13 May 2019

Approximately 25-30% of patients with breast cancer who are prescribed endocrine therapy do not complete the full course of treatment, and some patients never start. Side effects of endocrine therapy are well documented but there is very little literature on the role of the medical team in helping patients manage treatment-related side effects. 

This survey is being conducted for research purposes. It is a UCLA research survey, open to women and men with a history of breast cancer who have been treated with or who have received a recommendation for endocrine therapy. 

This survey is voluntary and is completely anonymous – no identifying information, including internet protocol (IP) addresses, will be collected. The survey should take approximately 15 minutes to complete. We value your time and your opinions. 

For questions regarding this study, you may contact principal investigator Dr. Deanna Attai By phone: (818) 333-2555; by email: dattai@mednet.ucla.edu; or by mail: 191 S. Buena Vista #415, Burbank, CA 91505

UCLA Office of the Human Research Protection Program (OHRPP):
If you have questions about your rights as a research subject, or if you have concerns or suggestions and you want to talk to someone other than the researchers, you may contact the UCLA OHRPP  By phone: (310) 206-2040; by email: participants@research.ucla.edu; or by mail: Box 951406, Los Angeles, CA  90095-1406

Research Survey Link

6 March 2019

The American Society of Breast Surgeons (ASBrS) held their annual meeting in Dallas last week. This meeting usually draws about 1500 breast surgeons (just under half the ASBrS membership) from around the world, for several days of pre-meeting courses, didactic sessions, and research presentations. In addition to the science, the meeting provides opportunities for breast surgeons in all types of practice settings and at all levels of training and practice to network and learn from each other. 

The following covers some highlights from the general session. 

The meeting started off with the Critical Issues in Breast Cancer Forum: Changing Paradigms for Breast Cancer Surgery. Dr. Cary Kaufman presented an update on current clinical trials for cryoablation for breast cancer. Cryoablation is a technique that freezes the tumor, using a small probe placed into the tumor (similar to a needle biopsy) under local anesthesia. There are several types of ablative therapy including laser, radiofrequency, high-frequency ultrasound, and cryoablation. Because cold is a natural anesthetic agent, patients undergoing cryoablation do not need any sedation, and the procedure is performed while they are awake. 

Cryoablation was initially tried with benign tumors (fibroadenomas). In many cases, the fibroadenoma reabsorbed, leaving no mass and only a tiny (3 millimeter) scar. Multiple studies have looked at the use of cryoablation for breast cancer, and most have restricted therapy to patients with small (1.5 cm or smaller) estrogen receptor positive, Her2/neu negative tumors. I participated in a national multi-center trial, the ACOSOG / ALLIANCE Z1072 trial, which was published in 2016 and demonstrated that cryoablation was successful in the majority of these patients. All patients in the ACOSOG / ALLIANCE Z1072 study underwent surgery within one month of the ablation, so that the tumor site could be removed and evaluated. Several subsequent studies have looked at cryoablation for breast cancer without surgery. The longest follow up was from Dr. Fukuma in Japan. After 12 years of follow up, he reported 3 local (in-breast) recurrences in 304 patients. Combining 3 published trials, Dr. Kaufman noted that local recurrence rates range from 0.98 – 1.4%, and he concluded that this is extremely promising technology. He also noted that cryoablation of breast cancer appears to have an immunologic benefit – when the tumor cell membranes are disrupted by the extreme cold, the patient is exposed to tumor antigens, which may prompt antibody formation. It is very premature to determine if this immunologic effect will help reduce recurrence rates.

Dr. William Small presented updates on 3 clinical trials of intraoperative radiation therapy (IORT). An advantage of IORT is that it is delivered at the time of lumpectomy, in the operating room, as a one-time treatment. A disadvantage is that status of the lumpectomy specimen margin and lymph nodes are not known at that time. If it is found on final pathology that there are positive margins, external beam radiation is recommended, and at least one trial noted that approximately 30% of patients who received IORT required additional whole breast radiation. Most studies of IORT have been limited to “low risk” lesions – small, low grade invasive cancers in older women. He discussed that a criticism of these studies is that some of these women may not have needed radiation therapy at all. Dr. Small noted that local recurrence rates are slightly higher (3.3 versus 1.3%) but that statistically, IORT is considered “non-inferior” to whole breast irradiation. He noted that seroma (fluid accumulation) is more common in patients who undergo IORT.  He concluded by stating that there is an “acceptable” toxicity, with non-inferior local recurrence. However, as there is relatively short follow up available in low risk patients, he questioned the applicability of this procedure to a broader patient population. A US registry is planned.

Dr. Antonio Toesca presented the results of his study of 100 patients who underwent robotic nipple sparing mastectomy (NSM) and implant reconstruction, and showed a fascinating video which highlighted the precise and meticulous dissection, along with improved visualization, compared to a standard surgical procedure. The average incision size was a little over 1 inch, and the specimen was removed intact (in one piece). The procedure averaged 1 hour and 18 minutes longer than their standard for a nipple sparing mastectomy and implant reconstruction (3 hours, 36 minutes for the robotic procedure. Patients who underwent the robotic procedure were less likely to have axillary web syndrome and reported Improved physical, psychological and sexual well-being. 

Why could performance of NSM using robotic technology become important? Dr. Tina Hieken presented the results of her study (abstract 580759, page 31) showing that as experience with the procedure has grown, indications are expanding and patients who previously were not candidates for the procedure are now being considered. A NSM is a technically challenging procedure, and it takes a toll on the neck and back of a surgeon. A 2017 study published in JAMA Surgery noted a high incidence of work-related musculoskeletal disorders among surgeons and interventionists. Dr. Katherine Kopkash presented her research (abstract 51837, page 52) using intraoperative electromyography (EMG) on the surgeon to assess muscle strain during NSM. Of course, oncologic safety is the primary concern, and more study on the long-term outcomes (as well as costs) of robotic procedures is required. 

The next session was Emerging Strategies in Breast Cancer Care, which focused on “de-escalation” of surgical therapy. Dr. Anna Weiss provided an update of clinical trials evaluating active surveillance for low-risk ductal carcinoma in-situ (DCIS): COMET, LORD and LORIS. Approximately 60,000 cases of DCIS are diagnosed annually. Patients undergoing active surveillance do not have surgery, some are treated with endocrine therapy, and all undergo regular monitoring. This is a accepted option in select cases of prostate cancer, and Dr. Weiss noted that there is no difference in overall survival in patients with low-grade DCIS who do not undergo treatment. The LORD and LORIS trials are open in the UK and the COMET study is open in the US. (Additional perspective)

Dr. Henry Kuerer presented his research on the percutaneous management of breast cancer in the setting of a pathology complete response (pCR) following neoaduvant (before surgery) chemotherapy. He noted that for survival and recurrence matter most, but side effects and complications are significant concerns for both patients and physicians. I’ve recently covered details of his research on this blog

Some of the twitter conversation related to this talk included patients who noted that they would rather undergo surgery than chemotherapy. It is important to note that the patients involved in this study are those who were going to be treated with chemotherapy regardless of surgical therapy because they have triple negative or Her2/neu positive breast cancer. In these patients, systemic (whole-body) therapy is necessary due to the higher likelihood of metastatic disease. Surgical therapy in these patients, especially the “exceptional responders”, may not improve outcomes, but of course more study is needed. Surgery remains the standard of care for breast cancer therapy.

Dr. Judy Boughey discussed several cooperative group trials evaluating management of the axillary (underarm) lymph nodes, and these studies are also focusing on how we can safely de-escalate axillary surgical therapy after neoadjuvant chemotherapy. This is an area that is rapidly evolving with expansion of the criteria for a less aggressive approach to the axilla.

In a session on Evidence-Based Prevention and Management of Surgical Complications, Dr. Suzanne Klimberg presented on chronic post-mastectomy seroma. A seroma is a fluid collection – fluid normally accumulates after mastectomy which is why drainage tubes are left in place. Normally, drains can be removed after 7-14 days, but about 30% of patients will develop prolonged drainage. This is a frustrating problem for patients and physicians as the persistent fluid can be uncomfortable, may increase the risk of infection, and may delay the start of planned chemotherapy or radiation. She noted that a surgical technique to close the tissue known as “quilting” can reduce the rate of chronic seroma, but that it results in excessive skin dimpling and has a significant impact on the cosmetic results. She stated that additional drainage tubes, various “sealant” agents and compression (such as wearing an ace wrap) are not effective. The area may be sclerosed (scarred) by instilling talc or antibiotics, and in some cases, re-operation to remove the inflamed tissue is indicated. Otherwise she recommended patience and repeat aspirations. She noted that there are no ways to successfully prevent seromas from forming.

Dr. Amal Khoury presented on chronic post-mastectomy pain, and noted that persistent pain occurs in 25-60% of patients undergoing any type of breast surgery. It is thought that this chronic and at times severe pain is due to damage to and neuroma formation of the cutaneous (skin) branches of nerves that run along the 4thand 5thribs, which are roughly at the inframammary fold (bra line below the breast). These cutaneous nerve branches are often not visible at the time of surgery. She noted that the pain syndrome it is often not recognized, and when recognized it is often not treated effectively. She stated that injections with a combination of long-acting local anesthetic and steroid (in a very small dose) at the trigger points is more effective than taking pain or other medications, and in their study at UCSF, 91% of patients required only one injection for lasting relief.

The next session was Practical Considerations for Systemic Treatment. Dr. Judy Boughey reviewed the I-SPY2 clinical trials, which utilize an innovative “adaptive randomization” approach in patients who are undergoing neoadjuvant chemotherapy for triple negative, Her2/neu positive, or other high risk breast cancers. pCR rates are assessed, and drugs that are successful move up higher in the randomization algorithm. This study and its flexible randomization protocol have accelerated the use of some novel agents. Patient reported outcomes assessing quality of life, fear of recurrence, symptoms and side effects are being assessed. If drug response rates are similar, the “winner” may be the one associated with fewer side effects. Dr. Barry Rosen discussed specific strategies to identify the previously involved axillary lymph nodes when chemotherapy is performed prior to surgery. Dr. Elizabeth Mittendorf presented on breast cancer immunotherapy and surgical implications of these treatments. She noted that one agent, atezolizumab, is currently approved for use in patients with metastatic triple negative breast cancer. She noted that there are concerns about wound healing complications with these agents but unfortunately the clinical trials did not specifically assess for this. In addition, she noted that some immunotherapy agents are associated with development of adrenal insufficiency – this complication has only been reported in a small percentage of patients, but it is an important consideration in any patient who is going to have surgery.

A session was held on breast imaging. Dr. Molly Sebastian presented on the impact of breast density on breast cancer risk, noting that it is more difficult to screen patients with dense breasts, and that these patients are also at increased risk for developing breast cancer. The associated breast cancer risk increases with the level of density. Approximately 50% of women in US are considered to have dense breast by mammogram, and she cited a 2010 study that found that 30% of breast cancers could be linked to highly dense breast tissue. Contributors to increased density include younger age, use of hormone replacement therapy, race (Asian), diet (Western), alcohol use, and hereditary factors. She did stress that the presence of a germline genetic mutation (such as BRCA 1/2) conveys a much higher level of risk (regardless of density) than breast density itself. 

Dr. Brigid Killelea discussed balancing high-risk screening (which usually includes MRI) with the concerns about gadolinium toxicity. Gadolinium is a “rare earth heavy metal”, and is used in the contrast material that is administered (using an intravenous line) when breast MRI is performed. Acute allergic reactions are uncommon but as gadolinium is excreted through the kidneys, there are concerns about the potential for kidney damage especially in patients with pre-existing renal insufficiency. Nephrogenic systemic fibrosis (NSF) is an unusual condition that results in progressive deposition of gadolinium in the skin. It has also been found that the number of exposures to the linear form of gadolinium (as opposed to macrocyclic, which is what is most commonly used with breast MRI) correlates with increasing deposits in the brain. More research is needed to determine if this leads to an increased risk of Parkinson’s or other diseases. Studies evaluating “fast” MRI protocols are ongoing but they still use gadolinium contrast. Some work is being done with non-contrast MRI and Dr. Killelea noted that it shows some promise in detecting certain lesions. 

In the session on Ethical Issues in Breast Cancer Surgery, Dr. Rachel Greenup discussed how to manage the situation when the principles of respect for patient autonomy conflict with the standard of care. She noted that patient autonomy allows for us (as physicians) to educate but not to decide care for patients, and that poor physician-patient communication is a key factor in patients opting for non-standard care. Factors associated with patients declining standard therapy include a negative first experience, an uncaring / insensitive / unnecessarily harsh oncologist, fear of side effects, and belief in the efficacy of alternative therapy.  In regards to endocrine therapy for breast cancer, she noted that unmanaged side effects are a significant contributor to stopping therapy. She also presented data showing poorer outcomes in patients who declined standard therapy, and that many, when faced with disease progression, did then opt for conventional treatment. She recommended that physicians review and present evidence to their patients in an understandable way, taking time to acknowledge fears and address patient barriers to treatment, provide time to adjust to diagnosis, suggest a 2ndopinion, and avoid abandonment or fear tactics. She also suggested that physicians be more open (when medically safe) to the combination of alternative and standard therapy. She stressed that patient autonomy is the priority, and that open communication can help align patient-centered care with evidence-based care. 

Dr. Terry Sarantou discussed the ethical issues of obtaining informed consent when performing a new surgical procedure, noting that there is FDA oversight for new drugs and surgical devices, but not for surgical procedures. He stressed that informed consent is a communication process, not a form to be signed. 

Recognizing the role that surgeons play in the current opioid crisis, Dr. Sarah DeSnyder discussed proper prescribing of narcotics in breast surgery. There was also an abstract presentation by Dr. Betty Fan (abstract 5808940, page 27) on this subject. She noted that women who expected postoperative pain or those who reported higher preoperative distress used more postoperative opioids for pain management. She stressed that physician and trainee education about proper prescribing is critical as is setting patient expectations for postoperative pain and providing non-narcotic options. The use of nerve blocks, long-acting local anesthetic agents, acetaminophen (Tylenol) and ibuprofen were also discussed. 

Photographs are an important part of breast and reconstructive surgery to document results both for patient and physician education as well as for quality assurance, and Dr. Toan Nguyen reviewed some of the ethical, legal and technical considerations to protect patient confidentiality and privacy. The ASBrS statement on this issue has been published in the Annals of Surgical Oncology.

In the session covering New Perspectives on Old Problems, Dr. Lee Wilke noted that with improved surgical techniques, breast conservation is now appropriate for select patients with more than one tumor in the breast. She did note that in up to 20-30% of patients with more than one tumor in the breast, the tumors are different subtypes, which may have implications for therapy – so pathologic analysis needs to be performed on all lesions. Dr. Stephen Grobmyer reviewed the current literature on local (in-breast) recurrence, noting that repeat breast conservation may be appropriate in some patients. However, if repeat radiation is performed, there is a higher risk of skin toxicity and potentially unacceptable cosmetic results. In addition, for left-sided breast cancers, repeat radiation raises concerns about cumulative radiation damage to the heart. Repeat lumpectomy without radiation is associated with a 20-40% risk of local recurrence. IORT may be utilized in some patients, but studies are ongoing and data is limited.

Dr. David Euhus discussed that genetic testing does not only potentially impact the surgical procedure that is recommended, but may influence the decision for radiation therapy as well as systemic therapy. In addition, results of genetic testing may impact surveillance for additional breast or other cancers in the patient as well as recommendations for family members. The ASBrS recently updated their genetic testing guideline, recommending that genetic testing be considered for newly diagnosed breast cancer patients. (Additional perspective)

In the session on Benign Breast Disease, Dr. Jane Mendez reviewed breast fistulas (persistent drainage through the skin) and infections, and Dr. Vincent Reid reviewed some of the non-malignant masses that can develop in the male breast. Dr. Katrina Mitchell, who is a breast surgeon as well as a certified lactation consultant, provided recommendations for management of post-partum patients who develop mastitis or breast abscess. One of the key recommendations was that patients should continue breast feeding (better than pumping for keeping the breast empty) and that patients do not need to “pump and dump” the milk while on antibiotics. 

Dr. Stephanie Valente discussed breast pain, which is a common problem that frustrates both patients and physicians. Pain is a symptom of breast cancer in less than 2% of cases.  Suggestions for treatment include decrease caffeine, nicotine, and dietary fat intake, and consider supplementation with essential fatty acids such as evening primrose oil (EPO) or vitamin E. However, she noted that that some studies show that EPO and vitamin E are no better than placebo. Both flaxseed and chasteberry have shown to be effective. Diclofenac (a non-narcotic pain medication) gel can be effective but it needs to be used for several weeks before improvement is seen and it is expensive. In severe cases, danazol (an androgen hormone) or tamoxifen can be used but are associated with significant side effects.

There were several sessions on oncoplastic surgery. Oncoplastics refers to combining oncologic (cancer) surgery with attention to cosmetic outcomes. Basic principles include placing the incision in the least conspicuous place and closure of as much of the breast tissue once the tumor has been removed as possible to minimize, or preferably avoid, a depression in the area. More advanced techniques include rotation flaps and mastopexy (lift) that may be performed by breast surgeons or breast surgeons collaborating with their plastic surgical colleagues. There was also a session discussing some of the advanced microvascular procedures that are being studied to treat lymphedema as well as a video session showing some basic techniques to perform a better (flat) closure for patients undergoing mastectomy without reconstruction. 

The keynote address was delivered by the actress Kathy Bates. Ms. Bates underwent a bilateral mastectomy for breast cancer and has bilateral arm lymphedema. She is a spokeswoman for the Lymphatic Education and Research Network, working to educate, support, and advocate for patients who have lymphedema. She delivered a moving and unique address to the group, combining science and her personal patient perspective. An abstract (abstract 581304, page 22) presented during the meeting demonstrated that postoperative surveillance with bioimpedence spectroscopy compared to tape measure resulted in a 10% decrease in the number of patients requiring complex decongestive physiotherapy. However, these results, which were a planned interim data analysis, did not reach statistical significance.

The new ASBrS screening mammography guidelines were released at the meeting. They recommend formal risk assessment starting at age 25 and a risk-based approach to screening, as well as annual mammography starting at age 40 for average-risk women. (Additional commentary)

All of the research abstracts and posters can be found here. There were many interesting and thought-providing presentations, but it is important to remember that abstracts represent incomplete data and have not been subject to the peer-review process. The oral abstracts that were presented will be published in manuscript form later this year. The poster gallery can be found here (not all posters have been uploaded by the presenters).

As usual if anyone is interested in one of the articles referenced but does not have access, or wants additional information, please send your email address to me: contact at drattai dot com and I will be happy to respond.

This post has not been endorsed by the American Society of Breast Surgeons.

7 April 2019

The Society of Surgical Oncology held their annual meeting in San Diego, CA from March 27-30, 2019. Approximately 1700 surgical oncologists were in attendance. As the organization is geared towards the entire field of surgical oncology, only a portion of the meeting covered breast cancer. Here are some of the highlights:

Genetic Testing and Management
Dr. Judy Garber – Dana Farber
Updates in Testing and Management of BRCA Mutations
BRCA Mutation information from the National Cancer Institute
– Consider repeat testing if original genetic testing was performed prior to 2012 as more genes as well as pathogenic mutations have been discovered
– NCCN guidelines for breast cancer surveillance in BRCA 1/2 mutation carriers:
o Clinical breast exam every 6-12 months starting at age 25
o Annual MRI age 25-75 (individualize after age 75)
o Annual mammogram age 30-75 (individualize after age 75)
– NCCN guidelines for breast cancer prevention in BRCA 1/2 mutation carriers: discuss mastectomy, discuss tamoxifen
– Premenopausal BRCA mutation carriers who undergo oophorectomy experience breast cancer risk reduction. The level of breast cancer risk reduction in BRCA1 carriers is lower than in BRCA2 carriers as BRCA1-associated tumors are more likely to be triple negative
– Prenatal genetic testing is available in mutation carriers, and may be used for selective reproduction
– BRCA 1/2 mutation status does not impact breast cancer outcomes; tumor biology impact on outcomes is independent of mutation status
– BRCA 1/2 are DNA repair genes. Tumors associated with BRCA 1 tend to be triple negative and tumors associated with BRCA 2 tend to be ER/PR+, Her2- (but all combinations have been seen)
– Clinical trials are evaluating the use of cisplatin chemotherapy in patients with BRCA mutations – cancer cells are not able to repair DNA-induced chemotherapy damage due to the defective BRCA gene
– PARP inhibitors interfere with DNA repair and have traditionally been used to treat ovarian cancer. Small studies show some effect in breast cancer in the setting of BRCA mutations. Larger studies are ongoing. So far they only seem to work in breast cancer when there are BRCA mutations
– A challenge to treatment with PARP inhibitors is that there are many mechanisms of resistance, and tumors demonstrate a variable response to therapy – tests are being developed to predict response
– Lurbinectedin – a drug from sea slugs (!) may have some effect
– A very interesting comment – Dr. Garber noted that DNA breaks may be immunogenic, so there may be a role to combine PARP inhibitors and immunotherapy treatments
– Denosumab, a RANK-ligand used for bone protection in breast cancer patients, may have breast cancer risk-reducing activity – a randomized trial is pending to assess its activity as a preventative agent

Thuy Vu, Genetic Counselor – Wake Forest
What Genetic Test Should I Order?
– Once the appropriate patient for genetic testing has been identified, how to decide what lab to use? Consider lab experience, as well as cost and insurance support
– Patients with a complicated family history (multiple different cancers in scattered relatives), absent family history (adopted), and evidence of multiple cancer syndromes will benefit from NGS (next-generation sequencing) genetic panel testing
– A disadvantage of broad genetic panel testing is that there is currently incomplete information on all of the mutations that may be identified. Risk for cancers unrelated to the current diagnosis may be identified. In addition, there will be an increased prevalence of variants of uncertain significance (VUS)
– She noted to use caution when patients bring in test results from ancestry.com and similar companies – these sites often assess for SNPs (single nucleotide polymorphisms), which is not the same as testing for a genetic mutation, and full genetic testing may need to be repeated
– She acknowledged that there is a shortage of genetic counselors, even in large university centers. Many testing companies and labs now have associated genetic counselors, and there are some independent companies offering telephone counseling services

Dr. David Euhus – Johns Hopkins
ATM, CHEK2 and Other Genes
– While multiple gene mutations influencing breast cancer risk have been identified, they do not all convey the same level of risk
– As testing for multiple genes has increased, BRCA mutations are no longer the most common mutations found
– High risk genes include BRCA 1/2, TP53, PTEN, PALB2, STK11, CDH1
– Moderate risk genes include ATM, CHEK2, NBN, NF1
– These and other genes explain approximately 14-28% of genetic risk for breast cancer – most patients with a strong family history of breast cancer do not have an identifiable mutation
– There is a range of risk associated with all of the genes that in part depends on the mutation type – what type of damage does the mutation cause to the DNA. Family history of breast cancer can modify risk.
– For most of these patients, NCCN guidelines recommend annual MRI in addition to mammograms. Age to start supplemental screening depends on the mutation.
– He noted that increased screening for other associated cancers when there is no clinical benefit leads to patient harms – financial, emotional, and physical
– A good question from the floor about the role of ultrasound as supplemental screening (in addition to MRI) – Dr. Euhus states he uses 3D mammogram / tomosynthesis and does not use ultrasound unless the patient is pregnant / lactating

Dr. Kevin Hughes – Massachusetts General Hospital
What the Surgeon Needs to Know about Genetic Testing
– High cost of testing is not the problem – interpretation of the results is the challenge
– Assuming that approximately 10% of breast cancers are hereditary, over 51,000 breast cancers could have been prevented with testing
– For the breast surgeon, understanding BRCA 1/2 is not enough. There are many genes, each have different spectrum of associated cancers and associated risk; treatment needs to be individualized for the patient taking into account their specific mutation and family history
– He emphasized the point Dr. Garber made that if testing on a breast cancer survivor was performed prior to 2012, those patients should be re-tested
– Recent American Society of Breast Surgeons guidelines call for consideration of genetic testing in all breast cancer patients
– Dr. Hughes notes that this is already a standard recommendation for other cancers such as ovarian, pancreas and others
– The field is becoming more complicated – it is not expected that anyone can memorize this – go to the internet and look it up!

Resources:
ASK2ME – All Syndromes Known to Man Evaluator
ClinVar – look up specific mutations to see how they have been classified
PROMPT registry for patients with rare mutations

Breast Cancer Treatments in the Young and Elderly
Dr. Mina Sedrak – City of Hope
Treatment Strategies in Octogenarians with Early Stage, High-Risk Breast Cancer
– Incidence and mortality from breast cancer increase with age; the number of older adults in the US is increasing
– Breast cancer outcomes are often worse for older (as well as younger) women
– Older adults are underrepresented in cancer clinical trials – 1/3 of patients with breast cancer are over the age of 70, but only a small percentage of them are included in clinical trials
– Because of lack of clinical trial data in older women, patients may be under- or over-treated [DJA note – we have a similar situation in men with breast cancer].
– There is no universal definition of “old”. Aging is a continuous spectrum, and chronological age does not accurately predict functional age. The ASCO Guidelines Geriatric Assessment can help understand factors other than chronological age to predict morbidity and mortality. US Life Tables can also be used to estimate life expectancy, as well as ePrognosis. Estimation of life expectancy should be performed for all older patients before making a treatment plan
– How to best treat cancer in the elderly patient: it depends on life expectancy, aging concerns, risks / benefits of treatment and the potential impact of co-existing medical problems
– What risks can we modify and what are the patient preferences? There is no “one size fits all”

Dr. Tyler Chesney – University of Toronto
Adjuvant Radiotherapy for Older Women after Breast Conserving Surgery
– 4 randomized clinical trials addressed if elderly patients with low-risk breast cancer need radiation therapy after breast conserving therapy: NSABP B-21, A. Fyles, CALGB 9343, and PRIME II studies
o Meta-analysis of these 4 studies: 2387 patients across all trials, early stage breast cancer, hormone receptor positive. Addition of radiation therapy reduces local recurrence from 60 versus 10 / 1000 at 5 years. 2 trials had 10 year follow up, noting recurrence was 80 versus 20 / 1000 women.
o 3 of the trials provided data on axillary recurrence: absolute benefit was small, 12 versus 3 / 1000 women. No difference in distant recurrence or overall survival
– Prime I study showed that older women who underwent radiation therapy had increased fatigue over 5-10 years but similar overall health-related quality of life
– Accelerated partial breast irradiation may be an option, but some studies have shown higher local recurrence and poorer cosmetic result (depending on treatment method)
– While toxicities of radiation therapy have improved with more modern techniques, logistical concerns such as time, need to travel, and cost may be of higher concern for older women

Dr. Laura Dominici – Dana Farber Cancer Institute
Reconstruction and Body Image in Young Patients
– More than 13,000 women under the age of 40 are diagnosed with breast cancer annually in the US, approximately 7% of all new diagnoses
– Younger women newly diagnosed with breast cancer have been shown to have higher rates of anxiety and distress after diagnosis, they have historically received more aggressive treatment, and have a long survivorship period
– More aggressive surgery such as mastectomy does not lead to improved overall or breast cancer specific survival. Local recurrence is related to tumor biology, not age of the patient
– Mastectomy (single and bilateral) rates are rising, especially among younger women. Rates of reconstruction are increasing, as are rates of post mastectomy radiation
– A growing number of patients are “going flat” after mastectomy, opting for no reconstruction
– Dana Farber young women’s multicenter prospective cohort study: poorer satisfaction with breast-related, psychosocial and sexual well-being after unilateral and bilateral mastectomy. Other factors impacting poorer satisfaction include financial status, lymphedema, and the need for radiation
– 42% of women age 50 and younger (in the Dana Farber study) regret their surgical decision including primary surgery and reconstruction decision. Patients in this study were not asked what the actual regret was – doing too much or too little
– Important for patients to understand the oncologic outcomes of their decisions, and for physicians to promote shared decision making that takes into account patient preferences and concerns

Dr. Jo Chien – University of California, San Francisco
Fertility in Young Breast Cancer Patients
– 51% of women under age 40 with breast cancer are concerned about fertility; 38% desire to have future children but up to 97% are at risk of treatment related infertility. 26% report that their concerns about infertility affected their treatment decisions
– Loss of reproductive potential after cancer treatment results in worse long-term quality of life, unresolved grief / depression, reduced life satisfaction. Fertility preservation associated with less regret among young cancer survivors
– Less than 25% of general oncologists refer young breast cancer patients to fertility specialists
– Factors impacting risk of chemotherapy-induced ovarian failure: older age, baseline ovarian reserve, type of chemotherapy, and chemotherapy dose / duration
– Menses is not a surrogate marker for fertility. Fertility decline occurs ~10 years before onset of menopause. For women who remain premenopausal after chemotherapy, the majority enter menopause prematurely
– Options for fertility preservation: ovarian stimulation and cryopreservation of embryos / oocytes, GnRH agonists, and experimental techniques such as cryopreservation of ovarian tissue and immature oocyte retrieval with in vitro maturation
– Several studies have evaluated safety of letrozole-gonadotropin protocol in women with breast cancer and have found no difference in relapse-free survival. Very limited data on safety of ovarian stimulation in the neoadjuvant setting. In subset (82 patients – 34 stimulation / 48 controls) of I-SPY2 trial, no delay in start of neoadjuvant treatment and no significant difference in pCR or recurrence or mortality rates in patients who underwent ovarian stimulation before chemotherapy
– As discussed in the genetics session, Dr. Chien noted that for BRCA mutation carriers, pre-implantation genetic diagnosis is an option. Multiple follicles / embryos are required, often needing multiple stimulation cycles
– Observational studies suggest that pregnancy is safe after breast cancer.
– When is it safe to become pregnant after treatment? It comes down to patient’s underlying risk and likely their risk aversion. Dr. Chien prefers to wait to 2-3 years, but notes there is no data to support that. The POSITIVE trial is studying the impact of adjuvant endocrine therapy interruption to allow for pregnancy

Key papers
Dr. Kandace McGuire from Virginia Commonwealth University Massey Cancer Center provided an overview of 3 practice-changing papers from 2018. She noted at the start of her talk that while this is a surgical audience, all of the studies were from the medial oncology literature. This comment highlighted the multidisciplinary nature of breast cancer care – the entire treatment team needs to be aware of the latest advances and updates.

The TAILORx study assessed Oncotype Dx results and noted that many patients previously classified as intermediate risk could now be classified as low risk. Therefore, a larger percentage of patients do not need chemotherapy. However, questions remain for patients under the age of 50.

The TEXT / SOFT trials evaluated the use of ovarian suppression in premenopausal women with hormone receptor positive breast cancer. Ovarian suppression resulted in improved disease free and overall survival, but the magnitude of improvement varied according to recurrence risk. High risk patients may have 10-15% improvement. However, quality of life and fertility may be impacted by ovarian suppression in these younger women

The KATHERINE study assessed the use of TDM1 in patients with Her2/neu over-expressed tumors who did not exhibit a pathologic complete response (pCR) after neoadjuvant (before surgery) chemotherapy. Those who received adjuvant TDM1 versus trastuzumab showed an improved disease free survival, but more study is needed to assess the effect on overall survival.

Dr. V. Craig Jordan delivered the American Cancer Society / SSO Basic Science Lecture: The SERM Saga: Something From Nothing. Dr. Jordan’s presentation was a nice history lesson about the discovery and use of tamoxifen as a treatment for breast cancer.
– Dr. Jordan noted the early clues that endocrine therapy might be effective for some breast cancers – removal of the ovaries, adrenal glands, and even part of the pituitary gland led to improved outcomes (with a fair amount of associated risk)
– Tamoxifen was initially developed as a contraceptive agent, but it was not successful and was going to be discarded by the manufacturer
– The link to endometrial cancer and tamoxifen was initially denied, despite some interesting studies by Dr. Jordon noting the association. He noted that the early studies evaluating tamoxifen simply did not assess for endometrial cancer
– He noted that the cumulative frequency of uterine cancer with 2 years of tamoxifen is ~1.5%, and with 5 years of tamoxifen ~5.5%. He commented that if the studies were performed today, the data monitoring committees would “go apoplectic” over these results
– Raloxifene in early studies showed decrease in breast cancer but also decrease in bone fractures – this led to the STAR trial which assessed the ability of raloxifene and tamoxifen to reduce breast cancer development in high-risk women
– He discussed other drugs, derived from tamoxifen, that are being developed – searching for those with improved side effect profiles
– He quoted George S. Patton: “If everyone is thinking alike, then someone isn’t thinking”

Presidential Address – Serendipity and Strategy on the Path of Progress
Dr. Armando Giuliano, known to some as the “father” of the sentinel node biopsy, provided some interesting details on how his research process unfolded. He noted that “my success has been due to good luck, mixed with hard work, strategic planning, and serendipity.” Like those before him who proposed less aggressive surgical therapy for breast cancer, he was met with a fair amount of criticism. Patients and surgeons have benefited from his perseverance and dedication.

All of the research abstracts and posters can be found here. There were many interesting and thought-providing presentations, but it is important to remember that abstracts have not been subject to the peer-review process, and may represent incomplete data.

As usual if anyone is interested in one of the articles but does not have access, please send your email address to me: contact at drattai dot com and I will be happy to send you a copy.

This post has not been endorsed by the Society of Surgical Oncology.

13 March 2019

A recent news article has called attention to an ongoing clinical trial, which is evaluating whether certain patients can avoid surgery for breast cancer. The article has raised many questions, so with the help of the trial principal investigator, surgical oncologist Dr. Henry Kuerer from M.D. Anderson, here is some clarification.

The most important point to stress is that currently, surgery is a necessary, “standard of care” component for the management of breast cancer. Patients interested in avoiding surgical resection of the tumor or tumor site should do so only in the context of a prospective controlled clinical trial, which has very specific eligibility requirements and other safety measures in place. 

Patients with triple negative and Her2/neu over-expressed (Her2+) breast cancers very often receive a recommendation for chemotherapy (even with no spread to the lymph nodes) due to the more aggressive nature of these tumors and improvements in survival with chemotherapy. Currently, neoadjuvant (before surgery) chemotherapy is usually used, which allows an assessment of tumor response. In about 50% of cases, no residual tumor is found in the area of surgical resection (because the chemotherapy killed all of the cancer cells) – known as a pathologic complete response (pCR). Patients and their surgeons began to ask: “If it’s all gone, why is surgery necessary?” Eligibility for the currently accruing clinical trial includes patients with triple negative or Her2+ cancers that are 5cm or smaller, with 4 or fewer involved axillary (underarm) lymph nodes.

Clinical trial participants first are treated with neoadjuvant chemotherapy. Follow up imaging after chemotherapy, including MRI, is performed. Needle biopsies (similar to those used to make the initial diagnosis) are performed at the original tumor site. If no cancer is found in these biopsy samples, the patient then undergoes a sentinel lymph node biopsy, or targeted axillary dissection (if she had originally biopsy proved axillary nodal disease). Currently, surgical removal of the sentinel / targeted nodes is necessary because it can be very challenging to perform lymph node needle biopsy after chemotherapy. If the lymph nodes are negative (“clear” / no cancer), the patients undergo radiation therapy. If there is residual disease in the lymph nodes after chemotherapy, an axillary dissection is performed prior to radiation therapy.  

A small pilot prospective clinical study at M.D. Anderson showed that utilizing image-guided biopsy in those patients who appear to have an excellent response could predict which patients in fact had residual disease in the breast with 98% accuracy – this was the basis for the current study.  Another feasibility trial, sponsored by the NRG Oncology cooperative group, in collaboration with the National Cancer Institute (NRG BR005), is ongoing.

A separate study, also performed at M.D. Anderson, was performed to address whether or not axillary surgery is required in these patients. The researchers found that when there is a pCR (including invasive and in-situ disease) after neoadjuvant chemotherapy, the likelihood of having any cancer in the axillary lymph nodes is extremely low if the patient had normal axillary lymph nodes demonstrated on ultrasound prior to beginning therapy. These patients may be able to then avoid any breast or axillary surgery.  A much larger study using the US National Cancer Database noted similar findings, but in addition, highlighted the need to perform axillary surgery in cases where there was initial biopsy-proven cancer in the lymph nodes prior to chemotherapy.

Dialing back the extent of surgical therapy for breast cancer is nothing new. Sir William Halsted died in 1922, but the extensive, disfiguring procedure bearing his name (the “Halsted radical mastectomy”) continued to be the standard of care well into the 1950-60’s. Noting that survival was not improving despite the extensive surgery, surgeons at the NSABP, led by Dr. Bernard Fisher, started to ask questions and design clinical trials. NSABP B-04 results demonstrated that there was no difference in overall survival or local recurrence whether patients underwent a radical mastectomy or a total mastectomy, and the radical mastectomy fell out of favor.

With increasing use of screening mammography, cancers were being detected in smaller sizes. Again, surgeons asked questions, and the NSABP B-06 trial was performed – this study found no difference in overall survival whether patients underwent a mastectomy with lymph node removal, a lumpectomy with lymph node removal, or a lumpectomy with lymph node removal and radiation therapy. The women who underwent lumpectomy without radiation had a higher rate of local (in the breast) recurrence (approximately 39% versus 14%), setting the standard that still holds today, for the use of radiation therapy after lumpectomy.

Less aggressive surgery for the axillary lymph nodes has also been carefully researched. Sentinel node biopsy and targeted node dissection, removing a smaller number of carefully identified lymph nodes (even in some settings where the cancer has spread into the lymph nodes) results in lower rates of lymphedema, chronic pain and arm mobility problems without impact on survival or recurrence.

Non-operative ablative therapy is also being researched, and techniques being investigated include cryoablation, as well as high frequency focused ultrasound and laser ablation.

While there may be many eyebrows raised regarding the current research (“no surgery???”), over the years it has been demonstrated through carefully constructed clinical trials that less extensive breast cancer surgery leads to similar outcomes in terms of survival and recurrence, but with lower rates of complications. Advances in the understanding of tumor biology, development of more precise targeted systemic therapy, and improvements in breast imaging and biopsy techniques have resulted in the identification of a subset of patients in whom surgery may not be required. As mentioned at the beginning of this post, this non-operative approach is currently only being offered in the context of a clinical trial, and is not yet considered standard therapy

SlideShare: History of Breast Cancer Surgery Including Landmark Clinical Trials (2015 Presentation)

30 January 2019

The buzz this morning came from a group of scientists in Israel, claiming that they have developed a cure for cancer – one that will work on ALL cancers – and it will be ready for patient care within a year. Amazing!!

But not so fast. The report, which first appeared in the Jerusalem Post, and then was picked up by multiple news outlets, described research that has only been carried out in mice. The article quotes the researchers: “the company has concluded its first exploratory mice experiment…” and then goes on to state: “Our results are consistent and repeatable.” The article read as a press release, and there was no link to any published research.

I am not a basic science researcher, so for a deep dive on the science please review Dr. David Gorski’s post. An important point that he highlighted – the research findings have not been published a peer-reviewed journal. Dr. Matthew Hall, who is the biology group leader for the National Center for Advancing Translational Sciences at the NIH, posted this thread on his twitter feed:


Dr. Hillary Stires, a breast cancer researcher at Georgetown, noted:

Many new drugs are first tested in mice. Dr. Susan Love notes that mice do not naturally develop breast cancer. Researchers inject tumor cells into the mice in order to then study the responses to treatment. Just because it works in a mouse does not mean it will work in a person!

 

We all want a cure for cancer. Yes – even the surgeons, oncologists and researchers. We will find something else to do if this disease is cured. But cancer is not one disease and the concept of “The Cure” that will work for all cancers is probably not realistic. Articles such as this, and the avalanche of coverage that followed, only raise false hope among patients and their loved ones.

The Modern Tragedy of Fake Cancer Cures
Scientists Say They’ll Have a Cure for Cancer Within a Year
American Cancer Society / Dr. Lichtenfeld Blog
If It Sounds Too Good To Be True… 

12 December 2018

The San Antonio Breast Cancer Symposium is the largest medical conference devoted to breast cancer. Held every year in San Antonio, TX, it attracts a large international audience and there are often practice-changing studies. While I was not able to attend the meeting in person, I’ve provided just a few of the studies that caught my attention. This is by no means a comprehensive post – the meeting is enormous – but I have also included several summary links below with additional information.

Her2/neu Positive Breast Cancer
The KATHERINE study assessed patients treated with chemotherapy and trastuzumab (Herceptin) prior to surgery. Patients who had residual disease at surgery (meaning the chemotherapy did not kill all of the cancer) were then treated either with trastuzumab (standard of care is to complete 52 weeks of therapy) or trastuzumab-emtansine (T-DM1, Kadcyla). The study found that after 3 years of follow up, patients treated postoperatively with trastuzumab emtansine had a 50% lower risk of developing recurrence of invasive breast cancer (12.2% versus 22.2%). The findings were published on the day of presentation in the New England Journal of Medicine.

Adverse events were more common in the trastuzumab-emtansine arm (98% versus 93%). 25.7% had grade 3 or higher adverse events in the trastuzumab-emtansine arm compared to 15.4% in the trastuzumab arm. While based on these results, there is some anticipation of FDA approval, cost of the medication and insurance coverage are significant concerns.

Relationship Between pCR and Outcomes
Patients who receive neoadjuvant (prior to surgery) chemotherapy and are found to have no residual tumor (pathologic complete response – pCR) at the time of surgery, had improvements in recurrence and survival rates. The meta-analysis showed that approximately 21% of treated patients had a pCR, which was more likely if the tumor was triple negative or Her2/neu positive. The event-free survival rate was 88% in patients who had a pCR versus 67% for those with residual disease. The authors noted that in patients who had a pCR, additional chemotherapy after surgery may not be necessary. In addition, they suggested that in whose  who had residual cancer, additional chemotherapy (see the KATHERINE study above) could be considered.
ASCO Post on pCR Meta-Analysis

Tamoxifen for DCIS, LCIS and ADH
Tamoxifen is often used to help reduce the risk of developing invasive breast cancer in patients who are at high risk, including those with ductal carcinoma in-situ (DCIS), lobular carcinoma in-situ (LCIS) and atypical ductal hyperplasia (ADH). The standard dose of tamoxifen is 20mg daily. Hot flashes and sleep disturbance impact some patients who take tamoxifen, and the medication is also associated with a risk of developing blood clots and endometrial cancer. These potential side effects keep some women from even starting the medication. In addition, studies note that approximately 25-30% of breast cancer patients treated with endocrine therapy stop treatment due to side effects.

The TAM-01 study compared a low dose of tamoxifen (5mg per day) to placebo in patients with DCIS, LCIS and ALH. 500 patients were randomized and treated for 3 years. After median follow up of 5 years, 5.5% of patients in the low dose tamoxifen arm and 11.3% of patients in the placebo arm had recurrence or development of new disease, suggesting a risk reduction of approximately 50%. This is what is also seen from the standard, 20mg dose. Side effects were similar in the 2 groups.

The findings suggest that a very low dose, 3 year (current standard is 5 years for risk reduction) of tamoxifen may be sufficient in these patients who are on the medication for risk reduction. Unfortunately, the results cannot be extrapolated to patients who are on tamoxifen as part of treatment for invasive breast cancer. It was also noted in some of the commentary that tamoxifen is not commercially available in 5mg doses, but patients may consider taking 10mg every other day.
ASCO Post on TAM-01

Genetic Testing
Genetic testing in patients diagnosed with breast cancer is based on age at diagnosis and family history of breast, ovarian and other cancers. A study presented and simultaneously published in the Journal of Clinical Oncology noted that approximately 50% of patients with a pathogenic or likely pathogenic mutation were missed by current testing guidelines. Of patients who did not meet current guidelines for genetic testing, 7.9% were found to have a pathogenic or likely pathogenic mutation. The authors recommended panel genetic testing for all newly diagnosed breast cancer patients, which certainly could impact treatment recommendations surveillance and treatment recommendations for family members.

Hot Flashes
Oxybutynin (Ditropan and others) is a medication commonly used for urinary incontinence. It was compared to placebo in a double-blinded study, to assess impact on menopausal symptoms in women being treated for breast cancer with tamoxifen or aromatase inhibitors. The study showed that patients taking oxybutynin had decreased hot flash scores and also reported improvements in sleep and quality of life.
ASCO Post interview with Dr. Leon-Ferre

Radiation Therapy after Lumpectomy
The long-awaited results of NSABP B-39 were presented by Dr. Frank Vicini. There are several ways to deliver radiation therapy after lumpectomy – traditional whole-breast irradiation and various forms of partial breast irradiation (external- and catheter-based). The study noted that after 10 years of follow up, local (in-breast) recurrence rates were low in all groups, approximately 4%. Patients treated with partial breast irradiation had a slightly higher (<1%) rate of in-breast recurrence. This study is important for 2 reasons:
– Local recurrence rates were very low, approximately 4%. We have traditionally quoted (based on older studies) a local recurrence rate of approximately 10% after lumpectomy and radiation. This current study notes that local recurrence rates after lumpectomy and radiation are very close to that of mastectomy (1-5%).
– Partial breast irradiation is a reasonable option for selected patients. There was a small (but statistically significant) increase in local recurrence compared to whole breast radiation. Whether that difference is important for an individual patient or not is something that should be discussed with her treatment team. The study noted no difference I overall survival. Grade 3 and 4-5 toxicities were slightly higher in the patients who received partial breast irradiation compared to whole breast irradiation (9.6% versus 7.1% grade 3 and 0.5% versus 0.3% grade 4-5).

It is important to note that at the time of study accrual, whole breast irradiation was given over the course of approximately 6 weeks. Current practice is to utilized a “hypofractionated” protocol, which treats in about 3 – 3 ½ weeks.  

Breast Surgery Choice and Quality of Life
A study assessing long-term quality of life in young patients with breast cancer found that those who underwent unilateral or bilateral mastectomy had lower breast satisfaction and sexual / psychosocial well-being scores compared to those who underwent breast conserving surgery. 561 patients were enrolled with a median age at diagnosis of 37. 28% underwent breast conserving surgery, and 72% underwent mastectomy. 72% of the mastectomy patients had a bilateral procedure. Assessments were performed using the BREAST-Q questionnaire, which is a validated survey tool. Patients were surveyed a median of 5.8 years after treatment.

While the results were presented in abstract (not full peer-reviewed manuscript) form, it is still important to consider this information either as a physician counseling a patient on her options or as a patient deciding on her treatment options.
ASCO Post interview with Dr. Dominici

Other Resources:
SABCS Abstracts
ASCO Post Symposium Updates

AACR Blog
Oncology Times – Dr. George Sledge
OncLive Podcast

This post has not been endorsed by the San Antonio Breast Cancer Symposium 

 

14 August 2018

I was honored to participate in a Sharsheret national webinar, where breast cancer research that had been presented at the June 2018 meeting of the American Society of Clinical Oncology was reviewed. The webinar video and transcript are linked below. Dr. Sharyn Lewin, a gynecologic oncologist, presented ovarian cancer research updates.

Transcript Link

Additional Sharsheret Symposia Transcripts

This post has not been endorsed by the American Society of Clinical Oncology

4 June 2018

The American Society of Clinical Oncology (ASCO) annual meeting, a gathering of over 40,000 oncology specialists, was held this past weekend in Chicago. One of the studies that received a significant amount of press attention was the TAILORx study.

There are several genomic tests which evaluate a tumor’s DNA to better determine how aggressive that tumor is, and how likely it is to recur without chemotherapy. The Oncotype Dx test was the first commercially available one. A sample of tumor is sent for analysis and the result is reported as a “score” which is then assigned to one of 3 categories – low, intermediate and high risk of recurrence. A sample of the report generated from the test is shown below. It is important to note that the Oncotype Dx test was validated in patients who received endocrine therapy, so the results assume treatment with tamoxifen or an aromatase inhibitor. It is appropriately used in patients with Stage I or II breast cancer, with spread to 1-3 underarm lymph nodes, if the tumors are estrogen receptor positive (ER+) and Her2/neu negative (Her2-). The results of the low risk cohort were published in 2015, which confirmed that patients with low scores receive little benefit from chemotherapy.

Sample Oncotype Dx Report

The study presented at ASCO reported on the results of the intermediate risk group. For the purposes of the study, intermediate risk was defined as a score of 11-26. It is important to note that in patients outside of the study, intermediate risk is a score of 18-31. However, as patients in the lowest risk category did not receive chemotherapy as part of this study, the categories were shifted to the left to be more cautious. Patients enrolled in the study were women between the ages of 18-75, with a median age of 55-58. Eligibility criteria included patients who had tumors smaller than 5 cm, ER+, Her2-, and with negative underarm lymph nodes (as determined by surgical pathology – all patients in this study underwent surgery). Patients with an Oncotype Dx score of 11-26 (69% of the total study population, about 6700 patients) were then randomized to chemotherapy followed by endocrine therapy, or endocrine therapy alone. Median follow up was 7.5 years.

The study showed that there was no significant difference in the overall survival (~94%), invasive cancer disease free survival (~84%) or distant disease free survival (~95%) between the 2 groups. However, in women under the age of 50, it was found that those with scores of 16-25 did receive some benefit from chemotherapy. It is unclear from the study if the benefit in these patients was specifically from the chemotherapy, or if it was that menstrual cycles and ovarian function are suppressed with chemotherapy, which then lowers estrogen levels. The authors raised the question of whether or not similar results in this group of patients could be achieved using medications to suppress the ovaries (which would induce menopause) and an aromatase inhibitor instead of chemotherapy.

It is important to note that a low risk score does not mean the patient will not develop a recurrence or metastatic disease – it simply means that the risk of recurrence is extremely low and that chemotherapy will not significantly improve on that low risk. It is also important to keep in mind that this study did not include patients with triple negative or Her2/neu positive breast cancer, or patients where the cancer had spread to the lymph nodes.

There are several commercially available genomic tests, and which test is used for a particular patient is often related to guideline recommendations and physician preference. Most of these tests are covered by insurance but the costs are high (~$4500.00) and patients should check with their insurance to determine if they have a share of cost. Most of the testing companies have payment assistance programs. For patients right on the edge of one of the risk categories, treatment decisions are not always as clear cut, and should be made in the context of the patient’s other disease factors and as part of a balanced discussion of the risks and benefits of treatment as well as patient preferences.

There has been a lot of focus on de-escalaton of therapy, and rightly so. While chemotherapy and other toxic treatments have their place, there are significant short term and long term side effects, so determining which patients have the best likelihood of benefit from these treatments is important. Not all cancers will respond to chemotherapy, and in those cases, the patient is subjected to all of the harms and receives none of the benefit.

Additional information from the ASCO Post 

10 May 2018

The American Society of Breast Surgeons held their Annual Meeting in Orlando, FL from May 2nd – 6th. As usual, it was well attended – the meeting is known for being very practical and full of information that breast surgeons can bring back to their practices to help improve patient care.

I’ve picked a few topics to highlight in this post: Genetics, Imaging, Local Therapy, Systemic Therapy, Immunotherapy, Liquid Biopsy, Diet and Hormone Therapy, and Changing Paradigms. The following are comments expressed by the meeting speakers. My own comments will be noted in bold italics.

Genetics:

  • BRCA 1 mutation carriers are more likely to have triple negative breast cancer.
  • BRCA 2 mutation carriers are more likely to have ER positive, Her2/neu negative breast cancers.
  • The risk of a 2nd breast cancer in BRCA mutation carriers on average is about 2% per year depending on the specific mutation and the age of affected relatives. It can approach 60-80% in some patients. This increased risk of a new breast cancer is why bilateral mastectomy is often recommended. Removal of the opposite breast may result in improved overall survival but results from studies are mixed.
  • For BRCA mutation carriers, it is recommended that clinical breast exam (breast exam by the physician) be performed every 6-12 months. From age 25-29 annual MRI is recommended, and from age 30-75 annual mammogram (3D mammogram or tomosynthesis was recommended) along with MRI was recommended. It was stated that this screening regimen has not been shown to improve survival, but the screen-detected cancers were less likely to have lymph node involvement. No specific recommendation was made for imaging or exam after bilateral mastectomy.
  • MRI every 6 months has been suggested by some, but there are concerns about gadolinium (a heavy metal material which is the contrast agent used for breast MRI) buildup.
  • Removal of the ovaries is recommended around age 40.
  • In patients with BRCA mutations who undergo salpingo-oophorectomy (removal of the ovaries and fallopian tubes), estrogen replacement therapy has not been shown to increase subsequent breast cancer risk. However, combined estrogen / progesterone therapy may increase subsequent breast cancer risk. It was suggested to consider removing the uterus at the time of ovary removal, so that estrogen alone could be used (if the uterus is not removed, estrogen alone could increase the risk of uterine cancer).
  • There are many other genetic mutations that have been identified that have a variable association with increased breast cancer risk. It was stressed that family history and other factors need to be considered when these less common mutations (such as CHEK2, ATM, PALB2 and many more) are present, before recommending mastectomy.
  • It was stressed that the presence of a variant of unknown significance (VUS) should NOT prompt aggressive surgery.
  • A study was presented that demonstrated that current breast cancer genetic testing guidelines exclude almost half of high-risk patients, and a recommendation was made for testing of all breast cancer patients regardless of age, family history or other factors.

Breast Imaging:

  • Dense breast (as determined by mammogram) reduces the sensitivity of mammograms, and also is associated with an increased risk of breast cancer.
  • It was stressed that determination of breast density is subjective and studies have shown significant variability in grading of breast density. Automated methods of assessing density are being evaluated.
  • 34 states have dense breast notification legislation. Some have supplemental screening (such as ultrasound) legislation (California does not).
  • An advantage of tomosynthesis (also known as 3D mammogram) in patients with dense breasts is that it decreases the likelihood of callbacks and improves the cancer detection rate
  • Abbreviated (3 minute scan) MRI shows promise for screening.
  • There is an ECOG/ACRIN study planned which will evaluate abbreviated MRI versus tomosynthesis in women with dense breasts.
  • Contrast-enhanced mammography is superior to digital mammography but it requires an IV contrast dye, and there is currently no ability to biopsy lesions seen only with this technique.
  • It was stressed that automated whole breast ultrasound (ABUS) should not replace mammography.
  • Molecular breast imaging has a much higher radiation dose due to the need to inject a radioactive material and cost is higher than other imaging modalities. There are only about 100 units in the US.
  • In addition to BRCA mutation carriers, patients who have a history of chest wall radiation at a young age (most commonly for treatment of Hodgkin’s lymphoma) or those who have a lifetime risk of breast cancer over 20% (assessed by various computer modes) should have annual MRI in addition to mammograms for surveillance.

Loco-Regional (breast and underarm lymph nodes) Therapy:

  • Recurrence of cancer in the breast (known as a local recurrence) was previously thought to be related to “disease burden” – the amount of tumor and size of clear margins. According to Dr. Monica Morrow, this has led to an “obsession” with margins, wider surgical resection than necessary, and the overuse of MRI.
  • Due to improvements in systemic therapy (chemotherapy and endocrine therapy), local recurrences have decreased over time.
  • Local recurrences are largely a function of tumor biology – more aggressive tumor types are more likely to recur. Bigger surgery does not overcome bad biology.
  • The rates of contralateral (opposite side) new breast cancer have been decreasing in the US; currently <1% at 5 years for patients who do not have a genetic mutation.
  • Updated 2018 ASTRO guidelines endorse hypofractionation (a shorter course of radiation therapy) in a larger group of patients.
  • There are 3 trials that will evaluate whether or not radiation therapy can be avoided in selected patients – LUMINA, IDEA and PRECISION.
  • ~30% of patients undergoing “direct to implant” reconstruction (no temporary tissue expander) need a second surgery. One of the plastic surgeons that I work with notes that “reconstruction is a process not a procedure!”
  • Managing expectations of the reconstruction process is important so patients don’t get frustrated and feel like their reconstruction has “failed.”
  • Post mastectomy radiation worsens outcome from implant reconstruction; severe capsular contracture occurs in about 30% of patients.
  • If radiation is performed on the permanent implant instead of the tissue expander, the rate of reconstruction failure goes down by 50%.
  • Many plastic surgeons prefer that autologous (patient’s own body) reconstruction be performed after radiation to avoid shrinkage of the flap. A tissue expander could be placed at the time of mastectomy which will be removed after radiation when the flap procedure is performed.
  • Lymphedema risk is about 25% with axillary node dissection versus 6-8% with sentinel node biopsy. In certain patients over age 70 with ER+ breast cancer, sentinel node biopsy can be avoided – this was also covered in the Society of Surgical Oncology’s Choosing Wisely statements. However, it is also important to take into account whether or not the patient will be treated with radiation and/or endocrine therapy. Sentinel node biopsy is also not recommended for most patients undergoing lumpectomy for DCIS. The SOUND trial is evaluating the use of axillary ultrasound to try to determine if this can help select patients who do not need sentinel node biopsy.

 Systemic Therapy:

  • The use of genomic tumor testing could avoid the use of ineffective (for the specific patient depending on tumor profile) chemotherapy in up to 50,000 patients per year.
  • Neoadjuvant (before surgery) chemotherapy is most commonly used to decrease tumor size so that patients have a higher likelihood of being able to undergo lumpectomy instead of mastectomy.
  • About 50% of patients who have positive lymph nodes before chemotherapy are converted to node-negative due to chemotherapy prior to surgery, and they may be able to avoid full axillary node dissection.
  • Response to neoadjuvant chemotherapy varies by tumor subtype. Her2/neu and triple negative breast cancers are more likely to respond compared to ER+ and Her2/neu negative tumors.
  • Technical considerations to improve the accuracy of sentinel node biopsy after neoadjuvant chemotherapy including the use of 2 dye agents to map the nodes and removal of at least 3 lymph nodes.
  • A multidisciplinary approach for management of patients who are being considered for neoadjuvant chemotherapy was stressed.
  • Recurrence patterns are different for ER+ versus ER- disease. Patients with ER+ breast cancer are at risk for late recurrence, even 20 years after treatment – the highest risk is in patients with multiple involved lymph nodes. Patients with ER- disease tend to recur earlier (within the first 2-5 years), and then the likelihood of recurrence decreases.
  • Recurrence in the breast is a marker of increased risk for development of metastatic disease.
  • Premenopausal patients who have “low risk” disease could consider stopping tamoxifen after 5 years. It is recommended that patients with “high risk” disease consider 10 years of tamoxifen therapy.
  • Postmenopausal patients who are considered “high risk” could consider 10 years of an aromatase inhibitor, although there is not currently data that shows this approach improves survival. Prolonged therapy in these patients does reduce the likelihood of developing a new breast cancer and reduces the likelihood of breast cancer recurrence.

Immunotherapy / Liquid Biopsy:

  • A brief session was held covering immunotherapy and liquid biopsy.
  • Immunotherapy for breast cancer has not had the success seen in melanoma, lung cancer, colon cancer and bladder cancer.
  • The combination of chemotherapy and a modified herpes virus has shown some promise in patients with triple negative breast cancer.
  • It is likely that immunotherapy treatments will vary depending on tumor subtype.
  • Circulating tumor DNA may predict metastatic disease 8-12 months before evidence of tumor spread – but we are not yet able to improve patient outcomes based on this information. Therefore, circulating tumor cell and circulating cancer cell DNA assessments are not recommended for routine clinical use.
  • It was predicted that “liquid biopsy” will eventually be used routinely to help manage breast cancer patients.

 

Diet and Hormone Replacement Therapy:

  • A low fat diet improved the likelihood of death from breast cancer only in obese women.
  • Currently there is more information regarding the impact of dietary fat versus dietary sugar on breast cancer risk. Dr. Rowan Chlebowski, who has been a lead author on the Women’s Health Initiative studies, stated that due to an increasing number of reports suggesting that sugar may impact breast cancer development, they plan to look more closely at this.
  • Insulin resistance is associated with cancer specific and all-cause mortality in postmenopausal women.
  • One of Dr. Chlebowski’s conclusions was to “avoid body fatness.” Unfortunately, specific guidance on how to best accomplish this was not discussed!
  • The risk of breast cancer associated with hormone replacement therapy (HRT) is greater if it is started around the time of menopause versus 3-5 years later.
  • Breast cancer risk in women taking HRT is higher in women with extremely dense breast versus fatty replaced breasts. The biggest risk from HRT is in lean women with extremely dense breasts. The lowest risk from HRT is in women with a body mass index (BMI) > 35 with fatty replaced breasts.
  • Combination estrogen / progesterone HRT should be avoided in lean (BMI <25) women especially if they have dense breast tissue.
  • The Black Women’s Health Study found no increased breast cancer risk if HRT use was <10 years, but cancer risk was increased if use was >10 years. Other studies showed either no risk or no association of risk from HRT with race.

 

Changing Paradigms – Avoiding Surgery for DCIS and Neoadjuvant Patients

  • Active surveillance is being evaluated for ductal carcinoma in-situ (DCIS). Over 60,000 cases of DCIS are diagnosed per year in the US. Not all cases of DCIS will progress to invasive cancer, and the likelihood of progression is lowest in low grade DCIS. In these patients, less than 10% develop invasive cancer in the same breast after 10 years and over 20% die from other causes within 10 years of diagnosis.
  • There are 3 ongoing clinical trials are evaluating active surveillance for low risk DCIS (LORIS, LORD, and COMET). The COMET trial is the only study open in the US. DCISOptions.org has additional information about DCIS and the COMET trial.
  • Some patients who undergo chemotherapy prior to surgery are found to have no residual tumor after the area has been removed, termed pathologic complete response (pCR).
  • Prompted by patients asking “why do I need surgery?” if it appears that all cancer has resolved after chemotherapy, researchers at MD Anderson Cancer Center are evaluating whether surgery can be omitted in patients who appear to have a pCR after chemotherapy. Patients who have no apparent tumor based on post-chemotherapy imaging (including MRI) undergo core needle biopsies. If these biopsies show no tumor, patients taking part in the study will undergo radiation without surgery.
  • Similar studies are taking place in the Netherlands, Germany, and the UK.
  • Henry Kuerer from MD Anderson stated that “surgeons have an obligation to study possibility of no surgery – and we must ensure safety and efficacy with well-designed trials.
  • Several types of ablative therapy (destroying the tumor without surgery) are being evaluated including cryoablation (freezing), laser, and transcutaneous (no needle puncture or scar) high frequency ultrasound.

Lifetime Achievement Award

Dr. Ernie Bodai, the breast surgeon who spearheaded the Breast Cancer Research Stamp, was honored with a lifetime achievement award. It was fascinating to hear his story and how one man (with a little help) got congress to change a law.

This post has not been endorsed by the American Society of Breast Surgeons

9 November 2017

In patients with a common form of breast cancer, known as estrogen receptor (ER) “positive”, endocrine therapy is often recommended after other treatments such as surgery, chemotherapy, and radiation are complete. Tamoxifen, most commonly used in pre-menopausal women, blocks the estrogen receptor on the breast cell, so estrogen cannot impact cell growth. In post-menopausal women, aromatase inhibitors (AI) are commonly used – these medications block the production of estrogen in the fat cells – a primary source of estrogen after menopause. Historically, these medications have been used for 5 years after completion of other treatment, although there are some studies suggesting longer courses may benefit certain patients. However, longer courses of therapy are associated with a higher incidence of side effects.

A study just published in the New England Journal of Medicine demonstrated that after 5 years of endocrine therapy, patients have an increasing risk of breast cancer recurrence with long term follow up. The authors evaluated individual patient data from a large database of randomized trials. They found that in patients with stage I tumors (tumor less than 2 centimeters and no lymph node involvement) the 20 year risk of recurrence was approximately 13%. In patients with 4-9 involved nodes, the risk ranged from 34-41% depending on the size of the main tumor.

This study is important as it confirms what many of us see in our practices – that breast cancer can and does recur, even many years after therapy. However, it also raises an important discussion point about our treatments. Studies have estimated that as many as 30% of women prescribed endocrine therapy stop treatment due to side effects which significantly interfere with quality of life such as menopausal symptoms, bone and joint pains, bone loss (osteoporosis) and fracture, and mental status changes (“chemobrain”). Patients should discuss any of these symptoms, especially if they are considering stopping their medication, with their physicians. Lifestyle changes, exercise programs, and medications may be of benefit. It is also important to understand that despite all appropriate treatment, cancer can and does come back – so health maintenance and surveillance are important even long after cancer therapy has ended.