Chemo first or Surgery?

J Clin Oncol. 2008 Feb 4;: 18250347 (P,S,G,E,B)

[My paper] Cornelia Liedtke, Chafika Mazouni, Kenneth R Hess, Fabrice André, Attila Tordai, Jaime A Mejia, W Fraser Symmans, Ana M Gonzalez-Angulo, Bryan Hennessy, Marjorie Green, Massimo Cristofanilli, Gabriel N Hortobagyi, Lajos Pusztai

Departments of Breast Medical Oncology, Biostatistics and Applied Mathematics, and Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Gynecology and Obstetrics, University of Münster, Münster, Germany; Department of Obstetrics and Gynecology, Marseille Public Hospital System, Marseille; and Breast Cancer Unit and Translational Research Unit UPRES03535, Institut Gustave Roussy, Villejuif, France.

PURPOSE: Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC. PATIENTS AND METHODS: Analysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pCR), survival measurements, and organ-specific relapse rates were compared between patients with TNBC and non-TNBC. RESULTS: Two hundred fifty-five patients (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates (22% v 11%; P =.034), but decreased 3-year progression-free survival rates (P <.0001) and 3-year overall survival (OS) rates (P <.0001). TNBC was associated with increased risk for visceral metastases (P =.0005), lower risk for bone recurrence (P =.027), and shorter postrecurrence survival (P <.0001). Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, patients with TNBC and non-TNBC had similar survival (P =.24). In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC (P <.0001). CONCLUSION: Patients with TNBC have increased pCR rates compared with non-TNBC, and those with pCR have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC, particularly in the first 3 years.

Chemotherapy

Triple-negative tumors do not respond to endocrine agents or trastuzumab and can only be treated with chemotherapy. Fortunately, increasing evidence suggests that the triple-negative subgroup derives substantial and preferential benefit from chemotherapy. The Cancer and Leukemia Group B (CALGB)^[6] recently reviewed data from 3 randomized trials: 8541, investigating escalating dose intensity; 9344, exploring the addition of paclitaxel to the doxorubicin and cyclophosphamide (AC) backbone; and 9741, studying the impact of dose density. A combined analysis of over 6600 patients treated on these studies, stratified by HR status, demonstrated greater reductions in risk of recurrence for the HR-negative subset, translating into larger absolute benefits in both disease-free and overall survival.

The neoadjuvant setting also provides an opportunity to determine in vivo tumor responses to chemotherapy. The National Breast and Bowel Project (NSABP) B27 trial^[7] of neoadjuvant AC with neoadjuvant vs adjuvant taxane demonstrated a higher rate of pathologic complete response (pCR) in ER-negative rather than ER-positive tumors. Prospective analysis of outcomes after neoadjuvant chemotherapy stratified by molecular subtype has demonstrated that the "basal-like" group has a greater frequency of pCR compared with HR-positive/HER2-negative subgroups.^[8,9]

At the 2007 SABCS, several abstracts supported these findings. Four studies^[10-13] presented in poster format reported outcomes after exposure to neoadjuvant anthracycline ± taxane-containing regimens. In all 4 studies, pCR rates were significantly higher in the triple-negative subgroup compared with the HR-positive subgroups, with similarly high pCR rates in women with HER2-positive tumors.^[10-12] Among women with triple-negative tumors, the pCR rates were 23% to 36%. For trials with longer-term follow-up, inferior outcomes were observed among patients in the triple-negative group, especially in those with residual disease at surgery.^[13] Taken together, these outcomes demonstrate that not only is chemotherapy the primary choice of systemic therapy for triple-negative tumors, but it may also be a more efficacious choice.

With respect to the standard chemotherapy repertoire, some agents may be more effective than others in the treatment of triple-negative tumors. The newest chemotherapeutic agent available for treatment of metastatic breast cancer is ixabepilone, an epothilone analog. Epothilones bind tubulin, leading to stabilization of microtubules, cell cycle arrest, and subsequent apoptotic cell death; preclinical study has suggested activity in both taxane-sensitive and taxane-refractory tumors.^[14] In the primary phase 3 study leading to US Food and Drug Administration (FDA) approval,^[15] ixabepilone 40 mg/m² every 3 weeks plus capecitabine 2000 mg/m² were superior to capecitabine 2500 mg/m² monotherapy in 752 patients with anthracycline- and taxane-pretreated disease. A subgroup analysis was performed in the 25% of patients with triple-negative disease from the phase 3 study. In a group of 187 patients with triple-negative disease,^[16] response rate (RR) increased from 9% to 27% with the addition of ixabepilone to the capecitabine therapy, and progression-free survival (PFS) improved from 2.1 to 4.1 months (hazard ratio 0.68, 95% confidence interval 0.50-0.93). These relative improvements in RR and PFS were comparable to those seen in the study cohort as a whole, although the low RR of 9% with capecitabine monotherapy highlights the difficulty in treating this patient population. In the neoadjuvant setting, monotherapy with ixabepilone in patients with triple-negative tumors led to a pCR rate of 26%, comparable to that seen with other chemotherapeutics.^[17] Overall, ixabepilone appears to have reasonable activity in the triple-negative population.  If you have been offered neoadjuvant chemotherapy - before surgery - please consider this option at least you will know that it worked on your tumor....it is so much more scientific than me keeping my fingers crossed because they would not let me have neoadjuvant!

Love,

Connie

 

When I was diagnosed they originally said to have the surgery first and then chemo, but when all the info came back, TN and a second tumor they didn't give me a choice-started the chemo at 8:30 am THAT day right after my Dr.s appt. in fact!  When my BRCA test came back postive too it reaffirmed that we had done the right thing.  Plus...it was very reassuring to actually feel the lump shrink during the chemo. 

And..I know this may sound a bit strange but I loved having the extra time with my boobs.  Even though I was completely on board with the bilateral it helped me to truly come to terms with losing them.

 

Blessings,

Kara

 

Your numbers sound about right if I understand your sentence correctly.

 

Glad to hear the chemo is working for you.  Why this first before surgery?  I hope you do well and feel you're best these weeks and in between.

 

Did you have your nodes checked prior to chemo?  Is that best?  I hadn't thought about that issue.  I might or may not have positive nodes...they aren't sure. 

 

Again, it was to start treatment asap at this point and chemo was quicker.

Best to you too in the weeks to come.  Thank you very much.

Thanks for all the advice and encouragement. I am receiving neoadjuvant therapy. My oncologist thinks that this will be the best possible outcome for me. I started A/C on 3/20/09. I have chemo every other friday (Doctor wants bi-weekly instead of tri-weekly- says its more aggressive). I finish next friday with my A/C then move to taxotere for another 4 tx's. Hope this shrinks the sucker before I have surgery. I hate having this cancerous mass inside of me, but at the same time I understand why he is doing what he is doing. I feel this is in my best interest.

 

Let me know if any of you ladies out there have any advise for me since I am a newbie. I would love to hear from you.

 

I feel comfort in this website, knowing there are other women out there with this same type of tumor.

 

All the women in the breast cancer support groups all have triple positive and are all doing well with their tamoxifen and herceptin. I feel like a third wheel so to speak because I can't relate to their therapy like I can with you gals.

 

You are all in my thoughts, and prayers

Michelle

Hi! to all,

I am undergoing A/C for four tx's with next friday being my last of the A/C. Then I will be going to taxotere for four tx's.

 

Does anyone know how many tx's of chemo till one starts to feel the tumor shrinking?

 

Like I mentioned above I have already had three tx's of A/C, and I thought that my lymph node was down and I got all excited. Come to find out on my last visit with the oncologist  he said that he could still feel it and it was about 1cm in size. I'm not sure how big it was before I started chemo.

 

My breast tumor was 4.2cm, and I can't tell if there is any shrinking there either. I want to say yes, but I said yes to the lymph node and I was wrong.

 

Are there tests done throughout chemo or at the end of chemo to determine how well the chemo is going? I don't want to continue with chemo if this therapy isn't working. How does the doctor determine what is and isn't working for me?

 

If anyone has any insight into this I would love to hear from you. I am so scared in the fact that I am wondering if this is working at all for me or does my doctor need to take a different route. Maybe I am just being plain paranoid.

 

Thanks for all your help,

Michelle