De-escalating Breast Cancer Treatment—Mission Forward

This month’s newsletter draws attention to a recent JAMA Oncology editorial, De-escalating Breast Cancer Surgery—Where is the Tipping Point (Dec 12, 2019), in which respected surgeons, Monica Morrow and Eric Winer,discussed the pros but mostly the cons of de-escalating breast cancer surgery in reference to effort to eliminate surgery in an effort to reduce the burden of breast cancer care.

As a breast cancer surgeon, I have a keen appreciation of the advantages and disadvantages of surgery. Depending on the patient’s unique circumstances, breast cancer surgery either can greatly enhance or greatly diminish the quality of life of a woman, often without improving overall survival. The art of medicine and surgery is to harmonize the treatment approach with anindividual patient’s goals and tumor characteristics in a way that maintains or improves cancer control while preserving or enhancing quality of life.

At times, this could mean escalating therapy, which means that the extent of treatment is intensified to improve cancer control.  However, increasingly this means de-escalating therapy, which means that the intensity and extent of therapy can be minimized to reduce the burden of therapy without compromising cancer control.      

Common examples of escalating therapy includes:

1. Adding radiation or chemotherapy after surgery based on new pathology detected in the tissue removed at the time of surgery;

2. Converting from mastectomy to lumpectomy when pathology results reviewed more extensive disease; or

3. Removal of all underarm lymph nodes if cancer is found in one or more nodes.

Due to more frequent detection of smaller cancers and more effective drug therapies, de-escalation of therapy is becoming increasingly more common. For example, I commonly use the following descalation therapies to reduce the burden of treatment and expedite recovery:  

1. Lumpectomy combined with breast reduction or breast lift instead of bilateral mastectomy and reconstruction to improve cancer removal, maintain breast symmetry and improve overall breast appearance;

2. Single dose Intraoperative partial breast radiotherapy instead of 16-fraction or 30-fraction postoperative whole breast radiotherapy to target radiation to the tumor site while sparing health tissues the effects of radiation.

3. Preoperative chemotherapy or pre-operative anti-estrogen therapy, as appropriate, to reduce the extent of breast cancer and the extent of required surgery;

4. Cryoablation instead of surgical removal of selected cancers.

One of the greatest concerns raised by Drs. Morrow and Winer was that the effort to minimize the burden of surgery might leave some women with an elevated risk of recurrence and reduced overall survival.  Another common concern is that heightened surveillance (that is, more mammograms and more biopsies) that accompanies non-operative management of breast cancer canproduce such significant patient anxiety that possibly exceeds the physical trauma of surgery.  Though valid, these concerns should not deter our efforts toadjust our treatment approach based on the extent of disease and risk of disease recurrence, which included ongoing scientific efforts to figure out which individual cancers or more likely to grow, spread, and recur.

Another point of significant disagreement is Dr. Morrow’s and Dr. Winer’s view that the voice of the patient has been excluded in the debate about reduce the need for surgery in selected cases.  Here, they really got it wrong or perhaps they haven’t been listening close enough.  

While it might not be the predominant viewpoint of women facing a breast cancer diagnosis, I have heard from maybe women who would option for a non-surgical approach if they could be confident that it could achieve comparable cancer control and survival. Completely missing in the article’s discussion of surgical de-escalation is the option of percutaneous ablation, such as cryoablation, which addresses many of the concerns raised by Drs. Morrow and Winer.

I was recently invited to write a chapter for a surgical textbook on non-surgical management of breast cancer.  Initially, I was quite reluctant to commit the time to research the topic and write a book chapter—after all, who actually reads textbooks? However, having completed the task, I am now convincedthat non-operative management of breast cancer in selected cases is a reasonable option for a subset of women looking to the avoid surgery.  The challenge for us as breast cancer researchers is to identity the most appropriate subset of women and circumstances in which non-operative management can be safely employed without compromising cancer control and patient survival.

As you already know, I am currently leading a multicenter, ongoing trial evaluating cryoablation as an alternative to surgery for stage one invasive breast cancer.  Thus far, preliminary findings are very promising.

As I write this post, I am also in the process of drafting a research protocol to examine the use of cryoablation for the management of stage 0 breast cancer or ductal carcinoma in situ (DCIS).  

The main aim of the DCIS-cryoablation study is to examine the use of cryoablation in the management of DCIS.  Although some patients elect to manage their DCIS with observation alone or observation plus Tamoxifen, one of the greatest ironies is breast cancer therapy is that DCIS (a condition that poses no direct risk to survival) is commonly treated more aggressively than invasive breast cancer, including an unacceptably high rate of mastectomy, a requirement for wider lumpectomy margins, and a high rate of reoperation.

Cryoablation can potentially serves as a compromise solution that balances the desire to disrupt the progression of DCIS toward invasive breast cancer while also minimizing the burden of wide excision, reoperation, and/or mastectomy.

The second aim of the DCIS study is to determine if cryoablation is capable of stimulating a beneficial immune response in women with DCIS.  Although multiple factors may influence if and when are a DCIS lesion might progress to invasive breast cancer, there is strong evidence that the immune microenvironment at the site of DCIS plays an important role in limiting disease progression from DCIS to microinvasive and invasive cancer. Thus, inducing a beneficial immune response with cryoablation might reduce the risk of DCIS progression to invasive breast cancer, the most endpoint of all DCIS therapies. Furthermore, understanding the immune response to cryoablation in DCIS might provide insights into ways to reduce the risk of recurrence of invasive breast cancer.

As a breast cancer surgeon, I earn my living by performing surgery on breast cancer patients, as outlined above. As a breast cancer researcher, I am drawn to the challenge of expanding the options for breast cancer therapy to include cryoablation in appropriate patients.

Understanding and Harnessing the Immune Effects of Cryoablation: A Work in Progress

Apart from the appeal of cryoablation as a minimally invasive alternative to surgery, many women are drawn to cryoablation because of its potential to stimulate an anti-cancer immune response. Their interest is understandable. Afterall, if we can turn the immune system into an effective anti-cancer force, we would have truly found the elusive “magic bullet.” However, before you completely abandon conventional anti-cancer therapy like anti-estrogen medications and/or chemotherapy, it’s important to understand that there is no definitive proof that cryoablation consistently generates an anti-cancer immune response that is strong enough and sustainable enough to be reliably protective against cancer recurrence.

To be sure, the absence of proof of a beneficial response does not mean that a beneficial immune response does not occur. As Aldous Huxley put it, “I’m too much of a skeptic to deny the possibility of anything.” Still, a cancer patient must be wary about placing all of her survival “eggs” in the immunotherapy “basket” without convincing proof that cryoablation can achieve the desired immune benefits.

We in the breast oncology community know that breast cancer cells are crafty and adaptable. By virtue of being living cells, they are capable of evolving in response to new stresses and developing resistance to specific therapies. That’s the main reason why “standard” cancer therapy always combines multiple complimentary treatments to attack cancer cells from different vantage points. Immunotherapy is just another potential tool in the cancer armamentarium that is not expected to eliminate the need for all other therapies.

Although I am among the strongest proponents of cryoablation, I also feel the obligation to caution the public that at the present time, enthusiasm about the immune benefits of cryoablation greatly exceeds the evidence that it happens in a reliable way in human cancers. Indeed, there are multiple examples of cryoablation of human cancers producing improved cancer control. However, for every successful case of beneficial immune response there a greater number of examples where an effective, generalized, protective anti-cancer effect was not achieved. This leaves us wondering which patient or tumor specific factors distinguish responders from non-responders.

The most compelling evidence to support a generalized, systemic anti-cancer response comes for animal studies that demonstrated disappearance of lung metastases in mice after cryoablation of their primary tumors. Unquestionably, these are a really exciting findings, but the reality is that we’ve “cured” cancer in mice many times over without successfully translating these successes into human cures. This speaks to the challenge of reproducing in humans research results obtained in the ideal environment of animal experiments where nearly every factor is controlled, including the animals’ genetic make-up. Still, these animal studies show us what is possible, at least in theory, and inspires us to work harder to achieve the same results in humans.

The medical journal article that I have selected for the January 2020 feature at www.cryoablation.com provides a comprehensive overview of what is currently known about the immune effects of cryoablation in various cancer types. The “take home message” from the journal article is that we have just begun to “scratch the surface” in understanding the immune effects of cancer cryoablation and have much to do to harness and promote its immune benefits. Consequently, there is great need for a broader selection of cryoablation cancer clinical trials and an even greater need for patient participation in cryoablation cancer clinical research. It is also clear from the journal article that a robust, sustained, beneficial immune response to cryoablation will likely require use of pharmacological agents or other therapies that are capable of enhancing specific aspects of the natural immune response. Use of immune system helpers might be particularly important in specific breast cancer or certain types of breast cancer that are not already immunogenic as evidence by the absence of an existing population of immune cells in the vicinity of the cancer.

Based on animal studies that cryoablation may facilitate an anti-cancer immune response, several medical practices around the world are currently offering cryoablation in combination with various forms of immunotherapy consisting of drugs or human cell lines. Unfortunately, nearly all of these practices are administering immunotherapy agents outside of the structure of formal controlled clinical trials and without the ability to objectively assess effectiveness and safety. Thus, these practices may benefit financially by marketing occasional treatment successes without acknowledging or even understanding if treatment successes or failures had anything to do with the agent administered. The lack of well-designed clinical trials is also why so few research studies are listed on www.clinicaltrials.gov on www.cryoablation.com. I challenge the places offering cryoablation combined with immunotherapy to conduct proper prospective clinical trials followed by publication of their outcomes for consideration and critique by their peers. They have a responsibility to science and an even greater obligation to trusting, vulnerable patients to conduct appropriate clinical trials to assess the effectiveness and safety of the remedies they offer. As it relates to medicine, I agree with Carl Sagan’s view that “extraordinary claims require extraordinary proof.” Put differently, we should bring at least the same degree of skepticism to claims of cryoablation and/or immunotherapy “cures” as we bring to anything else that “seems too good to be true.”

In an effort to be part of the solution and not just part the problem, I have initiated a cryoablation research plan that will continue to unfold in the coming years. The first has already been completed—the creation of www.cryoablation.com--which I hope to establish as a central clearinghouse of evidence-based information, clinical trials, and publications about breast cancer cryoablation. It will also provide a forum to facilitate communication between members of the lay public who have either undergone breast cancer cryoablation or are considering undergoing breast cancer cryoablation.

The next step is to introduce new breast cancer cryoablation clinical trials. For example, I have already started developing a clinical trial investigating the use of cryoablation in the management of ductal carcinoma in situ (DCIS) or non-invasive (Stage 0) breast cancer. This will be followed by additional trials examining the immune effects of cryoablation in DCIS and invasive breast cancer.

I also intend to form a U.S.-based cooperative group that will bring together stakeholders to develop and participate in multicenter clinical trials aimed at understanding and harnessing the immune effects of cryoablation. In some ways, this new cryoablation organization will resemble the TARGIT Collaborative Group (TCG), a national organization I established years 4 years ago to develop, advocate for, and conduct collaborative research on targeted intraoperative radiotherapy for breast and other cancers.

For cryoablation, the stakeholders will be clinicians who perform cryoablation or administer immunotherapy, basic scientists capable of conducting immunotherapy studies, patients interested in accessing cryo-immunotherapy clinical trials and funding research, and pharmaceutical companies capable of manufacturing immunotherapy agents as well as sponsoring cryo-immunology research. Each of these stakeholders has a vested interest in seeing cryo-immunology emerge as an effective tool in the cancer armamentarium.

If we can definitively prove that cryoablation has the dual effect of killing breast cancer while also enhancing the anti-cancer immune response (with or without the assistance of drug or other treatments), then cryoablation could one-day achieve each of the following: 

1) Provide an effective alternative to surgery for selected patients with early stage breast cancer;

2) Serve as an initial treatment administered prior to or in conjunction with chemotherapy and/or anti-estrogen therapy for later stage cancers whether or not surgery is planned; or

3) Offer an alternative to surgery for someone with stage IV (distantly metastatic) disease, combined with drug therapy. 

The effort to achieve the first goal is already well underway, but things are just beginning for the second and third goals. To accelerate these broad objectives, I invite you to support cryoablation by participating in, advocate for, and funding cryoablation and cryo-immunology research.

In Defense of A Status Quo Challenger

This letter to the editor was offered in response to a November 2019, Desert Sun article regarding a surgeon who was placed on probation by the California Medical Board related to offering cryoablation or “tumor freezing” to women seeking an alternative to surgery for early stage breast cancer.

As a breast cancer surgeon, researcher and patient advocate, I feel it necessary to challenge the negative impressions that the article creates regarding cryoablation, the surgeon and the growing number of women seeking alternatives to “traditional” surgical treatment.

Although cryoablation is new to most readers, the procedure has served a role in the management of cancer for decades. For example, cryoablation had long been used to treat pre-cancerous growths of the cervix and is now increasingly used for treatment of early stage prostate cancer. I have been performing breast cryoablation since 2003, initially as a treatment of benign breast tumors called fibroadenoma, and later beginning in 2009 for early stage breast cancer as part of a national clinical trial sponsored by the American College of Surgeons.

The American College of Surgeon’s 2009 trial found cryoablation to be 100% effective at killing invasive breast tumors that were 1 cm or smaller and 92% effective for tumors up to 2 cm. As a result of the lessons learned from that trial, two additional national trials were launched evaluating cryoablation as an alternative to surgery for early stage breast cancer. Currently, the early results of both trials are promising and I am honored to serve as lead principal investigator for one of them, the FROST Trial (https://clinicaltrials.gov/ct2/show/NCT01992250).

Internationally, the most promising breast cancer cryoablation experience comes from Japan, where a respected surgeon has treated more than 300 women with estrogen-sensitive breast cancers 1.5 cm or smaller with cryoablation, radiotherapy, and anti-estrogen therapy. This method has achieved a local control rate of 99% at 6 years average follow-up, and rivals what we can achieve with surgery. However, unlike surgery, cryoablation is a relatively pain-free procedure that can be performed through a 3 mm skin nick under local anesthesia as a 1 hour office procedure, with expedited return to normal activity and no long-term changes of breast shape or volume.

Based on growing international experience, I am certain that cryoablation will one-day become a standard option for U.S. women with early stage breast cancer and for some women with more advanced breast cancer. This view is supported by Medicare’s recent decision to establish a CPT (billing) code for breast cancer cryoablation and as well by the recent National Institute of Health suggestion to evaluate cryoablation as a treatment of Stage 0 breast cancer (ductal carcinoma in sit), an effort that I am currently undertaking. The challenge for breast surgeons and breast cancer researchers such as myself is to determine which patients and which breast cancer types are most appropriate for cryoablation.

The primary issue raised by the California Medical Board was “informed consent”. Informed consent is essential for everything we do as cancer specialists, whether it’s lumpectomy, mastectomy, radiation, chemotherapy, or other treatments. Each treatment can reduce cancer recurrence, but none is guaranteed to prevent recurrence. To varying degrees, each is also capable of causing physical or emotional harm that can impair short-term or long-term quality of life. The goal of informed consent is to ensure that patients are aware of these factors and possible alternatives so that they can determine which treatment regimen suits them best. As it turns out, compared to their doctors, patients tend to be more willing to accept risk and explore novel treatment options. However, as surgeon-innovators, we must also temper our enthusiasm to offer patients new treatment advancements by ensuring that they are fully informed about what is known and more importantly, unknown about the innovations we offer.

Criticism of the disciplined surgeon must also be judged in the context of a long history of surgeon-innovators and patient advocates who sought to make breast cancer surgery less disfiguring and less harmful to women. For example, if not for the advocacy and independent research efforts of Umberto Veronesi, an Italian surgeon, and Bernard Fisher, an American surgeon, women across the globe might still be subjected to radical mastectomy with removal of the entire breast, chest muscles and underarm lymph nodes. Radical mastectomy was the standard breast cancer operation for all stages of breast cancer as little as 40 years ago. Though criticized by the medical community-at-large and ostracized by surgical societies, the leadership provided by Drs. Veronesi and Fisher made it possible today for most women to be offered lumpectomy and radiotherapy instead of radical mastectomy. However, ultimate credit goes to the communities of women around the world who demanded different and better options for treating breast cancer. Today’s physicians are facing the same call-to-action. At the end of the day, most major advancements in cancer care are driven by physicians and patients seeking something better than the status quo.

Cryoablation is not the only place where the disciplined surgeon challenged the status quo. Readers might also be surprised to learn that he played a seminal, but similarly controversial role in establishing tamoxifen as a treatment option for breast cancer. His early advocacy for tamoxifen stimulated national research efforts that ultimately established tamoxifen and similar medications as the preferred anti-cancer medication for women with estrogen-sensitive breast cancer. The human impact of this innovation is immeasurable.

My first status quo challenge began in 2005 with my efforts to eliminate the side effects and burden of breast radiotherapy with the use of single-dose intraoperative radiotherapy (IORT), a procedure that reduced the usual 3- to 6-week course of radiation after lumpectomy to a brief 30-minute dose of radiation given during surgery immediately after lumpectomy. After facing years of criticism from the radiation oncology community but tremendous support from patients, the decade-long endeavor of myself, my colleagues and patients to make IORT a standard option for women has been vindicated by long-term data supporting its safety and effectiveness, increasing adoption by radiation oncologists, and coverage by Medicare and most health insurance plans. I now serve as President of the Targeted Intraoperative Radiotherapy Collaborative Group, a national organization of surgeons, radiation oncologists, and physicians committed to expanding access to IORT.

It is safe to say that most physicians are motivated by their sworn professional obligation to “first do no harm” and by the desire to achieve the best possible outcome for their patients. However, it is no longer acceptable for physicians to be the sole judge of what is best for individual patients and to impose their own value-system on their patients. The new standard is “patient-center care.” The Institute of Medicine defines patient-centered care as “providing care that is respectful of, and responsive to, individual patient preferences, needs and values, and ensuring that patient values guide all clinical decisions.” Thus, for patients wishing to avoid traditional surgery, radiotherapy, or chemotherapy, it is therefore the challenge and responsibility of physician-innovators and advocates to develop a range of treatment options that allow patients to select therapies appropriate for their tumor biology, tumor extent, physical anatomy, and willingness to tolerate risks and side effects. It is in this context that I support ongoing efforts to expand access to cryoablation including launching the following informational website: www.cryoablation.com.

In many ways, I feel that the reaction to cryoablation mirrors the early days of lumpectomy and IORT. However, I am confident that the next 10 years will see breast cryoablation emerge as an established option for women with breast cancer. For this to happen, we must continue to monitor the outcome of ongoing trials and develop new trials for early and later stage breast cancer. Patients must understand that breast cryoablation is not intended to be a substitute for all other cancer therapies. Much like lumpectomy and mastectomy, cryoablation works best when supplemented by radiotherapy and/or drug therapy, as appropriate. On the other hand, physicians must not hold cryoablation to a higher standard than we hold other cancer treatments. If a woman undergoes lumpectomy but later declined recommended radiation, we don’t deny all other women access to lumpectomy or insist that she return to the operating room for a mastectomy lest we fire her from our practice—at least most of us don’t. If a woman accepts tamoxifen but refuses chemotherapy despite its promise of additional survival benefit, we physicians still try to help her achieve the best possible outcome that can be achieved with tamoxifen alone. When the roles are reversed and the physician becomes the patient, we also expect our healthcare providers to respect our right of self-determination.

At the end of the day, our highest responsibility as physicians is to equip patients with the knowledge required to make informed decisions about a range of imperfect treatment options. This practice will empower them to make healthcare decisions that best suit their individual physical and emotional needs from both a survival and quality of life perspective.

Dennis R. Holmes, M.D., F.A.C.S.

Breast Cancer Surgeon and Researcher

Los Angeles, CA