October 2014 by SMCMA

S a n M at e o C o u n t y

October 2014

S A N M AT E O C O U N T Y M E D I C A L A S S O C I AT I O N

Volume 3 Issue 9

Physician Advances in the understanding and treatment of breast cancer

Breast cancer genomics: Are we ready for a change? Early detection and diagnosis of breast cancer: A 20-year perspective Management of breast cancer patients in the current era of personalized medicine Breast cancer and the radiation oncology evolution Breast cancer from a medical oncology perspective Big data and personalized medicine: The role of the pathologist

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S a n M at e o C o u n t y

Physician Editorial Committee Russ Granich, MD, Chair Uli Chettipally, MD Sharon Clark, MD Edward Morhauser, MD Gurpreet Padam, MD Sue U. Malone, Executive Director Shannon Goecke, Managing Editor

October 2014 / Volume 3, Issue 9 Columns President’s Message: A day without ribbons . . ..................................4 Vincent Mason, MD

SMCMA Leadership Vincent Mason, MD, President; Michael Norris, MD, President-Elect; Russ Granich, MD; SecretaryTreasurer; Amita Saxena, MD, Immediate Past President Alexander Ding, MD; Manjul Dixit, MD; Toby Frescholtz, MD; Edward Koo, MD; Alex Lakowsky, MD; Susan Nguyen, MD; Michael O’Holleran, MD; Kristen Willison, MD; Douglas Zuckermann, MD; David Goldschmid, MD, CMA Trustee; Scott A. Morrow, MD, Health Officer, County of San Mateo; Dirk Baumann, MD, AMA Alternate Delegate

Editorial/Advertising Inquiries San Mateo County Physician is published ten times per year by the San Mateo County Medical Association. Opinions expressed by authors are their own and not necessarily those of the SMCMA. San Mateo County Physician reserves the right to edit contributions for clarity and length, as well as to reject any material submitted. Acceptance and publication of advertising does not constitute approval or endorsement by the San Mateo County Medical Association of products or services advertised. For more information, contact the managing editor at (650) 312-1663 or sgoecke@smcma.org. Visit our website at smcma.org, like us at facebook.com/smcma, and follow us at twitter.com/SMCMedAssoc. © 2014 San Mateo County Medical Association

Feature Articles Advances in the understanding and treatment of breast cancer.................................................................8 Breast cancer genomics: Are we ready for a change? Mamatha Chivulka, MD, FASCP, FCAP Early detection and diagnosis of breast cancer: A 20-year perspective Harriet Borofsky, MD Management of breast cancer patients in the current era of personalized medicine Andrea Metkus, MD Breast cancer and the radiation oncology evolution Loan Tran, MD Breast cancer from a medical oncology perspective Jennifer Brown, MD Big data and personalized medicine: The role of the pathologist Keith Duncan, MD, PhD

Of Interest Member Updates, Index of Advertisers......................................... 14

President’s Message by Vincent Mason, MD

A day without ribbons

ctober is Breast Cancer Awareness Month. A time to contemplate the loss of a mother, grandmother, sister, wife, aunt, niece, cousin or friend who may have died from breast cancer. It is also a time to celebrate and appreciate the women who are still here, surviving and thriving. As I prepared to write this article I

was reminded of the impact breast cancer will have on women in the United States for 2014 (as per data from The American Cancer Society’s estimates): • About 232,579 new cases of invasive breast cancer will be diagnosed. • About 62,570 new cases of carcinoma in situ (CIS) of the breast will be found (CIS is non-invasive and is the earliest from of breast cancer). • About 40,000 deaths will occur from breast cancer. • Breast cancer is the most common cancer among women

in the United States, other than skin cancer. It is the second leading cause of cancer death in women after lung cancer. Over the years, breast cancer has moved from the canopy of shame and embarrassment to a point of recognition and activism. During the time of Hippocrates, 460 B.C, breast cancer was considered a “humoral” disease. The four humors are blood, phlegm, yellow bile and black bile; breast cancer during that time was considered to be due to an excessive amount of black bile. The cancer was described as karkinos, a Greek word for “crab,” because the tumors seemed to have tentacles, like the legs of a crab. By A.D. 200, Galen also described breast cancer and felt it was due to black bile as well. However, he postulated that medications like opium, castor oil, licorice, sulphur, salves, and so on were considered medicinal therapy for breast cancer. During this time, breast cancer was

“

seen as a disease, which affected the whole body, and thus surgery was not considered. I could continue with ancient history, but I think you get the point. What intrigues me most about the activism around breast cancer is a woman by the name of Charlotte Haley—the creator of the first breast cancer ribbon. It was a peach ribbon. In 1991, Charlotte began handmaking peach breast cancer ribbons in her dining room. Her motivation was two fold: She had lost women in her family to breast cancer, and she was concerned because the National Cancer Institute’s annual budget at that time was $1.8 billion and only 5 percent was going toward cancer prevention. She made the peach breast cancer ribbons and went about handing out cards at the local supermarket and writing to prominent women, everyone from former first ladies to “Dear Abby.” Charlotte Haley didn’t go unnoticed, but she was not interested in a

During the time of Hippocrates, 460 B.C, breast cancer was considered a “humoral”

““

4 SAN MATEO COUNTY PHYSICIAN | OCTOBER 2014

disease...though to be due to an excessive amount of black bile. The cancer was described as karkinos, Greek for “crab,” because the tumors seemed to have tentacles, like the legs of a crab.

broader audience when approached by Alexandra Penney, then the editor in chief of Self magazine, and Evelyn Lauder, senior vice president of cosmetics company Estée Lauder, who saw the potential of a ribbon branded to breast cancer. Charlotte felt they were too corporate and commercial for her. Penney and Lauder changed the color of the ribbon, and the pink ribbon for Breast Cancer awareness was born. There is a great documentary film, Pink Ribbons, Inc. regarding Charlotte Haley’s activism and the birth of the pink ribbon campaign. Charlotte Haley died February 2, 2014 at the age of 91 at her home in Simi Valley, CA. The pink ribbon associated with Breast Cancer Awareness month reminds us of women past, present and future affected by this disease. This issue includes several articles on breast cancer—authored by specialists in radiology, oncology, pathology, and surgery—that will give readers insight into breast cancer genomics, early detection and diagnosis, management, treatment, as well as the impact of big data and personalized medicine.

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October 2014 Dear Physician Colleagues,

777 MARINERS ISLAND BLVD. SUITE 100 SAN MATEO, CA 94404 Telephone: (650) 312-1663 Facsimile: (650) 312-1664 E-mail: smcma@smcma.org Website: www.smcma.org Officers Vincent R. Mason, M.D. President Michael Norris, M.D. President-Elect Russ Granich, M.D. Secretary-Treasurer Sue U. Malone Executive Director Board of Directors Alexander Ding, M.D. Manjul Dixit, M.D. Toby Frescholtz, M.D. Edward Y. Koo, M.D. Alex Lakowsky, M.D. Susan Nguyen, M.D. Michael O’ Holleran, M.D. Kristen Willison, M.D.

I need your help in protecting California’s Medical Injury Compensation Reform Act (MICRA). On November 4, 2014, voters will go to the ballot to vote on Prop 46. The importance of MICRA to physicians in the state of California is significant. I am not asking you to assemble and march on Sacramento as more than 800 physicians, nurses, lab technicians and hospital personnel did in a grass roots effort lead by the California Medical Association on May 13, 1975. Trial lawyers have sponsored Prop 46. If Prop 46 passes, the current MICRA cap will quadruple from $250,000 to $1.2 million on non-economic damages in medical malpractice lawsuits. If Prop 46 passes, it will result in higher health care cost for everyone and threaten patient’s access to care with his or her providers. If Prop 46 passes, California will be flooded with new lawsuits and big payouts to trial lawyers. The California Medical Association and county medical associations across the state have been working tirelessly to defeat this measure, but we still need your help. The next few weeks are crucial if we are to defeat Prop 46. I am asking you for a voluntary contribution ($25, $50, $100, $250, $500) to help us preserve MICRA. Please donate by debit card, credit card (Visa, MasterCard, or Discover) or personal check. You may contribute any amount you wish. Mail your check to: SMCMA – Prop 46, 777 Mariners Island Blvd. #100, San Mateo, CA 94404. Alternatively, go to www.smcma.org/NoOnProp46 and make your contributions electronically with your debit or credit card. When November 4 arrives, I hope we will be able to celebrate the defeat of Prop 46. Respectfully yours,

Douglas Zuckermann, M.D. Amita Saxena, M.D. Immediate Past President Ex Officio

Vincent R. Mason, MD President

David Goldschmid, M.D. CMA Trustee Dirk Baumann, M.D. AMA Alternate Delegate Scott A. Morrow, M.D. Health Officer, County of San Mateo

Editor’s Note: Some members may not receive this issue of San Mateo County Physician until after the November election, but this fundraiser will remain open until further notice. Your support helps enable us to keep fighting to protect the interests of today’s physicians. Thank you for your support.

6 SAN MATEO COUNTY PHYSICIAN | OCTOBER 2014

CAMPBELL LOCATION 3425 S. Bascom Avenue Suite I Campbell, CA 95008

ATHERTON LOCATION 3351 El Camino Real Suite 200 Atherton, CA 94027

appointments & referrals: 408-377-3331 online spine encyclopedia at: SanJoseNeurospine.com

Physician Profile Adebukola Onibokun, MD Board-certified Neurological Surgeon

Announcing a new Silicon Valley spine center option for those wanting freedom from back and neck pain We’re pleased to announce a new option for back and neck pain patients: San Jose Neurospine, which began seeing patients in early September through its offices in Campbell and Atherton. The spine center includes the expertise of Adebukola Onibokun, MD, a board-certified neurological surgeon who specializes in minimally invasive spine surgery. Over his career, he has done more than 2,000 successful surgeries. Dr. Adebukola Onibokun emphasizes a conservative approach to the care of his patients and encourages non-surgical treatment first. Some of these non-surgical treatment options for back and neck pain can include pain relieving spinal injections that reduce inflammation around a nerve root and spine-specialized therapy which increases the flexibility of the back, strengthens muscles and ligaments and reduces likelihood of future strain. In this regard, he works very closely and collaboratively with outside pain management specialists and therapists to coordinate non-surgical treatment options. If non-surgical options fail, or when symptoms progress to weakness/numbness in an arm or leg, the center uses minimally invasive spine surgery techniques that enable most patients to be home later the same day.

Minimally invasive spine surgeries performed MIS Lumbar Discectomy & Posterior Cervical Discectomy This procedure is done by making a small 1-inch incision over the herniated disc and inserting a tubular retractor. Then the surgeon removes a small amount of the lamina bone that allows the surgeon to view the spinal nerve and disc. Once the surgeon can view the spinal nerve and disc, the surgeon will retract the nerve, remove the damaged disc, and replaces it with bone graft material. MIS Lumbar Fusion A minimally invasive lumbar fusion can be performed the same way as traditional open lumbar fusion, either from the back, through the abdomen, or from the side. Lateral interbody fusion (LIF) A lateral interbody fusion, often used to treat spondylolysis, degenerative disc disease and herniated discs, is performed by removing a disc and replacing it with a spacer that will fuse with the surrounding vertebra. The procedure is completed on the side of the body in order to reduce the effect on the nerves and muscles.

Posterior cervical microforaminotomy (PCMF) A PCMF is performed to help relieve pressure and discomfort in the spine by making a small incision in the back of the neck and removing excess scar tissue and bone graft material. Anterior cervical discectomy An anterior cervical discectomy is used to reduce pressure or discomfort in the neck by removing a herniated disc through a small incision in the front of the neck. The space is then filled with bone graft material and plates or screws may be used to increase stability. Artificial Disc Replacement Artificial disc replacement is intended to be an alternative to spinal fusion surgery. Unlike a fusion that locks the two vertebrae in place, an artificial disc retains movement in the spine by simulating the natural rotational function of the disc.

San Jose Neurospine includes the expertise of Adebukola Onibokun, MD, a board-certified neurological surgeon who specializes in minimally invasive spine surgery. Dr. Onibokun (pronounced “Oh-kneebow-kun”) is Board Certified by the American Board of Neurological Surgery and is a fellow of the American Association of Neurological Surgeons. Dr. Onibokun received his medical degree from the prestigious Northwestern University Medical School, graduating with honors. He then completed 7 years of Neurosurgery Residency training at UCLA Medical Center, a program that consistently ranks as one of the top five neurosurgery programs in the country. Dr. Onibokun has previously served as Chief of Neurosurgery at Elmhurst Memorial Hospital in the Chicago area, where he established their Minimally Invasive Spine Surgery program. Prior to relocating to California, he was a Health System Clinician at the Northwestern Medicine Regional practice.

Home Remedy Book We provide a free 36-page Home Remedy Book that includes symptom charts that show when to see a doctor; home remedies; stretches that can relieve pain symptoms; and exercises that make the back stronger, more flexible and resistant to future strain. Call us, or email us at admin@ SanJoseNeurospine.com, and we’ll send 10 copies to your office for your patients. Our educational Internet presence at SanJoseNeurospine.com also has educational videos, medical illustrations, information on minimally invasive spine surgery options and a referral form.

View our video library to learn more about our practice online at: SanJoseNeurospine.com/videos

OCTOBER 2014 | SAN MATEO COUNTY PHYSICIAN 7

ADVANCES IN THE UNDERSTANDING AND TREATMENT OF BREAST CANCER October is Breast Cancer Awareness Month. This work is dedicated to the women diagnosed with breast cancer and their families who inspire our physician community to strive for excellence. Mamatha Chivukula, MD, FASCP, FCAP ■ Harriet Borofsky, MD ■ Andrea Metkus, MD Loan Tran, MD ■ Jennifer Brown, MD ■ Keith Duncan, MD, PhD

Breast cancer genomics: Are we ready for change? Mamatha Chivukula, MD, FASCP, FCAP Management of breast cancer has significantly changed with widespread screening, use of systemic chemotherapy, and radiation therapy impacting the outcome in breast cancer patients. In early breast cancer trials, tamoxifen has shown to prolong survival in a subset of estrogen expressing (ER+) cancers. In the neoadjuvant or metastatic setting, concurrent or sequential use of trastuzumab or/ and pertuzumab has shown a significant response in HER2-positive patients. Breast cancer demonstrates heterogeneity and diversity in its natural history and response to chemotherapy. In a seminal study published in Nature 2000, Perou and collegues have changed our understanding of breast cancer drastically. In this study, gene expression patterns using complimentary DNA (cDNA) microarrays were studied in a set of breast cancers. A hierarchical clustering method was used to isolate the groups of tumors with similar gene expression patterns. Based on clustering, four intrinsic subtypes were under identified—ER expressing group that includes luminal A and Luminal B subtypes; ER negative group that includes HER2 and triple negative subtypes. Although luminal A&B are hormoneexpressing tumors that have distinguishing characteristics, breast cancers expressing high levels of Ki-67, a nuclear marker of cell proliferation, are associated with worse outcomes. Luminal A tumors have shown to have higher expression of ER-related genes and lower expression of proliferative genes than luminal B. The fact that Luminal B tumors have poorer outcomes than luminal A tumors is probably related to their high proliferation. HER2 is a larger group of tumors identified by gene expression array showing over-expression of HER2

and other genes in the ERBB2 amplicon such as GRB7. These tumors also showed low levels of expression of ER and other genes related to ER expression, a trait they share with the basal-like tumors. The currently available HER2 tests are directed toward ERBB2 (HER2) gene, for which targeted therapy is available. HER2 testing is performed at our lab, using dual in situ hybridization (DISH) methodology approved by College of American Pathologists (CAP)/American Society of Clinical Oncologists, has neen successfully implemented in conjunction with immunohistochemistry (IHC). Since it’s not feasible to obtain gene arrays information, a simplified classification proposed by Cheang and Goldrich was found to be close to the approximation based on ER, PR, HER2 and Ki-67 expression by IHC method was accepted by St Galen’s consensus committee. Currently, in our practice we report the prognostically significant intrinsic subtypes in our breast cancer pathology reports. Breast cancer is a heterogeneous carcinoma with great diversity in morphology and clinical presentation. A major challenge for oncologists is determining the group of patients who might benefit from adjuvant therapy. As Dr. George Sledge has said, “tumors greater than one centimeter ought to be treated with chemotherapy. There’s no question that resulted in hugely over treating patients, so I think a test that reduces the quantity of human suffering by half in that group is a useful test.” Improvements in breast cancer screening and advancements in pathological diagnosis have led to early detection of small tumors. OncotypeDx (ODX) and Mammaprint are the two popular early breast cancer prognostic tests contributing significantly in management of breast cancer over the last decade. ODX is an assay that

8 SAN MATEO COUNTY PHYSICIAN | OCTOBER 2014

evaluates 21 genes of Estrogen receptor, proliferation, HER2 and others using reverse transcription polymerase chain reaction-based assay (RT-PCR) that may be performed on routinely processed, formalin-fixed, paraffin-embedded tissue. The results are reported for recurrence as risk categories—low, intermediate and high. In the last decade, data from large clinical trials (NSABP 14, 20, ATAC) have shown the association of ODX with distant recurrence in women with lymph node negative disease. The ODX high-risk category has shown a higher recurrence than other categories (3.0 vs 38.3). The ODX testing has been extended to lymph node-positive women. Two large trial data (ATAC and SWOG) have shown similar results. Mammaprint is a whole genomic assay that evaluates 25,000 genes and reports the results based on 70 significant prognostic genes into two outcome categories—good and poor signatures. The results from the RASTER study, the first and only prospective follow up of an impact study on gene expression signatures in ER(+), HER2(-), patients have shown that treatment has changed in 20% of patients according to mammaprint. The five-year Distant Recurrence Free Survival probabilities for MammaPrint® low-risk (n=219) and highrisk (n=208) patients were respectively 97.0% and 91.7%. In the Mammaprint Low-Risk group. only 15% of the patients received adjuvant chemotherapy, versus 81% in the Mammaprint High-Risk group. Is the gene array testing going to be routine? Multigene prognostic tests ODX and Mammaprint are available currently as reference lab tests. Peer reviewed papers, meeting abstracts, and company supplied brochures regarding clinical utility are also available. In large randomized clinical trials (B14, B20), ODX and Mammaprint have shown to be considered for clinical use.

Are we ready for application of the genomics? The role of “pathologist” has evolved in the era of personalized medicine. The burden on pathologists has increased as the understanding of the biology of the cancer and its genomics have progressed. There are many puzzling questions behind each patient tumor slide. What does the diagnosis mean for the patient and his or her loved ones? What additional information do I need to provide my clinical colleagues regarding the natural history of the diagnosis (therapies)? What genes are driving the tumor? Can we target it? What will be the resistance mechanisms? The explosion of “genomics” had resulted in a wave of efforts to advance in cancer care. Clinical impression of breast cancer heterogeneity has been proven at the gene expression level as well. Based on gene expression profile, molecular subtypes are recognized with distinct prognostic outcomes and classified using immunohistochemistry as well. The identification of intrinsic molecular subtypes of breast cancer has enhanced the understanding of biology, therapeutic targets, and clinical trial designs. To answer the question “are we ready for a change?” …the answer is yes. Progress made in breast cancer treatment has largely been due to improved understanding of the biology of the cancer. We are in exciting times as the improvement in screening, diagnosis and treatment of breast cancer is at an accelerated pace. Integration of radiologic, pathologic and surgical modalities in a multi-disciplinary approach will enormously contribute to breast cancer treatment. 1. Perou et al. Molecular portraits of human breast tumours. Nature. 2000 Aug 17;406(6797):747-52. 2. Comprehensive molecular portraits of human breast tumours. Nature. 2012 Oct 4;490(7418):61-70. Cancer genomic atlas network. MAMATHA CHIVULKA, MD, FASCP, FCAP is clinical associate professor from Magee Women’s Hospital of UPMC; she joined the Mills-Peninsula team in 2011. Her interests are breast cancer and gynecologic cancers pathology.

Early detection and diagnosis of breast cancer: A 20-year perspective Harriet Borofsky, MD While the intense debate amongst public health and breast specialists about the efficacy of screening for breast cancer continues, one fact remains undisputed: mammography has played a key role in reducing breast cancer mortality. Six randomized controlled trials, performed prior to the era of modern mammography, have confirmed a disease-specific mortality reduction in women invited to be screened of 21% to 44%. Since the emergence of dedicated breast centers, beginning in the 1990s in response to the increased demand for population-based screening and the Mammography Standards Act of 1998, setting national standards and quality requirements for facilities performing mammograms, the death rate from breast cancer has decreased by 34%. In fact, the success of mammography in detecting early stage breast cancers has been the driving force behind the evolution of novel surgical, radiation oncology and medical approaches that have resulted in increased treatment options and decreased morbidity for the majority of women facing this diagnosis; patients may forego chemotherapy. Of course, the benefits of populationbased screening mammography must be weighed against its inherent risks. Mammography has been validly criticized because of its lack of specificity and its limited sensitivity, particularly in women with dense breast tissue. False positive findings lead to recalls for additional imaging, added radiation exposure, biopsies, patient anxiety and health care costs. False negatives, or the failure of a mammogram to detect breast cancer within a year of diagnosis, lead to a false sense of security and delay in diagnosis. The truth is, early detection of this heterogeneously disease in the setting of the naturally heterogeneous and proliferative nature of women’s breasts, is a challenging and ever humbling endeavor. The shortcomings of mammography have been the driving force behind the major advances in breast imaging and diagnostic technologies

that have emerged in the past two decades; the most impactful of which have been core needle breast biopsies, dedicated breast ultrasound and breast MRI and, most recently, digital breast tomosynthesis, also known as 3D mammography. Because of the significant overlap in appearance of benign, proliferative changes in the breast and what may be the earliest manifestation of breast cancer, the positive predictive value, or percentage of “suspicious lesions” that prove to be cancer at biopsy, is quite low, with an ACR benchmark target of 25% to 40%. The majority of breast biopsies are, therefore, benign, which is considered to be the acceptable standard. For this reason, highly accurate, minimally invasive, percutaneous breast biopsies, under stereotactic, ultrasound and MRI guidance, using a variety of large core and vacuum-assisted needle devices, have replaced surgically excisional biopsies and have become the standard of care for diagnosis of imaging-detected lesions. These procedures are well tolerated and can be performed quickly, easily, and safely, often on the same day or week of imaging work-up. The ease of scheduling these procedures and their prompt pathology results markedly reduces patients’ anxiety. Preoperative biopsy results have contributed to the development of multidisciplinary breast tumor boards, comprised of radiologists, pathologists, surgeons, oncologists, radiation oncologists, plastic surgeons and geneticists, that meet weekly to review breast imaging findings with their pathology correlates, so that individualized treatment options may be planned and discussed with the patient. Supplemental modalities for breast cancer screening, such as ultrasound and MRI, have arisen from the demand for improved sensitivity beyond mammography; particularly in women with elevated risk for breast cancer and/or those with dense breast tissue. Readily accessible, well-tolerated, safe and inexpensive, ultrasound provides cross-sectional imaging, not limited by overlapping or dense tissue.

OCTOBER 2014 | SAN MATEO COUNTY PHYSICIAN 9

Three multi-center and six single-center trials showed that adding screening ultrasound to mammography in highrisk women with dense breast tissue increased the breast cancer detection rate (yield) by 3.5-4.4/1,000 women and increased the breast cancer detection rate by 13%- to 28%, with the majority of additional cancers detected being early stage, node negative invasive tumors. The criticism of screening ultrasound is the added level of expertise, time, additional personnel and cost required to perform these imaging procedures and the resultant, significant increase in false positives. The ACRIN 6666 study (JAMA, May, 2008) found that adding ultrasound to mammography resulted in four times the number of false positives findings requiring biopsy. Breast MRI is currently indicated for a select subset of high-risk women, regardless of breast density. MRI not only provides cross-sectional imaging and high soft tissue contrast, but also gives functional information about areas of enhancement, which may be an early indication of malignancy due to tumor neoangiogenesis. Nine studies evaluating the role of MRI, in addition to mammography, in high-risk women (risk based on family history, BRCA mutations prior biopsy showing atypica) showed an increase in breast cancer detection rate of 11-14/1,000 women screened, along with increased false positive findings leading to additional biopsies, due to limitations in specificity. An advanced application of digital mammography, Digital Breast Tomosynthesis (DBT), is poised to become the single, most impactful technologic advance in screening for breast cancer, in my medical career. Tomosynthesis utilizes multiple, limited angle exposures in an arc over the compressed breast, acquiring data that is then reconstructed at 1 mmthin sections and displayed on dedicated mammography computer monitors, along with either standard (2D) or synthesized (computer-generated - CR) views. This technology significantly improves upon the main limitation of mammography— overlapping tissue, which may lead to unnecessary recalls for additional views and/or missed breast cancer. Two European, single-site prospective trials,

(Skaane et al Radiology, 2013 and Ciatto et al, Lancet Oncol, 2013), comparing standard 2D mammography to 2D with tomosynthesis, showed a reduction in recalls of 15% and 17% and an increase in invasive breast cancer detection by 40% and 53%, respectively. In the U.S., the first multi-site, retrospective study comparing mammographic performance benchmarks before and after implementation of DBT, (Friedewald et al JAMA, 2014) showed a reduction in recall by 18% and an increase in invasive breast cancer detection by 41%. Our early, six month, clinical experience at Mills-Peninsula Women’s Center, having replaced all of our 5-mammography units with DBT, has similarly shown a decrease in recalls by 29%, along with an additional 14 invasive breast cancers detected on tomosynthesis images alone. DBT is the only new breast imaging modality to show a combined increase in invasive breast cancer detection, along with a reduction in false positives; quite compelling and significant evidence of the effective performance improvement that may be achieved with this technology. The success of mammographic screening, in the past two decades, in reducing mortality from breast cancer and in increasing treatment options for the many women diagnosed with this all too common disease, should not be overlooked or underappreciated. Mammography’s inherent limitations in specificity have been addressed with core needle biopsies, making accurate tissue diagnoses quick and minimally invasive. Mammography’s inherent limitations in sensitivity have been addressed with cross-sectional imaging modalities, such as digital breast tomosynthesis, markedly improving both specificity and sensitivity, and with the supplemental modalities of ultrasound and MRI. As we look toward the next 20 years, screening recommendations will increasingly be tailored for the individual woman, based on age, risk factors, breast density and personal preference and tolerance for screening and all that it entails. For me personally, this continues to be the most exciting and rewarding time to be dedicated to the early detection

10 SAN MATEO COUNTY PHYSICIAN | OCTOBER 2014

and diagnosis of breast cancer in our community. HARRIET BOROFSKY, MD, is medical director of breast imaging at MillsPeninsula Medical Center.

Management of breast cancer patients in the current era of personalized medicine Andrea Metkus, MD Surgery has been the primary treatment for breast cancer since the first mastectomy was performed in 1882. The thought leader of that era, William Halstead, theorized that radical surgery would lead to the best outcome, and the radical mastectomy was born. Over time, every aspect of breast cancer treatment has been de-radicalized—now smaller is better, less is more and treatment is targeted to the particular biology of each patient’s cancer characteristics. Throughout the 1970s and 1980s, several randomized controlled trials proved without doubt that breast conserving treatment (lumpectomy or partial mastectomy) had equivalent survival rate to mastectomy at every time point with more than 40 years of follow-up. Until the 1990s the staging or ”treatment” of the axillary lymph nodes included a complete axillary lymphadenectomy in all people with invasive breast cancer with its attendant morbidity of chronic pain and 25% lifetime risk of permanent lymphedema. Selecting a precise and less invasive way to stage the appropriate lymph node basin was proven for melanoma in the1990s, and the concept was re-proven in breast cancer through the 1990s. and fully accepted in the 2000s. The removal of the first draining lymph node(s) or “sentinel” node has become the standard of care in multiple cancers. On average, one or two lymph nodes are removed from the axilla having been identified by a radio-tracer dye or a blue dye injected pre-operatively. Up until a few years ago, we continued to perform radical axillary lymphadenectomy when the sentinel node had histologic evidence of breast cancer metastasis.

There has never been clear-cut evidence that radical axillary lymph node removal improves survival rates. The information about axillary lymph node metastasis is important because it reveals that the biology of the cancer gave cells the ability to spread. That information is most useful for adjuvant therapy decision making, especially the decision to recommend adjuvant chemotherapy, and may have some local control benefit. In 2011 the first randomized controlled trial omitting complete lymphadenectomy for a “positive” sentinel was published. The American College of Surgeon’s Z-11 trial proved a subgroup of patients with 1-2 positive sentinel nodes did not benefit from axillary lymph node dissection with six years of follow-up when treated with adjuvant whole-breast radiotherapy and systemic therapy.

Breast cancer and the radiation oncology evolution

allows women to return to everyday life more quickly.

Loan Tran, MD A paradigm shift is gathering momentum in the treatment of early-stage breast cancer, driven by data showing strong clinical outcomes for the use of more sophisticated therapies.

Clinical outcomes to date include more than 30 publications, including ten-year matched pair comparisons of PBI to WBI, a cooperative group Phase II trial, and two published Phase III clinical trials. The tumor control, toxicity rates, and cosmetic results compare favorably to breast conservation with WBI and mastectomy.

For 115 years, the entire breast has been treated for all stages of breast cancer, either with a scalpel (mastectomy) or a broad radiation beam (WBI). Because of the volume of tissue irradiated, WBI is given more than three to seven weeks of protracted daily treatments. Newer therapies using accelerated partial breast irradiation (APBI, also referred to as breast brachytherapy) offer properly selected patients several advantages over traditional WBI.

The five-year overall survival and diseasefree survival was 91.8% and 82.2%, respectively, whereas in the sentinel node only group, it was 92.5% and 83.9% (p=0.008). The trial only enrolled patients undergoing lumpectomy, and the data cannot be extrapolated to patients undergoing mastectomy. Although 27% patients who went on to have a complete axillary dissection in the trial (the control arm) had additional metastatic lymph nodes in the additional removed lymph nodes, the axillary failure rate was very low and not significantly different between the two groups.

Brachytherapy has been intensively studied and used in modern clinical practice since the early 1990s. Initial research dates back to the 1920s, when the British surgeon Jeffrey Keynes inserted radium needles into breasts with breast cancer before any external radiotherapy was available. Early techniques required the insertion of multiple catheters inserted individually into the breast.

This trial’s main shortcoming was the higher-than-expected numbers of patients with micro-metastatic disease in the sentinel node in both groups. However, this trial lead to a nearimmediate practice-changing paradigm having proved in the relatively short term that no harm comes from eliminating a full axillary node dissection when the metastatic burden in the axilla is low as long as the patient meets three criteria: lumpectomy, whole breast radiation and systemic therapy.

Today there are multiple innovative applicators available for breast brachytherapy that allow the radiation oncologists more control of the radiation dose to the skin and ribs, and more precisely deliver radiation to the tumor bed. As a result, radiation exposure to healthy tissue, such as the skin, chest wall, lungs and coronary arteries, could be limited, providing better cosmetic results, fewer side effects and less long-term toxicity.

ANDREA METKUS, MD, is Director of Breast Cancer Services at MillsPeninsula.

In 2002, the U.S. Food and Drug Administration (FDA) approved the first breast brachytherapy applicator involving insertion of just one device into the lumpectomy cavity.

Since the radiation dose cloud is sculpted to the breast tissue at risk, the volume treated is substantially less, and the overall treatment time can be shortened to five days vs. six weeks with the traditional WBI. Five-day breast cancer treatment also

This is exciting news for women, who deserve the highest standard of care— one that allows them to maintain their health and return to their normal lives as soon as possible. With more breast cancers being detected at early stages, we can now provide safe, effective and far more convenient radiation therapy. APBI is not for every patient, however. Patients with multiple lesions, nodal involvement, or in later stages of cancer cannot be effectively treated with APBI. LOAN TRAN, MD, is a radiation oncologist at Mills Peninsula specializing in breast and gynecology cancers and brachytherapy.

Breast cancer from a medical oncology perspective Jennifer Brown, MD From a medical oncology perspective, there have been exciting advances made in the treatment of patients with HER2positive breast cancer, which constitutes approximately 20% of all invasive breast cancer diagnoses. The initial development of trastuzumab (Herceptin) revolutionized the treatment of HER2-overexpressed breast cancer, with important roles now clearly established in the adjuvant and metastatic settings. However, new anti-HER2 agents are now available in practice, including pertuzumab (Perjeta), and T-DM1 (Kadcyla), and we are observing excellent results in our patients. Pertuzumab, like trastuzumab, is a recombinant monoclonal antibody and targets the extracellular dimerization domain of the HER2 receptor. Pertuzumab has shown efficacy and a favorable toxicity profile in the neoadjuvant and metastatic settings when combined with trastuzumaband chemotherapy. With

OCTOBER 2014 | SAN MATEO COUNTY PHYSICIAN 11

respect to neoadjuvant treatment, dual anti-HER2 therapy has improved the rate of pathologic complete response (pCR) in patients receiving systemic therapy prior to their breast surgery. The randomized phase II NeoSphere trial evaluated the neoadjuvant combination of pertuzumab, trastuzumab, and docetaxel (Taxotere) in patients with HER2-positive breast cancer. This drug combination nearly doubled the rate of pCR when compared to the other treatment arms. The phase III, randomized, placebocontrolled CLEOPATRA study evaluated the role for pertuzumab as first-line treatment for metastatic, HER2-positive breast cancer. Patients received docetaxel and trastuzumab with either pertuzumab or a placebo. When pertuzumab was added to docetaxel/trastuzumab, there was a significant improvement in progression-free survival (PFS). For patients with metastatic breast cancer who have previously received trastuzumab and taxane chemotherapy, T-DM1 (Kadcyla) is an exciting new therapy option. T-DM1 is an antibodydrug conjugate that targets the HER2 receptor and works by effectively delivering chemotherapy directly into breast cancer cells. As a result, this form of targeted therapy has been shown to increase the efficacy of treatment, while also decreasing drug-related side effects. In the EMILIA trial, women with HER2positive breast cancer received either T-DM1 or a combination of capecitabine (Xeloda) and lapatinib (Tykerb). Results again revealed an improvement in PFS in those patients receiving T-DM1. JENNIFER BROWN, MD, is a medical oncologist at California Cancer Care.

Big data and personalized medicine: The role of the pathologist Keith Duncan, MD, PhD Drs. Gu and Taylor (a former stellar mentor of mine at the University of Southern California) succinctly summarize the function of pathology in their article: Practicing pathology in the era of big data and personalized medicine: “The traditional task of the pathologist is to assist physicians in making the correct diagnosis of diseases at the earliest possible stage to effectuate the optimal treatment strategy for each individual patient.” The evolution of personalized medicine has transformed the specialty of pathology from simple classification of neoplasia and disease by the H&E slides, to pinpointing sites of origin for metastatic tumors by immunoperoxidase stains to newer biomarkers such as HER2/ neu markers in breast cancer, which allow targeted therapy. Not too long ago, terms like “translational medicine’”and “targeted therapy” were felt to be on the fringe of clinical practice but have gained rapid acceptance in mainstream practice. Pathologists play a crucial role as personalized medicine insinuates itself into clinical practice through the design of biomarker studies to developing optimal sample collections and data interpretation. Pharmaceutical and diagnostic companies are increasingly hiring anatomic and clinical pathologists because the importance of having pathologists’ input in the development of oncology drugs and companion diagnostics has been recognized; this practice is becoming a commonplace alternative to community or academic employment. Additionally, it is often the pathologist who educates their colleagues about the availability and use of new clinical laboratory tests. Over the years, pathologists have served clinicians by providing prognostic information of neoplasms and their typical growth pattern. New techniques

12 SAN MATEO COUNTY PHYSICIAN | OCTOBER 2014

of molecular biology have altered the role of the pathologist and the tools for characterizing neoplasms. With a unique perspective on disease processes and access to tissue specimens, the pathologist has become a key player in the area of personalized medicine and the development of new approaches to diagnosis and biomarkers to qualify patients for specific therapeutic drugs. Pathologists are the only professionals in health care that can interpret genomic, gene expression, and proteomic data in the context of tumor morphology. Only the pathologist can comment on the presence, absence, and differential expression of biomarkers in tumor cells versus the background normal cells, in in situ tumors versus invasive tumors, and in different grades and patterns of a tumor present within one tumor. For decades, pathologists have had the ability to correlate protein expression with histological patterns by employing immunohistochemical (IHC) methods. More recently, with the commercial release of light microscopy-based in situ hybridization methods, gene amplification has been an important tool that enables pathologists to visualize individual copies of genes and amplification states in the context of morphology. In the era of personalized medicine, the practice of pathology will need to undergo some changes to remain aligned with the needs of oncologists and their patients. Traditional morphologic diagnosis will not disappear but will take on greater importance as pathologists expand their ability to comprehensively profile patients’ tumors with nextgeneration, in situ methods. The pathologist’s role will be to integrate the data from these diverse technologies into a coherent report The pathology report of the future will contain not only diagnostic and prognostic information but also critical predictive information pertaining to which drugs will be effective. KEITH DUNCAN, MD, PhD, is medical director of pathology and laborabory medicine at Mills-Peninsula.

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