discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(long
 

term survivors) A single institution (U of Michigan, Ann Arbor)study

Breast Cancer Res Treat. 2016 Feb 13. [Epub ahead of print]
Clinical predictors of long-term survival in HER2-positive metastatic breast cancer.
Murthy P1, Kidwell KM2, Schott AF1, Merajver SD1, Griggs JJ1, Smerage JD1, Van Poznak CH1, Wicha MS1, Hayes DF1, Henry NL3.
Author information
Abstract
Prior to availability of anti-HER2 therapies, HER2-positive metastatic breast cancer (MBC) was associated with a poor prognosis. Prospective randomized trials have demonstrated survival benefit from anti-HER2 treatments. Anecdotal observations have suggested that a small but meaningful fraction of patients with HER2-positive MBC may be "exceptional responders" with long survival. We hypothesized that demographic and/or clinicopathologic characteristics can be identified to distinguish short-term from long-term survivors. A retrospective, single-institution review of 168 patients with HER2-positive MBC who received treatment with anti-HER2 therapy in the metastatic setting was performed. Cox proportional hazards analysis was used to assess factors associated with long-term survival. Median overall survival from the time of breast cancer recurrence was 3.9 years (95 % CI 3.4-5.2). From the time of diagnosis of MBC, 56 (33 %) survived for 5 or more years and 12 (7 %) survived more than 10 years. Of the 66 patients diagnosed with central nervous system metastases, 9 (14 %) survived more than 5 years following that diagnosis. Younger age at diagnosis, lower stage, hormone receptor positive status, and only having one organ involved at diagnosis were associated with longer survival. Four patients discontinued anti-HER2 therapy and are without evidence of progression of disease after a median 7.4 years (0.2-12.0) since stopping therapy. In a cohort of patients with HER2-positive MBC treated primarily with trastuzumab and lapatinib, 7 % of patients were "exceptional responders." Combining these clinical factors with molecular determinants of prolonged survival may provide insights for individualizing treatment selection.
KEYWORDS:
Brain metastasis; HER2 positive; Metastatic breast cancer; Survival
PMID: 26875184 [PubMed - as supplied by publisher]
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Re: discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(
 

This study does not give an answer to the post title, just tells us that a group of long term surviving patients has been narrowed down and identified through a U of Mich study.

Does not tell me where these patients live, if they are all from one treatment center or several, and a lot more unspecified.

I do particularly like this nugget of information:
"Four patients discontinued anti-HER2 therapy and are without evidence of progression of disease after a median 7.4 years (0.2-12.0) since stopping therapy."

My own case falls right into the median span of 7.4 years, at 7 years and 2 months since I had any Herceptin.

Would love to know what the next step is with what the study brought out.

Re: discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(
 

All patients diagnosed with HER2-positive MBC and treated with at least 21 days of trastuzumab or lapatinib in the metastatic setting at the University of Michigan (U-M) Comprehensive Cancer Center between 1991 and 2015 were included. Potentially eligible patients were identified through review of pharmacy records. Patients with distant metastatic disease were included; those with locoregional recurrence (including axillary or supraclavicular nodal disease) or second primary tumors were excluded. Those patients who received only a single 3-week dose or fewer than 4 weekly doses of trastuzumab were excluded (Supplemental Fig. 1). Biopsies of suspected metastatic sites were performed at the discretion of the treating physician. HER2 status was determined clinically at the time of primary or metastatic diagnosis using immunohistochemistry and/or fluorescence in situ hybridization (FISH) according to period-appropriate institutional guidelines. This retrospective, single-institutional study was approved by the Institutional Review Board, which granted a waiver of informed consent.
Clinicopathologic characteristics of eligible patients were abstracted from the electronic medical record by two reviewers (PM, NLH), including demographics; dates of diagnosis of primary breast cancer, MBC and first progression; tumor characteristics at the time of original diagnosis and at the time of disease recurrence; initial sites of metastatic disease; systemic treatments received in the adjuvant and metastatic settings; date of last follow-up at U-M; and date of death, if applicable. Site(s) of metastatic disease at the time of diagnosis of MBC were grouped into four categories based on the findings demonstrated on imaging studies: single organ involvement (bone, viscera, and central nervous system (CNS)) and multi-organ involvement.

Re: discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(
 

Two hundred and forty-eight potentially eligible patients were identified (Supplemental Figure S1). Patients with in-breast recurrence (N = 11), patients with locoregional recurrence only (N = 14), patients who did not receive at least 21 days of trastuzumab or lapatinib therapy after diagnosis of recurrent disease (N = 28), and patients who were subsequently determined to not have HER2-positive recurrent disease (N = 13) were excluded. In addition, patients with only a single clinic visit at the institution (N = 14) were excluded because of lack of data about treatments administered. A total of 168 patients were eligible and included in the analysis.
Demographic factors and primary and metastatic tumor pathological characteristics for all eligible patients are given in Supplemental Table S1. Mean age at initial diagnosis of breast cancer was 47.9 (range 25.3–91.9). At initial diagnosis, 77 (46 %) patients had grade 3 disease, 101 (60 %) had HR-positive disease, and 49 (29 %) had stage 4 disease. Twenty patients (12 %) received adjuvant trastuzumab.
Median time to distant metastatic disease was 2.2 years (range 0–19.2 years). All 168 patients had radiographic evidence of distant metastases. Ninety-six (57 %) underwent biopsy to confirm distant metastasis. Sixty-six (39 %) patients developed CNS metastases during their disease course; it was the initial metastatic site of disease for 7 (4 %) patients.
Timing of initiation of HER2-targeting therapy was influenced by the year of diagnosis and duration of survival. In this cohort, first-line systemic therapy for metastatic disease contained trastuzumab for 71 %, lapatinib for 2 %, and endocrine therapy or chemotherapy without HER2-targeted therapy for 26.2 %. Forty-six patients received treatment with lapatinib (27 %), 18 (11 %) received ado-trastuzumab emtansine, and 15 (9 %) received pertuzumab as part of their second-line or later treatment regimens.

Re: discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(
 

Median follow-up from the time of diagnosis of MBC was 3.2 years (range 0.1–16.3 years). Median OS from the time of MBC diagnosis was 3.9 years (95 % CI 3.4–5.2 years; Fig. 1a). Notably, 56 (33 %) and 12 (7 %) patients were alive ≥5 years and ≥10 or more years, respectively, after diagnosis of MBC. Median PFS from the time of diagnosis of MBC to initiation of second-line therapy was 1.3 years (95 % CI 1.1–1.6; Fig. 1b). Of the 96 patients with biopsy-proven distant metastases, 5 (5 %) were free of detectable active disease by routine imaging at ≥10 years. There was no difference in survival between those with and without biopsy confirmation of metastatic disease (HR 0.88 [95 % CI 0.6–1.3], P = 0.49). For the 39 % of patients who were diagnosed with CNS metastases at any time during their disease course, median survival from the time of diagnosis of CNS metastasis was 1.5 years (95 % CI 1.1–2.6).

Re: discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(
 

. Of those who survived more than 10 years after diagnosis of MBC, 25 % had CNS metastases, compared to 40 % of those who survived less than 10 years.

Re: discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(
 

Thanks Lani! My ambition is to be an exceptional responder.

Re: discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(
 

Hope some day the research community will be able to dig down to the reason some can have lasting complete response and the rest of the patients can't. Oh where, oh where is the KEY???

Re: discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(
 

I think this is a step in that direction.

Re: discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(
 

Pamelamary & StephN, are you both still on Herceptin?

Re: discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(
 

Hi Tracy,
I am still on herceptin, with no immediate plans for stopping _ it's only been 4 years. However, StephN is one of the true "exceptional responders", off herceptin since 2008. I hope you are currently doing OK on the taxol.
Regards.... Pam

Re: discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(
 

Doing much better on Taxol, physically. I'll have scans in March to see if Taxol is doing as well as the Taxotere did in maintaining stability. If it is, we're trying to decide if it's time for a chemo break. I'll stay on H&P q3w and Zometa if I can get my CA, PHOS, MG levels back up. There's talk of putting me on Arimidex for PR+ though there is no hard evidence that it will help. As long as the SEs aren't horrific, I think I will use it, every weapon I can. My goal is to reach your status of exceptional responder. I wonder how long H&P will be necessary, if I can get to NED. I'm informally collecting info about who is still on it long term and who went off and is doing well.

Re: discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(
 

Tracy, I went off herceptin in jan, 2015 after being Ned for 4 years.
I had my scans in nov, still clear, so will be Ned for 5 years feb 23.

Laurie

Re: discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(
 

I've been on Perception for 9 years. I discuss going off with my one. She said she would be comfortable with me going off. The problem is that there is really no data to support staying on or going off at this point. I have minimal side effects so will stay on and keep looking for evidence either way.

Re: discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(
 

StephN - Which vaccine trial did you participate in at UWash??
I am being considered for one at NIH: NCT01730118.

sj

Re: discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(
 

Hello SJ,
Glad you are having good results on your treatment. A vaccine trial could be a good fit for you at this juncture.

Yes, I have been off Herceptin and all other treatment (except twice-yearly Zometa) since Dec. of 2008.

The vaccine trial I was in was a peptide trial with an immune system booster. They have new trials now, but I am not sure what they all are.

Re: discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(
 

Thanks for posting this information. I guess I would be considered to be a long-term survivor since I've been NED since Oct. 2008, after having two lung recurrences and one brain met. I'm still on Herceptin.

I think I'm a long-term responder, but most oncologists probably wouldn't think so, since I reached NED through a combination of systemic treatment (Herceptin) and local interventions--surgery and RFA.

That's the dilemma.

I have oligometastatic breast cancer: see University of Chicago, Ludwig Center for Metastasis Research: Oligometastasis, a curable subset of metastatic disease (can't get link to work here in this post). And several of you who have been on this site for a long time know that I've mentioned this many times before.

Oligometastatic breast cancer is consider to be confined to 1 or 2 organs, with 5 or fewer mets in each organ.

I read about this in 2007 and firmly believed in it--especially in the age of targeted drug therapies (of which we HER2 survivors didn't have much back then). We are now so lucky to have several drugs in our toolbox! And think how many more of us could be long-term survivors if perhaps we used local interventions along with anti-HER2 therapies.

But, no. Most oncologists wouldn't dream of it, unless it's a last ditch effort (we've thrown the book at you and now your down to the end, so we'll ablate some of those liver tumors, because we have no other options).

Think of how frustrated we all get because we're excluded from clinical trials due to having had too many lines of therapy. That's right: the scientists want met survivors who perhaps haven't had any lines of therapy in the metastatic setting. But those same survivors probably have limited disease and would be able to use local interventions.

Then there's the snobby patients: those of us who would never dream of using a local intervention and who are most likely treated at a big fancy institution (that's ok. I fired Sloan-Kettering after a medical oncologist there tried to stop the RFA of my lung in 2008. The RFA has probably contributed to saving my life--at least up to this point, because I never consider myself cured. Sloan-Kettering couldn't care less about local interventions, unless of course you're at the end of your rope).

The best time to do it is from the get-go (like I did) or when you're stable, because eventually, the cancer is going to work it's way around the drugs that you're taking.

So, you can imagine how many more of us could be long-term survivors if you look at the stats in the article that Lani posted.

Clinical trials using radiation for only breast cancer mets. According to the first trial listed below:

"This randomized phase II/III trial studies how well standard of care therapy with stereotactic radiosurgery and/or surgery works and compares it to standard of care therapy alone in treating patients with breast cancer that has spread to one or two locations in the body (limited metastatic) that are previously untreated."

https://clinicaltrials.gov/ct2/show/...2364557&rank=1

https://clinicaltrials.gov/ct2/show/...1706432&rank=1

It seems as if U of Chicago radiation has been able to get through to the breast service there. Otherwise, they wouldn't be able to recruit enrollees.

Joan

Re: discovering why some Stage IVs are exceptional responders to herceptin/lapatinib(
 

I am not sure if I qualify as a long term responder yet, but I sure do plan on getting there. I believe the reason I have been stable/NED since I finished my initial chemo and switched to Herceptin and Tykerb is because we treated my cancer so aggressively from the beginning. The Drs thought I was stage 2 and so they were treating me with curative intent.