Wednesday, June 24, 2015

The Mammography Debate

Our Chief of Research, Constantine Kaniklidis,  has just published two reports in "Current Oncology" presenting an evidence-based review of the mammography debate. We are so very fortunate to have Constantine as our partner, friend and guiding light.

Below we present two abstracts with links to the articles.

Both articles were just published in the Current Oncology journal, and available (hyperlink below) online at (I include the brief abstracts for each):
 
Through a glass darkly: the mammography debate
[Invited Editorial]

About the ongoing breast cancer screening mammography debate - less a controversy, because many points of consensus and convergence are present if not always apparent - we can make these points as prelude: that it is complex; that it is naïvely implausible to expect any decisive final resolution to the residual issues that will be convincing to the principle contending parties; and that behind it all, the devil is in the methodology. In this editorial we propose: (1) a greater focus on moving beyond the current borders of the mammography debate to secure superior screening technologies that will erode the central status currently occupied by conventional mammography; (2) making research advances that will minimize the harms, especially of overdiagnosis (overdetection); and (3) furthering research to provide validated markers for the discrimination of low-risk and indolent disease.

Beyond the mammography debate: a moderate perspective [Perspectives in Oncology Review]

After some decades of contention, one can almost despair and conclude that (paraphrasing) “the mammography debate you will have with you always.” Against that sentiment, in this review I argue, after reflecting on some of the major themes of this long-standing debate, that we must begin to move beyond the narrow borders of claim and counterclaim to seek consensus on what the balance of methodologically sound and critically appraised evidence demonstrates, and also to find overlooked underlying convergences; after acknowledging the reality of some residual and non-trivial harms from mammography, to promote effective strategies for harm mitigation; and to encourage deployment of new screening modalities that will render many of the issues and concerns in the debate obsolete.

To these ends, I provide a sketch of what this looking forward and beyond the current debate might look like, leveraging advantages from abbreviated breast magnetic resonance imaging technologies (such as the ultra fast and twist protocols) and from digital breast tomosynthesis—also known as three-dimensional mammography. I also locate the debate within the broader context of mammography in the real world as it plays out not for the disputants, but for the stakeholders themselves: the screening-eligible patients and the physicians in the front lines who are charged with enabling both the acts of screening and the facts of screening at their maximally objective and patient-accessible levels to facilitate informed decisions.

(Both as HTML (above) and as PDF. For convenience, I attached the PDF versions to this posting.) A third article of mine will be published in the August issue, and I will post that when available.

 Through_a_Glass_Darkly_-_the_mammography_debate.pdf

Beyond_the_mammography_debate_-_a_moderate_perspective.pdf 


Constantine Kaniklidis
Research Director
No Surrender Breast Cancer Foundation (NSBCF)

Saturday, June 6, 2015

Controlling Pain in Breast Cancer Surgery

 The take-away:

Post operative pain in breast cancer surgery can be quite difficult for the patient particularly in the setting of sentinel node and axilla dissection. This scientific article shows ways to help control the pain.

It is most fortunate that acetaminophen is now available in an IV form because it can be given in the recovery room to enhance pain relief. Opioids are not always the answer or the best choice in controlling pain; their side effects often outweigh their benefits.

Localized (regional) pain relief with either a long acting numbing agent administered before the patient awakens from anesthesia and/or the insertion of a pain pump that delivers numbing action directly to the surgical site can “break the cycle” of pain before it begins for the patient. Thus, the patient feels better in recovery and is able to begin the healing process without pain being the main focus.


There is even some evidence that avoiding opioid use may improve survival, but there needs to be more studies to investigate this further.


Improving Patient Outcomes Through State-of-the-Art Pain Control in Breast Cancer Surgery
Jacob L. Hutchins, MD

Abstract
Acute post surgical pain continues to be difficult to manage in patients who undergo breast cancer surgery. Poorly controlled pain can lead to poor patient satisfaction, increased length of stay, and increased risk of opioid adverse events, and may be a factor in the development of chronic pain. A multimodal analgesic regimen that consists of 2 or more non-opioid medications and is initiated in the preoperative phase and continued during the intraoperative and acute postoperative phases may provide the best patient outcomes. These nonopioid medications include, but are not limited to, local anesthetics, acetaminophen, nonsteroidal anti-inflammatory drugs, antiepileptics, alpha-2-adrenergic antagonists, N-methyl-D-aspartate antagonists, and glucocorticoids. This multimodal approach can be a stand-alone protocol or a part of a more comprehensive enhanced recovery after surgery (ERAS) protocol.


Postoperative pain control remains a common problem for patients undergoing breast cancer surgery. A recent survey showed that patients’ number one concern leading up to surgery is pain.

Uncontrolled, acute postoperative pain can lead to an increased surgical stress response. This then has an effect on endocrine, metabolic, inflammatory, and immune functions, which can further stress various organ systems. Appropriate pain control can lead to improved postoperative outcomes as well as decreased pulmonary and cardiac complications.

In addition, uncontrolled acute postoperative pain is associated with longer stays in the postanesthesia care unit, longer hospital stays, decreased patient satisfaction and quality of life, and increased costs. Furthermore, while multifactorial in nature, the incidence of chronic pain may be decreased by an aggressive multimodal approach in the acute postoperative setting. As many as 4% to 63% of patients suffer chronic pain after mastectomy, and as such, effective acute pain control remains paramount to patient recovery following breast cancer surgery.

The mainstay of perioperative pain control has been opioids. However, opioids are associated with significant risks and adverse effects (AEs) such as pruritus, constipation, nausea/vomiting, urinary retention, oversedation, and respiratory depression. A recent sentinel event alert by The Joint Commission expressed the need for safe use of opioids in the hospital setting. This alert identified those most at risk for respiratory depression, including patients with obstructive sleep apnea or those who are opioid-naïve or obese, which are common characteristics of patients undergoing breast cancer surgery. Furthermore, opioid abuse is an ever-increasing problem in the United States. A recent survey in 2010 showed that 5.1 million US citizens had used opioids illicitly within the past month. Finding ways to minimize opioids in the treatment of perioperative pain may not only decrease AEs, but also decrease the exposure and subsequent misuse of opioids in society.

A multimodal approach has been used for perioperative pain control in various surgical procedures. Multimodal analgesia is the use of more than 1 class of nonopioid medication to reduce pain and minimize the AEs of any 1 class of pain medication. These medications act via different mechanisms and produce a synergistic effect on acute pain control. A successful multimodal protocol requires coordination between all phases of care: preoperative, intraoperative, and postoperative. Furthermore, the surgical, anesthesia, and nursing teams must all work together to ensure that all aspects of the multimodal plan are followed.

The Table lists a sample multimodal approach for breast cancer surgery. A preoperative regimen could consist of an antiepileptic medication, such as gabapentin or pregabalin, acetaminophen, and regional anesthesia. Preemptive analgesia ensures that the medication given is active before and during surgery. This also may decrease afferent transmission of pain signals and decrease acute postoperative pain. Several studies have shown opioid reduction and decreased acute and chronic pain using preemptive antiepileptics such as gabapentin or pregabalin. Regional anesthesia for breast cancer surgery could be either paravertebral blocks, pec blocks, or a thoracic epidural injection.  These blocks can be either a single-shot block or a continuous infusion via catheter. Several studies have shown  decreased  postoperative  pain  when these regional techniques are used for breast surgery. If a transverse rectus abdominis muscle (TRAM) or deep inferior epigastric perforator (DIEP) flap is performed, the use of transversus abdominis plane block (TAP) has also been shown to decrease postoperative opioid use and pain scores.



Intraoperatively, pain control should consist of zero to minimal short-acting opioids and a redose of acetaminophen if adequate time has passed. If the patient didn’t receive preoperative regional anesthesia, then the surgeon should perform infiltration with local  anesthetics.  This  can  be  liposomal bupivacaine, bupivacaine, or ropivacaine, or placement of a continuous wound infiltration catheter. The local anesthetic of choice for infiltration should be the one that provides the longest duration of action in order to provide maximal patient benefit. Liposomal bupivacaine, given via single-shot infiltration, may provide more prolonged or extended analgesia postoperatively than standard local anesthetics.  Recent data have shown liposomal bupivacaine given via infiltration to be an effective adjunct for postoperative pain  control  in  breast  augmentation  and reduction.

In addition, continuous peripheral or wound catheters can provide several days of pain relief using a continuous infusion of local anesthetic.

The postoperative pain regimen should consist of scheduled acetaminophen, scheduled antiepileptics, scheduled nonsteroidal anti-inflammatory drugs as soon as allowed, and intermittent short-acting opioids. This postoperative regimen should be continued for up to 1 week after surgery. In addition, complementary therapies such as acupuncture, aromatherapy, and healing touch can be offered to the patient. If a continuous catheter is in place, the infusion should consist of, at minimum, a local anesthetic and should be used in the acute postoperative period.

In  addition  to  the  medications  listed  in  the  preceding paragraphs and the Table, several other classes of medications can  also  be  used  pending  patient  selection.  Intravenous lidocaine has been used to decrease acute postsurgical pain in many surgical populations.  N-methyl-D-aspartate (NMDA) antagonists such as ketamine and magnesium may play a role in  central  sensitization.  The alpha-2-adrenergic antagonists clonidine and dexmedetomidine have been used in multimodal approaches in other surgical procedures with success, as they primarily act at the substantia gelatinosa of the spinal cord. Finally, glucocorticoids such as dexamethasone have been used to minimize inflammation and postoperative pain.

A comprehensive multimodal pain regimen will provide the patient with the most complete pain control. It will minimize opioids,  which  not only will  minimize  opioid-related  AEs and  opioid misuse, but may decrease  cancer  recurrence. 
A  retrospective  study  by  Exadaktylos  et  al showed  that paravertebral anesthesia and analgesia  decreased  breast cancer recurrence rates. Prospective studies have shown that paravertebral anesthetics, as opposed to general anesthetic with opioids and inhalation anesthetics, resulted in increased natural killer cell cytotoxicity as well as increased apoptosis in estrogen receptor–negative breast cancer cells.

In conclusion, this review of a multimodal approach to acute postsurgical pain can provide a framework for managing patients’ pain after breast cancer surgery. This could be used alone or in combination with an enhanced recovery after surgery (ERAS) protocol to improve patients’ postsurgical outcomes. However, future prospective randomized studies are needed to determine the exact combinations and dosages of multimodal medications to provide the optimal benefit for patients.

Affiliation: Dr Hutchins is from the University of Minnesota Department of Anesthesiology.
Disclosure: Dr Hutchins is on the speaker’s bureau, is a consultant for, and has received research funding from Pacira Pharmaceuticals and is on the speaker’s bureau for Halyard Health.
Address correspondence to: Jacob Hutchins, MD, B515 Mayo Memorial Building, University of Minnesota, 420 Delaware St, Minneapolis, MN 55455. Phone: 612-624-9990; fax: 612-626-2363; email: hutc0079@umn.edu.
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- See more at: http://www.gotoper.com/publications/ajho/2015/2015May/Improving-Patient-Outcomes-Through-State-of-the-Art-Pain-Control-in-Breast-Cancer-Surgery?mkt_tok=3RkMMJWWfF9wsRokuK%2FOZKXonjHpfsX56O8vUaOg38431UFwdcjKPmjr1YADTsp0aPyQAgobGp5I5FENTLjYUK1lt60FXg%3D%3D#sthash.iifTc5ca.dpuf

Tuesday, June 2, 2015

Clinical Trial Provides Access to Targeted Drugs To Patients Who Have Exhausted Conventional Therapy

This is very exciting and long awaited news. I have seen too many people who have exhausted all their options, and who were physically eligible for a new, targeted treatment, only to be turned down because it has not been approved for metastatic use or they are excluded because of all their previous therapies. 

When you have  no more choices, access to potentially life extending drugs is your only hope. Finally, ASCO understands this and five pharmaceutical companies are on board. This is a major breakthrough for advanced disease patients. All solid tumor and blood cancer patients are included. I have had friends with advanced lung and breast cancer beg for compassionate access only to be denied because of red tape. This trial will change that. Bravo ASCO and thank you.



ASCO Launches First-ever Clinical Trial: Aims to Learn from Patients with Advanced Cancer Who Lack Standard Treatment Options Five Leading Pharmaceutical Companies Will Support Innovative Study, Contribute Drugs


CHICAGO – The American Society of Clinical Oncology (ASCO) today announced its first-ever clinical trial that will offer patients with advanced cancer access to molecularly-targeted cancer drugs and collect “real-world” data on clinical outcomes to help learn the best uses of these drugs outside of indications approved by the Food and Drug Administration (FDA). Plans for the Targeted Agent and Profiling Utilization Registry (TAPUR) study, including the participation of major pharmaceutical companies that will contribute free drugs, were released in a news briefing at the Society’s 2015 Annual Meeting in Chicago.

The ASCO-sponsored prospective, non-randomized clinical trial will collect information on the anti-tumor activity and toxicity of commercially available, targeted cancer drugs in a range of cancer types, including any advanced solid tumor, multiple myeloma, or non-Hodgkin lymphoma with a genomic variation known to be a drug target.

“Oncologists often use therapies approved for a specific cancer indication to treat people with other types of advanced cancer, but we very rarely learn from that experience to benefit other patients,” said ASCO President Peter Paul Yu, MD, FACP, FASCO. “TAPUR will document the real-world experience of patients who receive commercially available targeted anti-cancer drugs and will describe the effectiveness and side effects of a range of targeted agents available in this study.”
ASCO will organize the operational aspects of the study, including the participation of multiple collaborators that are central to TAPUR’s success. TAPUR will involve not only patients and physicians, but also ASCO oversight committees, pharmaceutical companies, technology firms, and community-based study sites—representing a uniquely innovative and inclusive approach to studying the use of molecularly-targeted cancer drugs.

“We are leveraging ASCO’s unique ability to bring together a diverse group of collaborators to undertake something that’s never been done before, all while simplifying access to multiple cancer treatments across many tumor types,” said ASCO Chief Medical Officer Richard L. Schilsky, MD, FASCO. “Perhaps even more importantly, TAPUR will involve community-based research programs, where the majority of cancer patients receive treatment and will provide education and support to community oncologists to help them interpret complex genomic tests.”

TAPUR Next Steps
In the coming months, an Institutional Review Board will review the study protocol and consent form.  In addition, ASCO has established three oversight committees—each of which will include patient representatives, clinical oncologists, statisticians, and genomics specialists:


    •    Steering Committee to oversee study operations, establish data sharing and publication policies, review plans to add or remove drugs from the study, and approve participation of clinical study sites;
    •    Molecular Tumor Board to review the proposed drug-target match and suggest therapies on or off the study;
    •    Data and Safety Monitoring Board to regularly review study results to ensure that severe or unexpected adverse events are carefully monitored, to determine when enrollment of study cohorts should expand or cease, and to determine when to release data and to which parties.

Patient Participation
TAPUR is designed to include a broader patient population than is typically enrolled in clinical trials. It will accept patients who have any advanced solid tumor, multiple myeloma, or B cell non-Hodgkin lymphoma and are no longer responding to standard anti-cancer treatment or for whom no acceptable treatment is available. Patients will be screened to determine if they are healthy enough to participate based on broad inclusion/exclusion criteria.

If and when a patient meets the defined trial criteria, his or her treating physician will select a drug from among those available in the TAPUR study protocol that targets the identified genomic variation in the patient’s tumor. If a relevant drug-target match is not described in the protocol, a physician may consult the Molecular Tumor Board which will review the clinical and genomic features of the case and suggest potential therapies on or off the study. All patients who receive treatment through TAPUR will be monitored for standard toxicity and efficacy outcomes including tumor response, progression-free and overall survival, as well as duration of treatment.

Patients participating in TAPUR will receive the anti-cancer drugs at no charge. It is expected that routine clinical care costs will be covered by the patient’s insurance plan.

Participating Organizations ASCO has invited a number of pharmaceutical companies to provide marketed, targeted drugs and additional resources to support the development of the new study’s infrastructure. At the time of this announcement, ASCO reported that the following companies have signed memoranda of understanding agreeing to participate in the TAPUR study:

    •    AstraZeneca
    •    Bristol-Myers Squibb
    •    Eli Lilly and Company
    •    Genentech
    •    Pfizer

“At least 13 drugs that target more than 15 unique genomic variants will be provided by these companies. We are extremely grateful for the generosity of these companies without whose support TAPUR would not be possible,” said ASCO President Dr. Yu. “We anticipate additional companies will sign on, and are extremely encouraged with the level of interest we have received so far.”
ASCO will launch the TAPUR study at clinical sites that comprise the Michigan Cancer Research Consortium, the Cancer Research Consortium of West Michigan, and the Carolinas Healthcare System—existing research networks that run research trials for the National Cancer Institute and industry—with the ultimate goal of expanding nationally.

Two technology companies will provide key support to manage, analyze, and interpret the study data: Syapse will provide its Syapse Precision Medicine Platform to automate the study workflow and the Molecular Tumor Board process, and capture structured data from participating practices. Illumina will provide its NextBio knowledge base platform to support and inform the case review by the Molecular Tumor Board, as well as to support analysis of the TAPUR data by the study team.
Finally, the Society will collaborate and share data with the Netherlands Center for Personalized Cancer Treatment, which is conducting a clinical trial using a study protocol very similar to TAPUR.
“We are very fortunate that this leading cancer center has the same focus as TAPUR,” said Dr. Schilsky. “Technological advancements will allow us to pool our information in a seamless fashion and give us the ability to learn from the experience of a larger group of patients.”
Patient Advocates to Play Key Role in TAPUR

Patient advocates will play a central role throughout the study, providing guidance and oversight support. Jane Perlmutter, PhD, a cancer survivor and nationally recognized patient advocate, is lending her expertise in trial development and will help coordinate patient advocate recruitment and training for the study.

“TAPUR has enormous potential to improve our understanding of the effectiveness of currently available therapies in treating cancers with genomic variations and to learn from patients who are treated with off-label drugs,” said Dr. Perlmutter. 

“I applaud ASCO for undertaking this important study and believe its findings will improve cancer care, especially for those with advanced cancer for whom traditional therapies are no longer working.”

For more information about TAPUR, please go to http://www.asco.org/TAPUR.

Monday, June 1, 2015

New Drug Offers New Hope for HER2+ Metastatic Breast Cancer Patients

Promising clinical trial results presented at the American Society for Clinical Oncology (ASCO) Annual Meeting 2015 show activity of the investigational anti-cancer agent ONT-380 against HER2+ breast cancer, in one case specifically against brain metastases and in another case in overall survival of heavily pretreated HER2+ breast cancer patients.

"I am thrilled to have been able to offer this therapy to a patient in her early 40s. She didn't have any other great treatment options that we would have expected to have any meaningful impact, especially on her brain. Now she's been on the study over a year. The mets in her body are gone and the brain lesion has shrunk down to a little nubbin. She's living a normal life, fretting about the family business and how the kids are doing -- normal stuff," says Virginia Borges, MD, MMSc, director of the Breast Cancer Research Program and Young Women's Breast Cancer Translational Program at the University of Colorado Cancer Center and one of the study's authors.

Both sets of results being presented are from ongoing phase 1b clinical trials of ONT-380, one in combination with the drug TDM-1, and the other in combination with capecitabine and/or trastuzumab. Women on these studies include those whose disease had progressed after at least two previous rounds of therapy (sometimes including previous drugs used to target HER2).

In the first study of ONT-380 with TDM-1, all 8 evaluable patients experienced more than 50 percent reduction in primary brain tumor size.


"This drug has the potential to be the long-awaited, needed therapy that targets brain metastases in HER2+ brain cancer, and could even someday be used to prevent brain metastases in the first place," says Borges.

The second study presents overall response rates from a similar, ongoing phase 1b clinical trial of ONT-380 with capecitabine and/or trastuzumab. Of 8 heavily pretreated patients enrolled on the study, 4 showed partial response (reduction in tumor size of more than 30 percent), 2 achieved stable disease, and 2 progressed.

In about 25 percent of the 1-in-8 women who will develop breast cancer during their lifetimes, the HER2 gene creates an abnormal amount of HER2 protein, which acts as a "receptor" for human epidermal growth factor. The presence of more HER2 receptors allows a cell to trap more growth-promoting hormones, which tells the cell to grow in an out-of-control, cancerous way.

ONT-380, invented by Array Biopharma in Boulder, CO and now being developed by Oncothyreon in Seattle, WA, is a small molecule inhibitor of the HER2 growth factor receptor. The drug works by targeting the HER2 "tyrosine kinase" -- a link in the chain of communication that allows HER2 receptors to signal the growth of the cell. The fact that it is a small molecule means the drug is able to pass through the blood-brain barrier to act against brain metastases of the disease. HER2+ breast cancer is more likely to affect younger women and also more likely than other breast cancers to metastasize specifically to the brain.


"Usually we expect the results of a phase 1 clinical trial to give us data that we can use to guide the results of future treatments. This is a great case in which, for many of these patients, the results were immediate. There are women who are alive today because of this drug," Borges says.


University of Colorado Cancer Center. "ONT-380 has stage IV HER2+ breast cancer patient 'worrying about normal stuff again'." ScienceDaily. ScienceDaily, 29 May 2015. .

Wednesday, May 13, 2015

Sandra Lee Smart Self Advocacy

Television chef, Sandra Lee, has discovered she has breast cancer. It is apparently quite aggressive because her doctors have informed her she is a "ticking time bomb" and she will be undergoing a bilateral mastectomy this week. Ms. Lee is in her forties. She insisted on getting screened for breast cancer which is smart. She does not have a family history, but that didn't stop her. Perhaps she knew that eighty percent of breast cancers are found in people without a family history.

By finding her tumor early, she has the best chance of fighting it. She will have the cancerous tissue removed, receive the therapy necessary to eradicate the remaining cells, and if all goes well, she has an over ninety percent chance of beating the disease if it has not spread to her other organs.


This is all common sense. If we can find a disease early and treat it why would we ever take that for granted? It is a question for the United States Task Force, a government sanctioned group that insists that women should not have their first mammogram until after the age of 50. Where would that leave Ms. Lee? If she is a ticking time bomb now, what would become of her in a few years when she is "allowed" to obtain screening?

In today's NY Times, Ms. Lee is said,

“Without early detection on my side, I could be telling a very different story,” she said. “Or not be here to tell it at all.”

The Times went on to report on the task force's two sided view:

Regular mammograms for women in their 40s can be controversial. In April, the United States Preventive Services Task Force, a government panel, suggested that while mammograms are most beneficial for women over 50, mammograms for women in the 40s can “reduce their risk of dying from breast cancer.”

 And yet, they continue the most dangerous message of all:
Still the task force’s draft regulations also stated that women “undergoing regular screening mammography are at risk for the diagnosis and treatment of noninvasive and invasive breast cancer that would otherwise not have become a threat.”

 This is one of the most misinformed statements of the century. There is no such thing as a breast cancer that would "not become a threat." How do they know which cancer cells choose to divide and duplicate and take over a woman's body and kill her? Who are they to make this decision for women?

I was first diagnosed in my thirties. My original tumor was partially DCIS, meaning it was in situ, or "non-invasive" as the Task Force likes to call it. However, the tumor broke through the duct and became invasive, very invasive with a triple negative pathology. Where would I be now if I had waited 12 more years before my first mammogram? I would not have been here. My second breast cancer was in the lobes and rapidly spread to my lymph nodes. This was only five and half years after my first cancer. Two aggressive cancers, both under the age of the Task Force's permitted age for screening.

At the No Surrender Breast Cancer Foundation, we go a step further. We believe in baseline screening before the age of forty. Screening that saved my life in my thirties should be available to everyone. And women in high risk groups, particularly women of African American descent, need to be screened as early as possible because they are at the greatest risk of the finding the most aggressive forms of breast cancer while still in their thirties.

Ms. Lee's long time companion is New York Governor, Andrew Cuomo. In the same NY Times article, he said,

“She had always been diligent about her exams, and thank God she had been diligent about her exams,” the governor said, adding, “If she waited until she was 50, this would be a very different situation.”

Mr. Cuomo, as a fellow Long Islander and breast cancer survivor, after you are done helping the lovely Ms. Lee through her ordeal, please help the women of your state and then, hopefully, the nation. Eliminate the US Task Force's guidelines any way you can. Please, look into our Before Forty Initiative to help us spread the word of the risk young women face for aggressive breast cancers. The No Surrender Breast Cancer Foundation has been fighting hard for a long time. We could use your help.

Ms. Lee, we are here for you. We can help you through each step of your journey. And, personally, as someone who has been there, I am here to tell you that you can get through this and you will get your life back.

For more information about our foundation: No Surrender Breast Cancer Foundation: http://nosurrenderbreastcancerhelp.org/

Breast Cancer 101:
http://nosurrenderbreastcancerhelp.org/breastcancer101/BC101.html

The Before Forty Initiative:
http://nosurrenderbreastcancerhelp.org/About/B440/Before40.html