By Deanna J. Attai MD and Julie R. Gralow MD
The Breast Cancer Symposium is a multi-disciplinary breast cancer conference, co-sponsored by the American Society of Clinical Oncology, The American Society of Breast Surgeons, the Society of Surgical Oncology, and The American Society of Radiation Oncology. It is a unique meeting as representatives from surgery, medial oncology and radiation oncology share the stage to discuss the multidisciplinary treatment of breast cancer. It was a jam-packed 2 1/2 days! For those interested, the twitter transcript can be found here.
The #BCSM Crew was also well represented:
— Beth Thompson (@BreastCaUnder45) September 27, 2015
Many interesting abstracts and posters were presented. There were many excellent sessions, and it’s not possible to cover all of them here. A few that stood out:
State of The Art Breast Cancer Care – Past, Present and Future This was the opening session and a great way to kick off the meeting. Drs. Eleftherious Mamounas (surgery), Timothy Whelan (radiation oncology) and Eric Winer (medical oncology) covered our past, present and future. Dr. Mamounas started by discussing the Halsted theory of cancer spread. This proposed that breast cancer followed an orderly progression from the breast to the lymph nodes to other areas of the body, and was the rational for the Halsted radical mastectomy – the thought was that if local recurrence could be prevented by extensive surgical resection, metastatic disease could also be prevented. Bernard Fisher’s theory was that some breast cancers have metastatic potential from the start so that while local therapy (surgery and radiation) are important, they do not reduce the risk of metastatic disease. The Fisher theory formed the basis for the NSABP B04 and B06 trials which confirmed that more aggressive surgical treatment does not impact long term survival. We now have 30 years of follow up on those landmark trials.
Dr. Mamounas described the history of the sentinel lymph node biopsy, initially proposed during the 1980’s. The sentinel node biopsy mapping procedure identifies the first few lymph nodes that drain the breast, which are the ones where cancer is most likely to spread. Removing just those few nodes results in a much lower complication rate compared to full axillary dissection. There is no survival benefit or significant reduction in axillary recurrence rates from more aggressive axillary surgery. He made an important point – we are entering the era of loco-regional treatment individualization. This does not necessarily mean we are doing less – we are doing more or less, depending on the individual case. He discussed some of the new surgical developments such as the use of nipple sparing mastectomy, and improved definition of appropriate surgical margins for invasive breast cancer. He also discussed the increasing rates of contralateral prophylactic mastectomy rates in non-BRCA gene mutation carriers, noting that there are many factors involved.
Some areas of active research, sure to impact our treatment in the future: 1.) Surgical planning in the era of neoadjuvant (before surgery) chemotherapy , 2.) Omitting surgery in selected patients that have a complete response after neoadjuvant chemotherapy, 3.) Expanding the use of sentinel node biopsy alone in cases of positive sentinel nodes. Can we omit axillary staging in some patients?, 4.) Axillary radiation therapy instead of surgery, 5.) Defining appropriate surgical margins for DCIS, 6.) Technology for margin assessment
Dr. Timothy Whelan discussed radiation therapy for breast cancer, noting that post-lumpectomy radiation therapy results in a reduction of local recurrence. The benefit is seen primarily during the first 5 years. When patients followed longer term, radiation therapy after lumpectomy is associated with a survival benefit. The also discussed newer “hypofractionation” protocols, where the external beam radiation therapy is given over a shorter period of time. The studies show that this is effective in terms of local control and is not associated with an increase in adverse events. He discussed partial breast irradiation and intraoperative radiation. It is important to note that these newer forms of radiation therapy do not have long periods of follow up, but may be very reasonable to consider in certain cases.
He discussed how in the future, the concept of precision medicine would be applied to radiation therapy including: 1.) Avoiding radiation therapy in low risk patients, 2.) Tailoring of radiation therapy approaches such as hypofraction, 3D conformal and partial breast radiation techniques, 3.) Increasing use of tumor biomarkers to determine which patients will benefit from radiation therapy – the goal is to eliminate treatment in those who do not need it, 4.) Stereotactic ablative body radiotherapy for metastatic lesions
Dr. Eric Winer discussed advances from the medical oncology perspective. He started out by discussing how in 1989 (chosen as it was the year he finished his fellowship) treatment of breast cancer was a much “simpler”. We didn’t have information on tumor subtypes, there were about 6 chemotherapy agents, there were a few hormonal agents, there was no non-hormonal targeted therapy, and costs of treatment were not considered. He discussed how Dr. Gianni Bonadonna’s pioneering work demonstrated that chemotherapy (CMF – cyclophosphamide, methotrexate and flourouracil) administered after surgery led to improved survival rates. An NCI alert was issued informing physicians of the potential benefit of chemotherapy in patients with node-negative disease. In the 1990’s, things began to change with the use of anthracycles and taxanes. In 2000, an NIH consensus conference statement noted that due to the potential benefit, chemotherapy should be given to women with tumors greater than 1cm regardless of lymph node, menopausal, or hormone receptor status.
Regarding hormonal therapy, aromatase inhibitors were approved in the early 1990’s initially for metastatic disease and then for adjuvant therapy. Other hormonal agents have subsequently been developed. According to Dr. Winer, the real change came when we stopped regarding breast cancer as one disease.
A study published in 2001 by Sorlie et al noted that based on RNA expression, there were several different intrinsic breast cancer subtypes, and subtype correlated with outcome. Breast cancer then began to be viewed as a “family” of diseases. It still remains unclear how many families there are, but at minimum: 1.) Her2 positive, 2.) “Basal Like” triple negative, 3.) ER+ low grade “Luminal A”, 4.) ER+ high grade “Luminal B”.
He discussed that probably one of the greatest advances was in Her2 positive disease, in terms of understanding the biology and developing targeted therapies. Trastuzumab (Herceptin) administered in the adjuvant setting now has over 10 years of followup showing improvement in overall and disease free survival for patients with Her2 positive breast cancer. ER+ / Her2- breast cancer represents approximately 70% of all cases. We’ve learned that chemotherapy is effective in reducing recurrence during the first 5 years, but late recurrences remain a huge problem. Extended therapy with tamoxifen or aromatase inhibitors is beneficial, and multiple genomic predictors of recurrence and chemotherapy benefit have been developed. Newer agents are being developed for ER+ patients who develop metastatic disease.
Triple negative breast cancer remains a challenge. The most exciting finding in his opinion notes that in patients with metastatic disease who are BRCA mutation carriers, carboplatin therapy was superior to other treatments. He feels much of the focus needs to on understanding the multiple triple negative breast cancer subtypes.
He noted that breast cancer mortality is slowly declining, as well as successive improvements in outcomes in patients with metastatic disease. However, there remain many challenges: 1.) 40,000 women in the U.S. and over 100,000 women worldwide who die due to metastatic breast cancer, 2.) Drug resistance is a major problem, 3.) Many patients continue to be over-treated causing unnecessary toxicity, 4.) It’s not all about the tumor – the host matters (obesity, lifestyle factors), 5.) Disparities in access to care and outcomes remain challenging, 6.) Much hope in the genomic era but requires complex and costly trials, 7.) Cost of care remains a large obstacle to progress He concluded by stating that we need “real commitment, a large budget, and (ultimately) social change if we are to eliminate death from breast cancer and minimize treatment induced toxicity – sobering but surmountable”. ~DJA
Drs. Ben Smith and Shelly Hwang debated whether or not DCIS should be considered “cancer”. They both acknowledged the various controversies, and while they did not settle the issue, they held a very entertaining and spirited debate. They had different perspectives, both relating the development of invasive cancer to a crime. From Dr. Smith:
And from Dr. Hwang:
Clearly, the jury is still out on this! ~DJA
Another session covered Clinical Trials. The session was moderated by Drs. Norman Wolmark and Kelly Hunt, and speakers included Drs. Carol Lee, Judy Boughey, Debu Tripathy, and Lori Goldstein. They covered ongoing clinical trials involving imaging, surgery, and systemic therapy for early-stage and metastatic disease. 2 important comments during this session:
There was also information about the first ASCO clinical trial, and more detail was provided by Dr. Robert Miller:
The Quality of Life / Survivorship session was excellent (I might be a little biased because I participated!). It was co-chaired by Mary-Lou Smith, a breast and ovarian cancer survivor, and featured 2 patients on the panel: Alicia Staley discussing online communities for cancer support, and Shirley Mertz who is president of the Metastatic Breast Cancer Network. Before the panel started there was the obligatory selfie:
Dr. Ann Partridge then started the session discussing fertility issues and early menopause in breast cancer patients. She noted that the prospect of infertility is often cited by young women as the most difficult aspect of their treatment, and she noted a study in which 29% of women under the age of 40 cited fertility and premature menopause concerns as having an influence on their treatment decisions. Surveys of cancer survivors note increased emotional distress among those who become infertile during treatment and long-term quality of life is affected by unresolved grief and depression. She also advised physicians not to assume that our patients are done having children. The risk of amenorrhea is related to increasing age as well as the type of treatment. She noted that tamoxifen does not necessarily cause infertility, but as women may be on it for several years, fertility naturally declines with age. It’s important to realize that chemotherapy-related amenorrhea may not be associated with infertility – a young woman may not be having menstrual periods but may still be fertile.
ASCO recommendations include assessment of risk of infertility and discussion regarding the patient’s preferences, followed by referral to a specialist if fertility preservation is desired. She noted that oocyte (egg) cryopreservation [freezing] is no longer considered experimental, important for women who do not have a current partner. Regarding pregnancy after breast cancer, she noted that historically we have recommended waiting until after the period of increased risk for recurrence (2-3+ years), but there is no data to suggest harms from pregnancy earlier in terms of increased risk of recurrence. She concluded by noting that taking into account patient preferences and managing expectations is critical. Physical and emotional side effects of premature menopause need to be addressed and she called for continued support of research in this area.
Alicia Staley then spoke on the role of a online support as a cancer survivor.
She noted how during treatment, she never really found a support group that was helpful – the group you were “assigned” to depended where and when you were treated, noting when she was undergoing treatment for Hodgkins lymphoma, she was the youngest in the support group by a good 50 years. While recovering from her bilateral mastectomy, she discovered Twitter, and found a whole community of patients talking about various aspects of their cancer. She co-founded the breast cancer support community known as #BCSM, and started weekly chats covering a wide variety of topics. She tried to pull the number of impressions since the first chat in 2011, but the Symplur servers wouldn’t support that! There have been at least 500,000 #BCSM tweets (not impressions!) since July 2011. She noted that “BCSM is great, but do we make a difference?”, and the answer was “YES!”, citing the study published in the Journal of Medical Internet Research showing that participation in the #BCSM chats improved education and decreased anxiety.
Next in the session was Dr. Michelle Fingeret, who discussed body image. She noted that body image is not just about physical appearance, body image is inherently subjective, and body image changes over time. There is often a disconnect between patients and their physicians regarding body image, and a negative body image is associated with many adverse psychosocial outcomes. She provided examples of ways to change the conversation with patients to ensure that we are adequately addressing their concerns, and advised not to provide premature reassurances or cheerleading – “take a moment” to connect with your patients. She also advised physicians to maintain relationships with mental health professionals who are important members of the treatment team, as well as compiling resources such as support groups, educational materials, and products and services that may enhance a patient’s body image.
Dr. Shari Goldfarb covered sexual function in breast cancer patients. Approximately 76% of women report some type of overall sexual dysfunction after undergoing treatment. Patients cited chemotherapy, anxiety, effects of surgery, hormonal therapy, and changes in relationship with their partner as factors that contribute to worsening sexual function. Vaginal dryness is a common problem, and she detailed the different lubricants and vaginal moisturizers. She also noted the important role of counseling, sexual therapy and pelvic floor therapy. Intravaginal estrogens are the most effective therapy for vaginal dryness and atrophy, but their use is controversial in women with breast cancer. 17 beta estradiol vaginal tablets result in the lowest amount of absorption, followed by the estadiol vaginal ring. A small study she participated in noted improvement in sexual function in patients using a vaginal estrogen tablet with low systemic absorption, but called for more study. A new medication, filbansterin, is approved for decreased libido, and other drugs are under development.
Dr. Partridge spoke on long term issues for metastatic breast cancer patients from the physician perspective, filling in for Dr. Sharon Giordano. She noted that approximately 40,000 women in the US die every year from metastatic breast cancer, and it is estimated that 150,000-200,000 women in the US are living with metastatic breast cancer, While there are a growing number of long-term metastatic breast cancer patients , the majority will experience progression and the goals of treatment need to include prolonging survival and improving quality of life. She noted that especially in terms of balancing survival and quality of life, physicians don’t do a good enough job at eliciting patient preferences. There needs to be constant communication regarding preferences and goals of care.
Shirley Mertz, President of the Metastatic Breast Cancer Network, gave an excellent talk on metastatic breast cancer from the patient perspective. She noted that she underwent a bilateral mastectomy for early stage breast disease “because I wanted to beat cancer”. She noted that there has been a slight improvement in overall survival but the median survival after a diagnosis of metastatic disease is only 2-3 years. Some of the factors contributing to long-term patients: 1.) biopsies of the metastatic lesion to tailor subsequent treatment [the metastatic lesion may be different from the original tumor], 2.) targeted therapies with tolerable toxicities, 3.) patient access to quality therapies, 4.) collaborative clinicians, and 5.) patient engagement.
She noted that “Scan, Treat, Repeat” defines the life of a patient with metastatic breast cancer patient. She noted that the true prevalence of metastatic breast cancer is not known, and the SEER database only captures patients with metastatic disease at initial diagnosis and deaths – because of this, we don’t know the recurrence rates after early stage disease. 40,000 deaths each year = 110 / day. She noted that there is media “fatigue” regarding metastatic breast cancer. In a 2014 study, 60% of US adults age 18-69 knew little or nothing about metastatic breast cancer, and 72% thought that metastatic breast cancer was curable if caught early. She closed with a call for action, requesting 1.) help educate others about metastatic breast cancer, 2.) support research focused on metastatic breast cancer, 3.) seek policy and regulatory reforms, and 4.) offer information, psychological and emotional support to newly diagnosed and long-term metastatic breast cancer patients. ~DJA
One of the Sunday sessions focused on the emerging field of Genomics and Personalized/Precision Medicine, and concluded with a Next-Generation Tumor Board with 2 actual patient cases.
Dr. Dan Hayes kicked off the session with a review of “Everyday Clinical Omics.” “Omics” refers to a field of biology. For example, “Genomics” is the study of genes, “Proteomics” is the study of proteins, “Transcriptomics” refers to the study of RNA, which is the intermediate transcription step between the code contained in our DNA (our genes) and its translation into the proteins required for the structure, function, and regulation of cells, tissues, and organs.
Next Dr. Adrian Lee discussed “Sequencing Breast Cancer Genomes.” The NIH-funded Cancer Genome Atlas (TCGA) project is an effort to accelerate our understanding of the molecular basis of cancer through genome analysis technologies, including genome sequencing. The TCGA has completed analysis of 20 cancer types with 500 cancers per subtype (of which breast is one). Through TCGA we have learned that breast cancer has a very low rate of “somatic” mutations (those that are not inherited, but are acquired as part of the process of cancer development). Through gene sequencing we have found that P53 and PI3Kinase are the most common gene abnormalities in breast cancer, and other mutations are found only in small numbers of cases. Instead of mutations, breast cancer is more commonly associated with gene “copy number variation” – amplifications or deletions of genes that can be missed by standard gene sequencing. HER2 is an example of a gene that is rarely mutated in breast cancer, but is amplified in 20-25% of tumors, leading to accelerated cell growth and spread. Estrogen receptor is almost never mutated in primary breast cancers at the time of initial diagnosis, but we are learning that between 20-50% of metastatic breast cancer recurrences can have a mutation in the estrogen receptor gene (ESR1) that can lead to resistance to anti-estrogen therapy.
Finally, Dr. Nancy Davidson reviewed “New Strategies for Clinical Trials in Omics.” She discussed important ongoing and proposed studies evaluating whether assigning treatment based on cancer genomics will result in better outcomes compared to our current, standard therapies. This “individualization” of treatment to the specific patient and cancer is called precision medicine. The NCI MATCH trial is an example of a trial that matches genomics to targeted therapies – it is open to all solid tumors and lymphomas across the country. It’s important to note that we can’t assume that a drug will work just because there is a target – we must prove this in trials.
Dr. Anne Schott led the case presentations in the “Next-Generation Tumor Board,” in which the panel discussed how to use genomic profiling in everyday practice to help actual cancer patients. She reported that in the University of Michigan experience with genomic profiling, they found that 25% of the time there was something found in the genomic analysis that allowed “action” to be taken. This action included possible enrollment in a trial of a new agent targeted to an abnormality found in the genomic profiling, the ability to obtain a targeted drug “off-label” (an agent already FDA-approved for another indication, but not breast cancer), or a referral to genetic counseling to work up what might be an unsuspected inherited mutation with implications for the whole family. ~JRG
Dr. Ingrid Mayer overviewed strategies for optimizing endocrine therapy in ER+ breast cancer, including adding targeted agents to anti-estrogen therapies for improved responses. The mTOR pathway inhibitor everolimus (Affinitor) and the CDK4/6 (cell cycle) pathway inhibitor palbocicilb (Ibrance) are two of the newest drugs approved in breast cancer. Both have shown improved progression-free survival (length of time without tumor progression) in metastatic ER+ breast cancer when combined with endocrine therapy compared to endocrine therapy alone. Both agents are being studied in the early stage breast cancer setting to see if they can treat not only metastatic disease but also reduce recurrence.
Next Dr. Kim Blackwell discussed new strategies in HER2-targeted breast cancer. An interesting new (and not yet approved) drug is margetuximab, a modified version of trastuzumab (Herceptin) that is designed to elicit more immune response. She also reviewed data on the oral HER2 drug neratinib, which was presented in the oral abstract session earlier in the meeting (abstract 117). HER2 vaccines have moved into Phase III clinical trials (fairly far along in the drug approval process), although we await the results of those trials. A very interesting molecule called ONT-380 is perhaps showing very early promise in treating HER2 brain metastases.
Dr. Ian Krop went beyond HER2 and ER to discuss new targets, including those that might be relevant to triple negative breast cancer (TNBC). He presented promising recent data from trials testing anti-androgen drugs more commonly used to treat prostate cancer (bicalutimide, enzalutamide), in triple negative breast cancer patients whose tumors express the androgen receptor. He also reviewed several agents targeting the PI3Kinase pathway. A disappointingly negative trial of the PI3K inhibitor pictilisib was recently reported, but it’s thought that newer and more specific agents targeting this pathway are still of great interest. Dr. Krop also reviewed ongoing trials of antibodies in TNBC, including the IMMU-132 antibody that targets Trop2 and the CDX-011 antibody that targets GPNMB.
Dr. Rita Nanda reviewed immunotherapy in breast cancer, describing how complicated the human immune system is, with lots of stimulatory and inhibitory regulation. An interesting strategy for helping the immune system combat cancer is to loosen up “immune checkpoints” and allow immune cells that are capable and even primed to react to cancer cells, like T cells, to do so. One way the immune system controls the activity of T cells is through the PD-1/PDL-1 pathway. Cancer cells can hide from T-cell attack by taking control of the PD-1 pathway, which stops T cells from attacking the cancer. Immune checkpoint inhibitors like pembrolizumab (Keytruda), an antibody to PD-1, can unblock the cancer’s suppression of the T cells, allowing the immune system to fight the cancer. Pembolizumab and other immune checkpoint inhibitors are already approved in other cancer types and under investigation in breast cancer.
The final talk of the conference was given by me. I discussed using adjuvant bone-targeted therapy to reduce recurrence in early stage breast cancer. Bone is the most common site of distant recurrence in breast cancer, and cancer cells can remain dormant in the bone for years before becoming activated and causing bone lesions. Interfering with the bone environment may make the cancer cells less likely to survive. A large meta-analysis has been recently published of 26 randomized trials of bisphosphonates (drugs that prevent bone breakdown that are used to treat osteoporosis and also bone metastases) started shortly after diagnosis to reduce breast cancer recurrence. Postmenopausal women who received drugs in this class (clodronate, zoledronic acid, ibandronate) for anywhere from 2-5 years had a lower rate of recurrence in the bone, and less chance of dying of breast cancer. Premenopausal women did not seem to have the same benefit unless they were also receiving ovarian suppression as part of their therapy. Use of bisphosphonates in early stage breast cancer has previously been shown to reduce bone loss (osteoporosis) and fractures, and new data now shows that they can also reduce bone recurrence and improve survival. ~JRG