Post-BMX - Stage 1a IDC HER2+ - Facing Herceptin/Chemotherapy

I just spoke to my wife by telephone from Beijing.  She has been doing her own information gathering only it is through support groups and with people and not with bulletin boards like me.  She found somebody and spoke to somebody taking Taxotere Cytoxan and Herceptin.  She has 100 percent decided to have the treatments.  She has no doubts that is the right decision and now the objective is to find out as much as possible about side effects management, Cytoxan versus Carboplatin, etc.  My wife is spending time with her friends.  She saw the movie Footloose.  Before I left for China there were two Halloween parties.  And I took my kids trick or treating.  My wife's spirits are high.  So everything will be OK.  I will take it easy in Beijing today because of rain.  Maybe go to a museum that I have not been to before.  My wife also goes to church a lot and spent time with the priest talking about her situation.  More later.

Dear susieq58 - TCH for my wife but it remains to be seen whether the "C" will be Cytoxan or Carboplatin.  I wish I could get a definitive answer on the difference between the two.

Dear dragonfly1 - I cut and paste your post about weekly Herceptin dosing schedule during chemo into an e-mail to my wife and asked her to ask the first and second oncologist about it next week.

Dear TheLadyGrey - I can understand because it is horrible to have something like this.  I intend to pass everything on to my wife - not just by e-mail.  I asked my wife to ask about the Cytoxan and Carboplatin for the second opinion and also the second visit to the first oncologist.  I also asked her to take good notes.  After the two visits are done, we will have a video conference on Skype and discuss the visits.  I wonder how I can convince my wife to consider a port.  I have told her that she must drink a lot of water or else not drinking enough water will be a quick road to a port.  I hope she is drinking more water.  You are write that I should space out my e-mails - that is a very good suggestion.  Mostly I write in detail about how I spent my free time in Beijing and Hong Kong.  Please let us know how your doctor visits go and if you get any additional information on TCH with Cytoxan instead of Carboplatin.

My wife just met with the second oncologist and I just spoke to her on my cellphone.  Phone calls from Hong Kong and China on my cellphone are expensive so we are going to talk via Skype in an hour in more detail.  The second oncologist thinks my wife should hold off on chemotherapy and just do hormone therapy.  Again, my wife had three foci of HER2 positive invasive ductal carcinoma - 3.5 mm, 1.0 mm and less than 1.0 mm.  The second oncologist says anything under 5 mm (0.5 cm) should be monitored and treated with Tamoxifen or Arimidex.  The second oncologist believes that my wife should be "monitored" - how I am not sure until we speak via Skype.  The second oncologist said it is the size of the biggest tumor that counts.  She would treat with Herceptin if over 0.5 cm (5 mm).  The first oncologist added up all three foci to make his recommendation.  The second oncologist was trained at Dana Farber Cancer Institute at Harvard.  The second oncologists thinking does not make me hundred percent comfortable.  HER2 positive and all the articles about how aggressive it is are scary.  However, this still is within NCCN guidelines if the key is to go by the biggest tumor 3.5 mm and not to add all three tumors together.  I would be interested in all of your opinions as quickly as possible.  I think everyone on my thread has a tumor at least 0.5 cm in size or more. 

This article seems to address the situation that my wife finds herself in. 

Uncertainty Rules Adjuvant Chemo for Early HER2 Breast Cancer

Elsevier Global Medical News. 2011 Aug 15, D Mahoney

To treat or not to treat? When it comes to deciding whether adjuvant chemotherapy is the appropriate management choice for patients with HER2 positive, node-negative breast cancer less than 1 cm in size, the only sure thing is that there is no sure thing, and seemingly conflicting research data exacerbates the uncertainty.

A recent study demonstrated that patients who did not receive adjuvant chemotherapy or trastuzumab for node-negative, non-metastasized HER2 positive T1a (less than or equal to 0.1 cm to 0.5 cm) or T1b (greater than 0.5 cm to 1.0 cm) tumors were at greater risk for worse recurrence-free survival and worse distant recurrence-free survival than patients with hormone-receptor-positive disease.

This was especially true for those younger than age 35 years - and also was the case in similarly staged patients with triple-negative breast cancer, according to the report from the University of Texas M.D. Anderson Cancer Center in Houston.

The authors concluded that planning systemic treatment based on disease stage alone "appears to lead to worse outcomes," and that individualized treatment plans may be better informed by taking into account aggressive biological subtypes of small, node-negative breast cancers, as well as age at diagnosis (Clin. Breast Cancer. 2011 July 15 [doi: 10.1016/j.clbc.2011.05.002]).

While the findings of this retrospective, single-institution study validate the large body of evidence suggesting that younger patients with aggressive tumor subtypes have worse outcomes when not treated with adjuvant chemotherapy or trastuzumab (Herceptin), the authors do not recommend universal treatment of this patient population.

Rather, the results provide a strong argument for the inclusion of women with small tumors that have biologically aggressive traits in prospective clinical trials "to evaluate the extent of therapeutic benefits," they wrote. Further, patient age and disease subtype "should be considered when counseling patients about treatment interventions."

No Treatment Not Worse for Some

With the absolute benefits of treatment yet to be determined, investigators also are looking closely at the risks associated with skipping adjuvant treatment.

The findings of an observational cohort study presented at the annual meeting of the American Society of Clinical Oncology (ASCO) suggest that women with early HER2 positive T1aN0M0 breast cancers can safely do so because of the low distant recurrence rate observed in this patient subgroup. A higher rate was observed in those with T1bN0M0, indicating that adjuvant systemic therapy may be more relevant in this patient population.

The study assessed outcomes among 237 women with HER2-positive T1a (116 patients) or T1b (121 patients) tumors diagnosed between 2000 and 2006, all of whom had negative nodes and no metastases. Most did not receive adjuvant chemotherapy or trastuzumab.

With a median duration of follow-up of 5.8 years, the rate of distant recurrence was 0.9% among patients with T1a tumors versus 5.8% among those with T1b, lead investigator Dr. Louis Fehrenbacher, an oncologist with Kaiser Permanente in Vallejo, Calif., reported in a poster presentation, analyzing data from the tumor registry of the Kaiser Permanente Clinical Care Program of Northern California.

The investigators chose distant recurrence-free survival as the main outcome measure, rather than the more commonly used disease-free survival rate, because they "did not want to include non-breast malignancies, contralateral malignancies, or deaths from any other cause," Dr. Fehrenbacher said. "That isn't the real important factor in deciding to give intensive chemotherapy to these patients," he explained.

By tumor size, the rate of distant recurrence ranged from 0% to 5.8% for tumors measuring 0.1 cm to 0.9 cm, but it was 10.7% for the tumors measuring 1.0 cm. In other words, Dr. Fehrenbacher said, "the 1.0-cm tumors carried the burden of the distant recurrence risk."

Results for the actuarial distant recurrence-free interval showed a 5-year rate of 96.5% for the patients as a whole, with 99.1% and 94.0% in the T1a and T1b groups, respectively.

Overall, 25% of the study patients received chemotherapy and 8% received trastuzumab. "Most of these patients had only a smattering of chemotherapy or trastuzumab, and it didn't seem to affect outcome," Dr. Fehrenbacher commented, but he acknowledged that there may have been bias influencing who received chemotherapy. While 59% of the patients had tumors that were positive for estrogen receptors, there was little difference in recurrence rate according to estrogen receptor status, he said.

"The take-home message is, I think, the T1a's have too low of a risk of distant invasive recurrence to justify chemotherapy or trastuzumab," Dr. Fehrenbacher said in an interview. "We need to specifically individualize the risk of the patient based on the size of their primary [tumor], because the T1a's and T1b's are quite different in our findings."

Dr. Lajos Pusztai, a professor in the department of breast medical oncology at M.D. Anderson agrees with Dr. Fehrenbacher's conclusion. "I think the findings are correct, as several other studies have also indicated a very low risk of recurrence for very small HER2-positive cancers," he said in an interview.

"It may also be important to remember that HER2 has not been considered by the ASCO biomarker review panels [to be] an important prognostic marker, but rather a predictive marker for trastuzumab therapy."

Review Warns of Cardiotoxicity

In a recent review article looking into whether the existing data supports a definitive treatment threshold for patients with T1aN0M0 or T1bN0M0 HER2-positive breast cancer, Dr. Pusztai, along with lead author Dr. Catherine M. Kelly of Waterford Regional Hospital in Waterford, Ireland and colleagues, wrote that "a blanket recommendation to treat all small HER2 positive breast cancer with trastuzumab-based therapy will almost certainly lead to clinically significant cardiotoxicity in some without any benefit in breast cancer recurrence."

Similarly, they noted, "withholding this form of adjuvant therapy from all small HER2 positive cancers will result in some otherwise avoidable breast cancer recurrence. Unfortunately, today we do not have accurate tools to identify precisely the subset of patients for whom the risks of trastuzumab outweigh the benefits."

Lacking such tools, shared medical decision making based on estimates achieved using established risk calculators and discussion of the risks with patients should be the order of the day, they said, with the decision depending upon the patients' perspective and risk tolerance level. If trastuzumab-based treatment is an option, the authors stressed that regimens with the lowest risk of cardiotoxicity should be pursued (Ann. Oncol. 2011 Mar. 15 [doi:10.1093/annonc/mdq786]).

In the absence of randomized controlled trials to establish or refute the benefit from adjuvant trastuzumab in this patient subset, the authors called for the development of molecular predictors of prognosis within HER2 positive disease to further optimize risk/benefit estimates. The development of better prediction tools for more precise estimations of the risk of death from comorbid illnesses and the risk of cardiac death, in particular, are important, they said.

Level 1 Evidence Lacking

The lack of level 1 evidence from large, prospective trials contributes to the overall uncertainty surrounding the role of adjuvant chemotherapy in early HER2 breast cancer, according to Dr. Gabriel Hortobágyi, professor and chair of the department of Breast Medical Oncology at M.D. Anderson.

Studies examining the prognostic value of HER2 are limited by their reliance on retrospective database analyses and small cohort sized, Dr. Hortobágyi said in an interview. "I think it is critically important to perform a couple of larger trials with prospective collection of patients, HER2 checked centrally in a high-volume lab, and long enough follow-up to determine the real outcomes of these patients."

In this regard, the Southwest Oncology Group's breast committee, chaired by Dr. Hortobágyi, is trying to activate a clinical trial for HER2 positive T1a and T1b patients comparing trastuzumab alone and in combination with lapatinib "to determine whether treatment with targeted chemotherapy would be effective enough for these patients." Additionally, he said investigators at Dana Farber Cancer Institute are completing recruitment to a single-arm trial for patients with small, HER2 positive breast cancer treated uniformly with paclitaxel and trastuzumab.

"Both trials will give us prospective data and should contribute significantly to our assessment of the real prognosis of this group of patients," he said.

In the meantime, Dr. Hortobágyi said that his group, and many others, "considers that risk of recurrence exceeding about 10% deserves adjuvant chemotherapy, and in the HER2 positive group we believe the risk exceeds, by far, that level. Therefore, we discuss trastuzumab and chemotherapy with all patients without significant comorbid conditions if they have any size-invasive, HER2 positive breast cancer."

The uncertainty regarding the role of adjuvant chemotherapy in early HER2 breast cancer touches on a "fascinating aspect of medicine: how to deal with and communicate uncertainty in diagnosis and treatment benefit," observed Dr. Pusztai.

"Medicine is a very imprecise science and the handling of imprecision is what makes it, as some would call it, an art," he said. "I suspect that what patients perceive as a 'good' vs. 'not so good' doctor often comes down to how efficiently one can make decisions under uncertainty of information and how effectively one communicates this uncertainty and the decision that is based on it."

Dr. Fehrenbacher, Dr. Pusztai, and Dr. Hortobágyi reported no relevant conflicts of interest with respect to the information presented.

Susan London contributed to this report.

Hopeful

I have been corresponding with the second oncologist who is very very helpful.  Her hospital's pathology department has also reviewed the slides from my wife's removed breast.  They refer to the 3.5 mm foci as "isolated nests of cells" as opposed to "a solid sheet of cells".  They are not sure that they agree with the characterization of the 3.5 mm area as "full invasive ductal carcinoma" and I have asked them if since these are isolated nests of cells whether it is better to characterize this as "microinvasion".  If it is microinvasion then that points even more away from Herceptin and chemo.  We are going to get the third opinion doctor's hospital (U. Penn or Sloan Kettering) pathology department to review the slides and give an opinion the pathology as well.