRI is approximately 1-2% – “In this era of constrained healthcare costs, is this really where we want to be spending our money?”. She noted that her research demonstrated that having a preoperative MRI triples your likelihood of undergoing a mastectomy, whether needed or not. She also noted that in their subset analysis, there was no benefit for patients with invasive lobular cancer, but there again, more mastectomies were performed. She closed by stating “The belief that MRI should improve surgical outcomes does not make it a clinical reality”.
During the Q&A and answer session, Dr. Esserman noted that the fact that only about 4% of patients receive neoadjuvant therapy represents an area where improvement is needed – she feels it should be closer to 25% of patients. The point was made by Dr. Morrow that while many are aware of the lack of evidence, the use of MRI continues to increase.
Another great debate session addressed overtreatment of DCIS, and surgical margins. Drs. Murray Brennan and Terry Mamounas debated DCIS treatment – Dr. Brennan gave a very entertaining discussion on how many cases of DCIS do not require treatment and could have easily “won” that debate based on his presentation style alone. There is no question that some (many?) cases of at least low-grade DCIS do not progress – as Dr. Esserman stated earlier, we need more research into biomarkers and other means of sorting out which patients require treatment.
Drs. Lee Wilke and Dr. Alastair Thompson debated surgical margins – a topic that was also covered in detail at the Miami Breast Cancer Conference. As we’ve heard over and over again – more surgery does not lead to better outcomes or make up for bad tumor biology. Dr. Wilke (taking the side of smaller margins) clearly “won” this debate.
I was privileged to be part of a panel discussion on genetic testing with Drs. David Euhus, James Howe, Kevin Hughes, and Mark Robson, and genetic counselor Sara Pirzadeh-Miller. Dr. Hughes spoke on when to perform genetic testing and for what diseases. He stated that it is important to think of every patient, not just those newly diagnosed, as potentially needing genetic testing, and whether or not they need testing for a disease other than what you are seeing them for. It is best to identify patients prior to the development of disease, but the vast majority of patients are unidentified. It is estimated that there are approximately 220,000 unaffected (no cancer) BRCA mutation carriers in the US of which only 5-6% have been identified, and approximately 35,000 breast cancer patients who carry BRCA mutations, of which only about 30% have been identified. There are a large number of patients who are not receiving appropriate counseling, surveillance, and treatment. He quoted Mary-Claire King “To identify a woman only after she develops cancer is a failure of cancer prevention”.
The majority of tumor genes are tumor suppressor genes. Knudson’s “2 Hit” hypothesis explains how cancers develop. In sporadic cancer cases, patient is born with 2 normal genes, develops a mutation in one, then another, and then develops cancer – these cancers tend to occur later in life. In hereditary cancer, a person is born with a mutation in one of the genes. If the other gene develops a mutation, cancer develops; these cancers develop early in life, often and in multiple organs. But if a 2nd gene mutation does not develop, that patient may never develop cancer. It is critical for physicians to take a 3-generation family history, to help determine who may require testing. Questions to ask: are multiple relatives affected with the cancers seen in a specific syndrome, is the cancer diagnosed at a young age, are multiple cancers seen in one person, have other relatives been tested, and are unusual cancers present? Race/ethnicity is also important – BRCA mutations are much more prevalent in the Ashkenazi Jewish population, although these mutations have been described in every race and ethnicity.
Dr. Mark Robson (@MarkRobsonMD) discussed variants of uncertain significance (VUS) and less common genetic mutations. BRCA 1/2 are relatively rare mutations in the population but confer a high risk of cancer. Some of the rare syndromes include Cowden’s Syndrome (PTEN mutation – macrocephaly [large head], lesions of the tongue and skin, autism, and breast cancer); Peutz-Jegher’s Syndrome (STK11/LKB1 – multiple polyps, breast/pancreatic cancers, subtype of ovarian cancer); Li-Fraumeni Syndrome (TP53 – early onset breast cancer, sarcoma, brain tumors, possible leukemias, childhood adrenal cancer); Hereditary Diffuse Gastric Cancer (CDH1 – early onset gastric cancer, early onset lobular breast cancer). In patients that have a family history of one of these cancer syndromes but test negative for that mutation (“true negative”, their cancer risk is about that of the average population.
Panel testing has become more common – we have the ability now with a single sample to obtain information on many genetic abnormalities. However, only a small percentage of the genetic abnormalities identified convey an increased risk of cancer development, and many may not even specifically relate to breast cancer. Finding a mutation in a moderate penetrance gene raises clinical questions – do you need to take action or not? In addition, almost 40% of patients in one series had variants of uncertain significance – a gene abnormality that may or may not convey an increased risk. We need to make sure that the detection of a VUS does not trigger inappropriate action (such as prophylactic surgery when the patient will not benefit from it). He acknowledged the complexity of testing and how difficult it is for patients (and clinicians) to sort it all out. He noted that we have a “massive” educational effort ahead of us. He also discussed the PROMPT Study – a Prospective Registry of Multiplex Testing – a collaborative effort to evaluate the variants of uncertain significance.
I was thrilled to finally meet Dr. Niraj Gusani (@NirajGusani) – we’ve collaborated on twitter but it was wonderful to finally meet in person. He gave a talk on the role of social media in continuous professional development. It was fantastic to see this topic on the agenda of an academic meeting. He pointed out how social media can help physicians keep up with the literature, conferences, and best practices. He described his involvement in a twitter journal club (@IGSJC), and how social media can be used to predict the impact of scientific articles as well playing a role in research and peer review. He explained how meeting tweeting can be invaluable for sharing information and interacting with colleagues as well as all who are interested in the meeting content. He also gave a shout-out to #BCSM as well as other patient-physician communities such as #PancSM.
Dr. Guasani, Dr. Cowher and I also presented our poster, detailing the twitter activity from the 2014 Society of Surgical Oncology and American Society of Breast Surgeons meetings.
Dr. Cowher and I had the opportunity to present our #BCSM poster, demonstrating that participation in an online support group leads to increased education and decreased anxiety.
And of course, we had to get a picture with Dr. Dana Abraham (@Dr_Dana).
Cost and Value
One of the highlights of the SSO 2015 program for me was an afternoon panel session that dedicated 1.5 hours to “Issues of Cost and Value in Surgical Oncology Care” moderated by Dr. Timothy Eberlein. When I saw this topic on the schedule I was intrigued as I could not remember seeing a similar topic at any other national meeting I had been to. Also, it is a particularly difficult subject to discuss with individual cancer patients for whom “no expense should be spared” is the paradigm that both clinicians and patients wish we could function under – but we realize we can’t. Also, issues of cost and quality are frequently politicized, and accusations of rationing and terms like ‘death panels’ get injected into the conversation. That being said, I know that more cost effective care could lead to more available research funds to advance medical knowledge, and fewer patients would find themselves in debt after receiving treatment.
Unlike other medical meeting sessions I’ve attended, I was pleased to see that patient needs and wishes were included in the beginning of the conversation, where speakers reminded us that patients say “don’t hurt me, cure me, see me quickly, and don’t bankrupt me.” We were reminded that the financial toxicity of cancer treatment may persist long after treatment: a 2005-2007 study showed that 33% of breast cancer patients reported a decline in financial status at 4 years after their treatment, and similar data was presented for patients with colorectal cancer. Dr. Richie Ehlers (@richieehlers) noted when dealing with the financial toxicity from cancer treatment, “affluent patients go bankrupt and poorer ones avoid some treatments.” One of the surgeon panelists noted that “I cringe when patients ask why my surgery will cost… because I have no idea.” I was not the only one in the audience who murmured agreement.
Dr. Rachel Greenup, a breast surgeon from Duke, presented “locoregional treatment costs of early-stage breast cancer.” She reminded us that breast cancer treatment costs are among the highest of all cancer types, beginning with screening: 50 million screening mammograms cost $7.8 billion in 2010, which was twice the cost of the NIH budget. Once diagnosed with early stage breast cancer, 20% of patients undergo staging studies like PET or CT scans, and only 20% of these (4% overall) are done appropriately per nationally “accepted” guidelines. She reminded us that “value is more important than absolute costs, and… there are lots of opportunities in early stage breast cancer to practice evidence based medicine and reduce costs.
Lastly, the speakers addressed more national issues of cancer treatment costs. Dr. Sandra Wong (@sandralwong) presented “Cost and Value from the Payer and Policy Maker Perspective.” She reminded us that surgeons were largely left out of the Accountable Care Act drafting leadership, and that given the changes in payment models surgeons may change from being revenue generators for hospitals to cost center liabilities as our procedures take a large part of a the global disease based payment. We were reminded, however, that the current rate of growth in health care costs is unsustainable – by the year 2050, 100% of US GDP will be for health care! Dr. Eberlein concluded that “it is the responsibility of the Society of Surgical Oncology to fight for access to the ‘grey’ patient treatment decisions.”
At the end, a large portion of time was allotted for audience questions. While many were unanswerable, it was a great example of group conversation at a medical meeting. I’ll list a few of the best questions and comments here: “We talk about 80% futility in treatments, but how can you deny a patient a (expensive) therapy when one in five does great?” “What is a reasonable cost for a drug that extends life 6 months?” A visiting physician from the Netherlands reminded us that under socialized medicine “no one becomes bankrupt by cancer.” Another noted that “we are talking about health care costs only now because the spigot has been turned off.” Finally, the big question was asked “How many of you would be willing to accept a 50%, 75% reduction in your personal income to reduce the costs of health care?” Needless to say, it was a powerful 15 minutes to end the afternoon session. While I’m not sure any new solutions were conceived for the cancer cost issue, I’m sure that conversations like this, by professionals ‘in the trenches’ of modern health care, are where they will originate.
Another highlight of the 2015 SSO meeting was the American Cancer Society / SSO Basic Science Lecture “Clinical Implications of Cancer Stem Cells” by Dr. Max Wicha of the University of Michigan Comprehensive Cancer Center. He began by reminding us of the progress we have made with targeted cancer therapy in HER2 positive disease, saying “when I woman has HER2+ breast cancer, I used to think it was bad news… Now I tell her it’s good news.” While I’ve been happy to avoid most basic science since medical school, the update on stem cell carcinogenesis was fascinating. Stem cells are cells that can differentiate into other types of cells as they divide. I learned that there are three basic types of stem cells – embryonic, adult, and cancer. Recent evidence suggests that most breast cancers, regardless of subtype, comes from a particular cancer stem cell. These cancer stem cells will be the future target of therapies. I also learned that cancer cells can communicate with each other! Interleukin-8, a chemokine released by dying cancer cells, actually stimulates cancer stem cells to produce more cancer cells, and this may be a future pathway to target with therapeutic agents. I think Dr. Richie Ehlers summarized my impression well with his tweet “humbling talk on cancer stem cells by Dr. Wicha. Cancers are so smart. Glad we have scientists who are smarter.”