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edge

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TNBC Case  Challenge (from Kathy Miller) and Commentary

 

The great Kathy Miller at Indiana University recently presented a fascinating real-world challenge of a complex case of a triple negative breast cancer patient of hers who after an initial period of disease control and complete remission for 3.5 years, courtesy of  neoadjuvant FEC-T (FEC followed by docetaxel (Taxotere), then developed rapidly progressing visceral metastases (first lung, then lung and liver). 

 

I think the case  is highly instructive - and  hopeful - and teaches a lot about how to make optimal decisions in oncology, so I  will present  an abbreviated essential version of the case, along with my own commentary and semi-Talmudic reflections, and although it is in the triple negative disease settings, it has insights and lessons for any advanced breast cancer disease.

 

Note: Any one who wants to comment can post comments in either the Triple Negative or the Cutting Edge topic.

 


Patient History:

  • 46-year-old, premenopausal, white female
  • Dx at age 42 
  • Initial presentation:
    • node-negative with 7.0 x 8.5 cm right breast mass
    • plus a smaller 1 x 2 cm mass in the right lower outer breast
    • Bloom-Scarf-Richardson (BSR) score = 8 for each mass
    • Tumor biology:  TNBC (ER-/PR-/HER2-),
    • BRCA1/2-negative,
    • bone and chest CT negative for metastatic disease

 

Initial Treatment:

  • Neoadjuvant FECx4
  • Repeat mammogram: primary tumor mass reduced to 3 x 4 cm
  • 1 x 2 cm lesion completely eradicated
  • Underwent mastectomy with axillary node dissection.
  • Clear surgical margins
  • 3/12 axillary lymph nodes positive for micrometastatic disease
  • Four weeks post-surgery: docetaxel (Taxotere) monotherapy for 4 cycles,
  • followed by chest wall radiation
  • At completion of therapy: no evidence of residual disease.

 



Current Presentation
:

  • For the next 3.5 years: no evidence of recurrent disease
  • But a month after last appointment:
    • palpable right supraclavicular mass
    • imaging reveals multiple enlarged mediastinal lymph nodes
    • plus small 1 x 1.5 cm peripheral lung nodule in right upper lobe

 

Treatment Choices Considered

A:  Weekly Paclitaxel

B:  Paclitaxel/Bevacizumab (E2100)

C:  Docetaxel/Capecitabine (TX)

 

Commentary

  1. Based on  the positive findings of the E2100 trial (Kathy Miller investigator), option B would be the optimal choice. 
  2. In addition, since adding BEV is superior to paclitaxel (Taxol) alone, option A is suboptimal, and finally because the patient has already been treated with docetaxel therapy with subsequent (delayed)  disease progression, option C is also  suboptimal. 
  3. I would also agree with Dr. Miller's observation that some currently emerging data suggest that the E2100 T-BEV  regimen may actually provide clinical benefit that is similar to  that observed in endocrine-positive patients.  For me this shows that certain therapies like E2100, and dose-densified chemotherapy, for example, are risk-prognosis levelers and bring TNBC  disease to the response and benefit level of putatively more favorable endocrine disease. 
  4. Undiscussed is  an even more optimal  option, namely  what I call E2100+ which substitutes nab-paclitaxel (Abraxane) for the paclitaxel, with Abraxane known to be superior over both the traditional taxanes (paclitaxel (Taxol) and docetaxel  (Taxotere)), assuming coverage can be  supported.

 



First Progression

  • After 6 cycles E2100, patient develops grade 3 peripheral neuropathy and  consequently elects to halt paclitaxel but continue on bevacizumab (Avastin) for 10 additional months.
  • Patient  then presents with new bilateral supraclavicular adenopathy
  • Repeat chest CT: 2 new peripheral right upper lobe lung nodules.
  • Original 1 x 1.5 cm right upper lobe nodule has more than doubled in growth, to 3 x 3 cm.
  • Increase in the size and number of mediastinal lymph nodes.
  • Patient expresses concerns about (1) another bout of hair loss, (2) not wanting to spend too much time away from job and (3) away from family commitments.

 

Treatment Choices Considered

A:  Capecitabine (Xeloda)

B:  Single-agent gemcitabine (Gemzar) OR vinorelbine (Navelbine)

C:  Retreatment with a taxane

 

Commentary

  1. Weighing both efficacy and patient's concerns, Drf. Miller judged option A (capecitabine (Xeloda)) to be the best choice: capecitabine has a reasonable likelihood of response and less likely to cause alopecia compared to taxanes,  and being oral administration offers added patient convenience work and family.
  2. Option B is deprecated somewhat, largely because, although both agents  are active in MBC setting, there is absence of direct  evidence to suggest that either single-agent gemcitabine (Gemzar) or vinorelbine (Navelbine) is more active or better tolerated than capecitabine.
  3. As to Option C, despite an excellent response to previous taxane therapy, patient developed delayed disease progression on docetaxel (Taxotere) therapy, and her  previous exposure to paclitaxel  (Taxol) caused significant peripheral neuropathy and alopecia.
  4. What I find controversial here is not the choice of capecitabine (Xeloda) per se - capecitabine (Xeloda) is one of  our most consistent  effective agents -  but  of deploying it as monotherapy (single-agent), rather than continuing the bevacizumab (Avastin) with the capecitabine (Xeloda).  And I like the BEV-X  regimen also because (1) the potential to  cross the  blood-brain barrier (BBB) which may  be of  benefit in mitigating risk of metastases to brain and/or spine as sanctuary in TNBC disease, and (2) the potential for bevacizumab (Avastin) to  control or  remit  any micrometastatic disease.
  5. Furthermore, with (1) new bilateral supraclavicular adenopathy, (2) two new peripheral lung nodules, (3) doubling of the size of the original lung  nodule, along with (4) multiple enlarged mediastinal lymph nodes, I would have  considered adding to BEV-X (bevacizumab (Avastin + capecitabine (Xeloda)) another chemotherapy agent, either
    1. cisplatin to yield BEV-CIS-X;
    2. ixabepilone (Ixempra) to yield BEV-IX, which trades on the known benefit of IX as per its FDA approval;
    3. PLD (pegylated liposomal doxorubicin), namely Doxil to yield BEV-DX, noting that she has not received an anthracycline in years  since her FEC regimen to which she was highly responsive, or
    4. gemcitabine (Gemzar) to yield  BEV-GX,  trading on the fact that GX (aka, GEM-CAP) was  found superior  to GV (aka, GEM-VIN using vinorelbine (Navelbine), and superior to GP  (aka, GEM-CIS using cisplatin), as per the findings of the Freier team data presented at ASCO 2008.
  1. All these add-on agents - cisplatin, ixabepilone (Ixempra), Doxil, and gemcitabine (Gemzar) have good reputations of efficacy in visceral metastases (lung and  liver).  Absent other pathological or molecular data, I would lean towards either BEV-GX or BEV-CIS-X for rapid control of visceral disease. 

 



Second Progression

  • Treatment for 9 months with approximately 9 months with oral capecitabine (Xeloda).
  • A which time: disease progression with development of a nonproductive cough and mild dyspnea, and
    • increased supraclavicular adenopathy,
    • new lesions suspicious of liver (with normal liver function tests) and lung metastases
    • Peripheral neuropathy improves to grade 1 on capecitabine (Xeloda).
  • Patient agrees to  enroll in Phase I clinical trial of an oral multikinase inhibitor (MKI), but after 3 weeks develops acute shortness of breath; chest x-ray shows large pericardial effusion, a large left pleural infusion, and physical examination, EKG and CT findings confirm a serious cardiovascular condition called pericardial tamponade
  • Patient undergoes and emergency cardiac procedure (pericardiocentesis) and improves significantly

 

Treatment Choices Considered

A:  Cisplatin/Vinorelbine
B:  Vinorelbine (Navelbine)
C:  Gemcitabine (Gemzar)

 

Commentary

 

  1. Dr. Miller selected option A (CIS-VIN) as  the  optimal choice as it is likely to be aggressive against rapid disease progression and deterioration in health, and the preclinical  data suggests particular sensitivity to platinum therapy in TNBC disease, with CIS-GEM being an equally reasonable choice (even preferable if there is significant neuropathy, but neuropathy had already improved to grade 1).
  2. Dr. Miller viewed option B (vinorelbine (Navelbine) as suboptimal  because of  the fact that as monotherapy it produces few objective responses heavily pretreated MBC patients; ditto for option C (gemcitabine (Gemzar)).

 



Evolution of Case

  • The patient begins CIS-VIN (cisplatin/vinorelbine (Navelbine)) therapy, achieving  an excellent partial response, although increasing peripheral neuropathy requires eventual discontinuation of cisplatin.
  • Where We Are At  Now:
    The patient continues on
    weekly vinorelbine, remaining highly functional and with good QoL.

 



Lessons Learned

Dr. Kathy Miller concludes quite hopefully from the clinical course of this case that even TNBC patients can be treated successfully while achieving outcomes comparable to those observed in patients with more favorable disease characteristics, and that it  is possible to control even rapidly progressing lung and liver metastases in TNBC disease.

 

And although I have some reservations and differences of opinion here and there, and would have exercised a more preemptive and aggressive intervention policy - I would like to think  that my more aggressive interventions after the first  progression may  have forestalled  any further (second) progression altogether - but  nonetheless any one would be highly fortunate to fall under the exceptional care of Dr.  Kathy Miller, one  of our greatest  breast oncologists, and along with Joseph Sparano, the leading expert on bevacizumab (Avastin) and anti-VEGF/antiangiogenic  therapy, and like Lisa Carey, Dr. Kathy Miller herself is an expert in triple negative disease.     

 


Constantine Kaniklidis

Breast Cancer  Watch

edge@evidencewatch.com 

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